This Article Abstract Full Text (PDF) A correction has been published Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints, Permissions and Rights Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mukherjee, A. B. Articles by Chilton, B. S. Search for Related Content PubMed PubMed Citation Articles by Mukherjee, A. B. Articles by Chilton, B. S. Pubmed/NCBI databases Substance via MeSH

Uteroglobin: A Steroid-Inducible Immunomodulatory Protein That Founded the Secretoglobin Superfamily

Section on Developmental Genetics (A.B.M., Z.Z.), Heritable Disorders Branch, The National Institute of Child Health and Human Development, The National Institutes of Health, Bethesda, Maryland 20892-1830; and Department of Cell Biology and Anatomy (B.S.C.), Texas Tech University Health Sciences Center, Lubbock, Texas 79430

Correspondence: Address all correspondence and requests for reprints to: Anil B. Mukherjee, M.D., Ph.D., Head, Section on Developmental Genetics, Endocrinology and Genetics Program, National Institute of Child Health and Human Development, Building 10, Room 9D42, 10 Center Drive, Bethesda, Maryland 20892-1830. E-mail: mukherja{at}exchange.nih.gov

	Abstract

Top Abstract I. Introduction II. Structural Features of... III. Uteroglobin cDNA and... IV. From Uteroglobin to... V. Transcriptional Regulation of... VI. Biological Properties of... VII. Uteroglobin-Derived... VIII. Uteroglobin-Knockout Mice IX. Uteroglobin Gene... X. Potential Therapeutic... XI. Concluding Remarks and... References

 
Blastokinin or uteroglobin (UG) is a steroid-inducible, evolutionarily conserved, secreted protein that has been extensively studied from the standpoint of its structure and molecular biology. However, the physiological function(s) of UG still remains elusive. Isolated from the uterus of rabbits during early pregnancy, UG is the founding member of a growing superfamily of proteins called Secretoglobin (Scgb). Numerous studies demonstrated that UG is a multifunctional protein with antiinflammatory/ immunomodulatory properties. It inhibits soluble phospholipase A₂ activity and binds and perhaps sequesters hydrophobic ligands such as progesterone, retinols, polychlorinated biphenyls, phospholipids, and prostaglandins. In addition to its antiinflammatory activities, UG manifests antichemotactic, antiallergic, antitumorigenic, and embryonic growth-stimulatory activities. The tissue-specific expression of the UG gene is regulated by several steroid hormones, although a nonsteroid hormone, prolactin, further augments its expression in the uterus. The mucosal epithelia of virtually all organs that communicate with the external environment express UG, and it is present in the blood, urine, and other body fluids. Although the physiological functions of this protein are still under investigation, a single nucleotide polymorphism in the UG gene appears to be associated with several inflammatory/autoimmune diseases. Investigations with UG-knockout mice revealed that the absence of this protein leads to phenotypes that suggest its critical homeostatic role(s) against oxidative damage, inflammation, autoimmunity, and cancer. Recent studies on UG-binding proteins (receptors) provide further insight into the multifunctional nature of this protein. Based on its antiinflammatory and antiallergic properties, UG is a potential drug target.

I. Introduction

II. Structural Features of Uteroglobin

III. Uteroglobin cDNA and the Gene

IV. From Uteroglobin to the Secretoglobin Superfamily of Proteins

V. Transcriptional Regulation of the Uteroglobin Gene

VI. Biological Properties of Uteroglobin

A. Interaction with hydrophobic ligands

B. Substrate of transglutaminase

C. Antichemotactic effects

D. Inhibitory effects on platelet aggregation

E. Growth-stimulatory effects on preimplantation embryos

F. Inhibitory effects on migration and invasion of normal and cancer cells

G. Inhibitory effects on tumorigenesis

VII. Uteroglobin-Derived Bioactive Peptides

VIII. Uteroglobin-Knockout Mice

IX. Uteroglobin Gene Polymorphism(s) in Health and Disease

A. UG gene polymorphism in allergic and inflammatory diseases

B. UG gene polymorphism in IgA-nephropathy

X. Potential Therapeutic Applications of Recombinant Human Uteroglobin

XI. Concluding Remarks and Perspectives

	I. Introduction

Top Abstract I. Introduction II. Structural Features of... III. Uteroglobin cDNA and... IV. From Uteroglobin to... V. Transcriptional Regulation of... VI. Biological Properties of... VII. Uteroglobin-Derived... VIII. Uteroglobin-Knockout Mice IX. Uteroglobin Gene... X. Potential Therapeutic... XI. Concluding Remarks and... References

 
FOUR DECADES AGO, Joseph Daniel, Jr., (1) in the United States and Henning Beier (2) in Germany reported the isolation and characterization of a steroid-inducible, low molecular weight, secreted protein from the rabbit uterus during early pregnancy. The former called this protein "blastokinin" because it stimulated the growth of preimplantation embryos (1), and the latter named it "uteroglobin" (UG) (2). The detailed historical background of this discovery has been chronicled in a recent international symposium on this subject (3, 4), and it will not be discussed in this review. After the discovery of UG, several investigators around the world reported the isolation and characterization of soluble proteins from different biological sources and coined various names that reflected either on the organs from which the protein was isolated or on a property (physical or chemical) it manifested. Thus, the name Clara cell 10-kDa protein or CC10 was given because this protein was expressed by the nonciliated Clara cells in the lungs, and its electrophoretic mobility was consistent with that of a protein with an apparent molecular mass of 10 kDa (5). However, the actual calculated molecular mass turned out to be closer to 16 kDa, and hence the name CC16 (6, 7). Similarly, the name urine protein-1 (8) was given because it was isolated from human urine. Although names such as UG (2), CC10 (5), and CC16 (6, 7) are the most frequently used, they represent one and the same protein (9). In the year 2000, an international conference on "Uteroglobin/Clara Cell Protein Family" was held, and a nomenclature committee recognized UG as the founding member of a new and growing superfamily of proteins called Secretoglobin (Scgb) (10). Because in the published literature UG is the name most frequently used for this founding member of the Scgb superfamily, for consistency and simplicity, we will use the name UG throughout this review.

	II. Structural Features of Uteroglobin

Top Abstract I. Introduction II. Structural Features of... III. Uteroglobin cDNA and... IV. From Uteroglobin to... V. Transcriptional Regulation of... VI. Biological Properties of... VII. Uteroglobin-Derived... VIII. Uteroglobin-Knockout Mice IX. Uteroglobin Gene... X. Potential Therapeutic... XI. Concluding Remarks and... References

 
Structural studies on UG were initiated soon after the discovery of this protein in the rabbit uterus. The structure of rabbit UG/CC10 has been resolved by x-ray crystallography (11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23) and by multidimensional nuclear magnetic resonance (24, 25). These studies allowed the determination of the quaternary structure of UG (11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25). The detailed structural features of UG have been extensively reviewed (21, 23), and readers may find these reviews most informative. What emerged from these structural studies is that UG is a homodimeric protein with identical 70-amino acid subunits that are joined in an antiparallel orientation by two disulfide bridges. More specifically, the two disulfide bonds connecting the two subunits are formed between Cys 3 and Cys 69' and between Cys 3' and Cys 69, respectively. Each of the subunits forms three -helices with one β-turn between -helices 2 and 3. In Fig. 1A, the ribbon diagram of the crystal structure of recombinant human UG (rhUG) dimer is shown. In this figure, the two pairs of cysteine residues forming the two disulfide bridges are also shown as Corey-Pauling-Koltun representations in which only the side chain atoms of cysteine residues are visible. It is clear that the disulfide bridges facilitate the stabilization of the UG dimer and the formation of a central hydrophobic cavity, C1 (Fig. 1B). This cavity is formed by the two subunits and is made up mostly of Tyr-21 and Tyr-21'. This cavity provides an adequate volume to accommodate small hydrophobic molecules such as progesterone, polychlorinated biphenyls, or retinol. Each of the UG monomers also forms minor hydrophobic cavities, C2 and C3 (Fig. 1B). Although the exact significance of these cavities is not clearly understood, a combination of molecular modeling and binding studies (26, 27) has shown that hydrophobic ligands such as prostaglandin (PG) D₂ and PGF₂ may be sequestered into these hydrophobic cavities (Fig. 1, C and D). Molecular modeling studies also revealed that UG bears a striking structural similarity with that of the pore-forming domain of colicin A (Fig. 2), and this similarity may suggest a hitherto unexplained function of UG (28). The significance of these results will be discussed in further detail later in this review. It should be noted that interaction of hydrophobic molecules such as progesterone (29), polychlorinated biphenyls (30), and retinoids (31) with UG have been previously reported. Although the physiological functions of hydrophobic ligand binding by UG have not yet been clarified, it is possible that by scavenging these substances UG reduces their toxicity by facilitating elimination from the body.

View larger version (72K): [in this window] [in a new window]   FIG. 1. Structural features of UG and human UG-PG complexes. A, Ribbon diagram of the crystal structure of rhUG dimer. Four cysteine residues forming two disulfide bridges are shown as Corey-Pauling-Koltun representations. Only the side chain atoms are shown for CYS residues. B, Solvent-accessible molecular surface representation of the crystal structure of the rhUG dimer. The outer molecular surface is represented by the pale color, whereas the cavities are represented by teal. The largest cavity, labeled as C1, is formed by the two identical subunits. Two other (symmetric) smaller cavities, C2 and C3, are formed by helix-1, helix-2, and helix-3. For the sake of clarity the front surface of the protein is clipped. C, Molecular modeling of PGD2-UG interaction. Energy-minimized structure of PGD2 docked into the central cavity of the dimer crystal structure of rhUG. In this figure, the structure of the human UG dimer is represented as yellow ribbons and PGD2 as color-coded van der Waals (space-filling) model. In this figure, only the lowest energy structure of the human UG-PGD2 complex is shown. Colored bonds show the two symmetrically related tyrosines (Y21) in the UG dimer. One of the tyrosines forms a hydrogen bond with the carboxyl group of PGD2. D, Molecular modeling. Two molecules of PGF2 docked into the hydrophobic cavity of human UG, which is represented by cyan ribbon. Tyrosine-21 (Y21) and tyrosine 21' (Y21') from the two UG monomers are shown by stick model. The picture was produced using the program CHIMERA (University of California, San Francisco). [A and B, Reprinted with permission from A. B. Mukherjee et al.: Cell Mol Life Sci 55:771–787, 1999 (227 ); copyright, Springer, license no. 170139084490. C, Reprinted from A. K. Mandal et al.: J Exp Med 199:1317–1330, 2004 (26 ); copyright Rockefeller University Press. D, Reprinted from A. K. Mandal et al.: J Biol Chem 280:32897–32904, 2005 (27 ); copyright American Society of Biochemistry and Molecular Biology.)

View larger version (101K): [in this window] [in a new window]   FIG. 2. A, Stereo drawing of the superposition of UG monomer and pore-forming domain of colicin A (COLA). For each protein, only the C connections are shown. All residues are shown for the UG monomer (green), but only a 58-residue fragment is shown for COLA (magenta), which includes the 52 aligned residues. Small spheres indicate the aligned residues. Labeled residues are for the UG monomer. The figure was made using the in-house program GEMM. B, Accessible surface of the aligned motif. Accessible surface of the interior (left) and exterior (right) sides of UG monomer (top) and COLA fragment (bottom) are shown. The hydrophobic atoms (carbon and sulfur) are shown in brown and all others in blue. Different amounts of brown and blue surface patches on the two sides indicate the amphipathic character of the motif. The figure was generated using the program GRASP (see Ref.258 ). [Reprinted with permission from X. de la Cruz and B. Lee: Protein Sci 5:857–861, 1996 (28 ). Copyright Cold Spring Harbor Laboratory Press.]

	III. Uteroglobin cDNA and the Gene

Top Abstract I. Introduction II. Structural Features of... III. Uteroglobin cDNA and... IV. From Uteroglobin to... V. Transcriptional Regulation of... VI. Biological Properties of... VII. Uteroglobin-Derived... VIII. Uteroglobin-Knockout Mice IX. Uteroglobin Gene... X. Potential Therapeutic... XI. Concluding Remarks and... References

View larger version (24K): [in this window] [in a new window]   FIG. 3. Organization of the UG gene. The three exons are black boxes, and the intervening introns are open boxes. PRE designates a cluster of progesterone response elements. The 404-bp BamH1 rabbit promoter (–394/+10) is enlarged to show the locations of an ERE, two Sp1/3 binding sites, a SOX17 site, a RUSH (RUSH/SMARCA3) site, and a YY1 site juxtaposed to the TACA box. The cis-binding sites that are most important in the rabbit promoter are shown in bold relief against less important elements.

	IV. From Uteroglobin to the Secretoglobin Superfamily of Proteins

Top Abstract I. Introduction II. Structural Features of... III. Uteroglobin cDNA and... IV. From Uteroglobin to... V. Transcriptional Regulation of... VI. Biological Properties of... VII. Uteroglobin-Derived... VIII. Uteroglobin-Knockout Mice IX. Uteroglobin Gene... X. Potential Therapeutic... XI. Concluding Remarks and... References

The amino acid sequence similarities among the known members of the SCGB superfamily are shown in Table 1. It should be noted that this list is incomplete because new members are continuously being added. A nomenclature link (http://www.genenames.org/genefamily/scgb.html) has also been established, and readers may obtain updated information by visiting this web site.

View larger version (53K): [in this window] [in a new window]   FIG. 7. Multiple sequence alignment of Secretoglobin family of proteins Multiple sequence alignment of UG family proteins. GenBank accession numbers are given for the cognate cDNA entries. The two known N-glycosylation sites within sequence nos. 13 and 23 are highlighted in underlined bold type. The three amino acids conserved in all 24 sequences are marked by asterisks and gray columns. The third cysteine present in sequence nos. 9–23 is also emphasized in gray. [Sequences 1-23 are reproduced from J. Ni et al.: Ann NY Acad Sci 923:25–42, 2000 (259 ), with permission from the author and Wiley-Blackwell Publishers.] A nomenclature link (http://www.genenames.org/genefamily/scgb.html) for the Secretoglobin superfamily has now been established, and this site will be updated in the near future.

	V. Transcriptional Regulation of the Uteroglobin Gene

Top Abstract I. Introduction II. Structural Features of... III. Uteroglobin cDNA and... IV. From Uteroglobin to... V. Transcriptional Regulation of... VI. Biological Properties of... VII. Uteroglobin-Derived... VIII. Uteroglobin-Knockout Mice IX. Uteroglobin Gene... X. Potential Therapeutic... XI. Concluding Remarks and... References

With advances in cloning technology, UG emerged as the prototypical model for studies on the molecular action of progesterone (88, 89). Studies on the effects of progesterone on UG expression led to the cloning of the rabbit progesterone receptor (90). Rabbit cDNA probes were then used to clone the human progesterone receptor (91). The presence of progesterone receptor in the three different target organs, i.e., uterus, lung, and oviduct, was insufficient to account for the tissue-specific patterns of UG expression. Moreover, "male UG" was identified in the secretions of rabbit seminal vesicle (92). As a result, UG became a model mammalian gene for the study of differential hormone regulation (93).

The progesterone-inducible nature of the rabbit UG gene contributed to the isolation of its message (94) and the demonstration that transcription was mediated by progesterone (82, 86, 95, 96). Cloning of the cDNA (97) and genomic fragments (37, 38, 39) preceded the assembly of the gene (98). A cDNA probe was used to localize message in the ontogenetically unrelated epithelia of rabbit uterus and lung (99). The intensity of specific labeling in the uterus was greatest in the glandular vs. the luminal epithelium. The increase in uterine message during pregnancy as detected by in situ hybridization was comparable to the increase in message and translated protein as measured by in vitro assay (100, 101).

Peri et al. (102) used RT-PCR to show persistent UG expression in uterine epithelium throughout gestation. The precipitous decline in UG expression just before parturition paralleled changes in serum progesterone levels. These findings are more consistent with the progesterone-driven character of the gene, compared with earlier observations with limited technology, which showed a decline in UG after the first week of pregnancy. Advances in technology also allowed Guy et al. (103) to show that alveolar type II cells as well as Clara cells in rabbit lung synthesize and secrete UG. Understanding cell-specific gene expression advanced with transgenic analysis. For example, in the mouse endogenous UG expression is restricted to Clara cells in the conducting airways. Transgenes driven by the rabbit promoter localized to the lung (104), promoting bronchioalveolar neoplasms (105). In contrast, endogenous UG in the rat is expressed in a subset of alveolar type II cells. Transgenes driven by the rat promoter in the mouse were expressed in the conducting airways and in alveolar type II cells (106).

The putative rabbit promoter (Fig. 3), a BamHI fragment from –394/+10, was described as containing two progesterone receptor binding sites (98). Later, Bailly et al. (107) used purified receptor binding to correct this erroneous report and to map a cluster of progesterone response elements to positions –2709/–2620 and –2427/–2376. Cato et al. (108) had previously reported that the –2.6 kb region contained putative binding sites for the glucocorticoid receptor. Progesterone receptor binding at these positions was visualized by electron microscopy (109). Footprinting revealed that the –2.7/–2.6-kb region has three progesterone receptor binding sites about 140 bp upstream of the –2.4-kb region that has two additional sites (110). The cluster of progesterone receptor binding sites is conserved in the rabbit and human (58) but not in rats (111) and mice (41). Companion experiments confirmed that there was no progesterone receptor binding in the promoter.

Menne et al. (39) identified a noncanonical TATA motif (TACA box) in the rabbit promoter. Klug and Beato (112) showed that an authentic binding site for the pleiotropic mammalian transcription factor, Yin Yang-1 (YY1) overlaps the weak TACA box. This YY1 site is not conserved in the human, rat, mouse, or hamster promoters, which have strong TATA boxes. YY1, which is constitutively expressed in rabbit endometrium (113), acts as a weak activator via an unusual substitution (CTT) in the consensus 5'-CCATNTT-3' sequence. YY1 is also capable of directing histone deacetylases and histone acetyltransferases to the promoter via protein-protein interactions, thereby inviting chromatin modifications as a component of its function (112, 114). YY1, a member of the GLI-Kruppel class of zinc finger proteins, with four zinc fingers at its C terminus, is not the only zinc-finger protein known to regulate UG transcription.

Suske et al. (115) analyzed progressive 5'-deletion mutants and randomly generated linker-scanning mutants to identify putative response elements in the rabbit promoter. These studies were based on the demonstration by Misseyanni et al. (116) that all mutations in these regions resulted in a reduction in promoter activity and all DNase I footprinting showed that the mutation-sensitive regions were protected by nuclear proteins. Two sites centered at –65 and –230 were identified as binding sites for Sp1/3 transcription factors (117, 118), which have three Cys2His2 zinc fingers in their C-terminal domains. The integrity of these two sites, plus Sp1 not Sp3 binding, was necessary for wild-type promoter activity in vitro (119). An estrogen response element (ERE) centered at –258 is located immediately upstream of the Sp1 site centered at –232. This estrogen receptor binding site, which differs at one position from the consensus ERE, was authenticated with binding and cell transfection assays (120). Scholz et al. (121) later demonstrated estrogen-induced simultaneous occupancy of the ERE and the adjacent Sp1 site. The in vitro binding was noncooperative, and mutation of the Sp1 site dramatically reduced the estrogen effect on the promoter. The detection of an estrogen-inducible DNase I-hypersensitive site in the active promoter supports the speculation that a change in chromatin structure accommodates Sp1 binding. Both the presence and juxtaposition of the ERE/Sp1 site are unique to the rabbit. They are absent from rat (111), human (58), mouse (57), and hamster (50) UG promoters. In addition to YY1 and Sp1, SOX17 is a factor that regulates UG gene transcription (122). This HMG-box protein from the nuclear extract of progesterone-treated rabbits binds to the sequence CACAATG (–183/–177) in the UG promoter in gel shift/super shift assays. Sox17 overexpression enhanced transcription of the UG promoter (–394/+10) construct 2- to 3-fold in transient transfection assays with uterine HEC-1A cells.

Daniel et al. (123) demonstrated the positive effect of prolactin on UG production by the uterus. Chilton et al. (124) showed that prolactin augmented the progesterone-dependent increase in the steady-state level of UG message. Rider and Bullock (125) identified a novel progesterone-dependent binding activity in the UG promoter. Rider and Peterson (126) then provided indirect evidence that transcriptional activation of the UG promoter by progesterone required protein binding at position –160/–120. Kleis-SanFrancisco et al. (127) showed that the prolactin effect was mediated by protein binding to that same region in the UG promoter. The search for the candidate signal transduction intermediate culminated in the cloning and characterization of RUSH/SMARCA3 (Ring-finger motif UG promoter-binding SWI/SNF-related, Helicase)/(SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin subfamily a, member 3) transcription factors (128). Hewetson et al. (129) identified the RUSH binding site (–126/–121) and authenticated the role of RUSH as a nuclear effector of prolactin signals in a rabbit epithelial cell line (130, 131). SMARCA3 proteins also display strong ATPase activity (132), which means they can affect transcription by remodeling chromatin. The highly permissive RUSH/SMARCA3 binding site is not conserved in the promoter of the human UG gene.

The RUSH/SMARCA3 binding site is a subelement of the more distal member of a pair of functional HNF3/Oct 1 sites centered at –130 and –95 (133). The degenerate octamer motifs are bound by Oct 1 in vitro. Both HNF3 elements contribute to promoter activity in human pulmonary adenocarcinoma H441 cells (133) that display a Clara cell-like phenotype. HNF3 and HNF3β activate the rabbit, rat, and human promoters. In insect SL2 cells, neither HNF3 nor HNF3β is capable of activating transcription alone. However, both factors strongly enhance Sp1-mediated activation in a synergistic manner. Transient transfection assays and a transgenic mouse model (134) in which the mouse UG promoter was fused to the human GH gene showed the response element (–282/–273) for the NKx 2.1 homeobox protein, thyroid transcription factor 1 (TTF1) is a major regulator of pulmonary gene expression (135). TTF1 also enhanced transcription from the rat UG promoter. However, it had no effect on the human and rabbit promoters (133).

Despite the highly conserved structure of the UG gene, the promoter and other regulatory elements are more disparate. For example, the rabbit and human genes, unlike their rodent counterparts, are progesterone targets. The rabbit gene is the prototypical hormone target because transcription is regulated by progesterone, estrogen, and prolactin (Fig. 3). Progesterone induces transcriptional activation of the gene through a cluster of remotely positioned response elements. Prolactin augments progesterone-dependent transcriptional activation via the progesterone-dependent transcription factor, RUSH/SMARCA3, which binds to a permissive site in the proximal promoter. Estrogen effects are mediated in the proximal promoter with the aid of an ERE/Sp1 collaboration. New directions will undoubtedly include kinetic analysis of transcription factor recruitment to the UG promoter. The guiding principle is that the precise timing and sequence of factor recruitment events at the promoter orchestrate the magnitude of response to a transcriptional stimulus. The human gene is a promising target for further studies on transcriptional regulation because of its antiinflammatory effects. Molecular models for chronic inflammatory diseases such as asthma are focused on activation/deactivation of relevant genes through changes in chromatin structure and histone acetylation (136).

	VI. Biological Properties of Uteroglobin

Top Abstract I. Introduction II. Structural Features of... III. Uteroglobin cDNA and... IV. From Uteroglobin to... V. Transcriptional Regulation of... VI. Biological Properties of... VII. Uteroglobin-Derived... VIII. Uteroglobin-Knockout Mice IX. Uteroglobin Gene... X. Potential Therapeutic... XI. Concluding Remarks and... References

 
A. Interaction with hydrophobic ligands
Earlier studies on rabbit UG revealed that this protein interacts with hydrophobic ligands such as progesterone (29), polychlorinated biphenyls (30), and retinoids (31). Although the physiological significance of these observations has not been clearly defined, it is conceivable that by binding and possibly sequestering these compounds, UGs suppress their toxic effects. Recently, it has been reported that rhUG also binds PGs such as PGD₂ (26) and PGF₂ (27), both of which are potent lipid mediators of inflammation. Molecular modeling studies showed that the central hydrophobic cavity in UG dimer is capable of accommodating these PGs. Although it has not been demonstrated that UG binds leukotrienes (LTs), Volovitz et al. (137) and Kikukawa et al. (43) reported an inverse relationship between a UG-like protein and eicosanoids including PGs and LTs in the nasal mucosa of children and in the human uterus, respectively. Now, several years later, it has been shown that UG binds PGs and probably sequesters these eicosanoids in its central hydrophobic cavity. Although the biological importance of sequestering proinflammatory PGs by UG is yet to be clearly delineated, it adds another dimension to its already reported antiinflammatory properties. The binding and sequestering of PGs may have an important role in the maintenance of pregnancy because some PGs, such as PGF₂, are leuteolytic (138) and are known to cause myometrial contractility (139), which leads to abortion (140). The binding of PGs by UG is also significant because one of the reported biological properties of UG was its ability to inhibit the soluble phospholipase A₂ (sPLA₂) activity, first demonstrated by Levin et al. (141). These results were confirmed by Singh et al. (142). PLA₂ are a large group of acylesterases that catalyze the hydrolysis of the ester bond at the Sn-2 position in glycerophospholipids releasing a free fatty acid (143). This free fatty acid is often arachidonic acid (AA), which is further metabolized to generate PGs and LTs by cyclooxygenase and lipoxygenase, respectively. Both PGs and LTs are well-known mediators of inflammation. Thus, by inhibiting PLA₂ activity, UG prevents the generation of the critical substrate, AA, for the production of lipid mediators of inflammation such as PGs and LTs. Taken together, these findings indicate that UG is capable of suppressing the production of the rate-limiting substrate, AA, for the production of PGs and LTs and has the capacity to bind and potentially sequester these inflammatory mediators.

B. Substrate of transglutaminase
During early pregnancy, the rabbit uterine epithelia express high levels of UG, whereas the prostate constitutively expresses high levels of this protein. In addition, the uterus and the prostate also express transglutaminase (TG; coagulation factor XIII), an enzyme that catalyzes the covalent crosslinking of glutamine in one protein with a lysine residue of another by forming an isopeptide bond (reviewed in Refs. 144 and 145). In 1980, a hypothesis was proposed that covalent crosslinking of UG with ₂-microglobulin (component of major histocompatibility 2 antigen) on the surface of mammalian preimplantation embryos was catalyzed by TG to protect these embryos from the immunological assault of the maternal organism because the fetus is an allograft to the mother (146). Later, it was demonstrated by in vitro experiments that cells from preimplantation embryos (147) as well as the epidedymal spermatozoa (148) when mixed with lymphocytes in culture are protected from immunological attack if they are pretreated with pure UG and a catalytic amount of TG. These discoveries were followed by the demonstration that UG is an excellent substrate of TG and that large polymers of UG are produced when UG is incubated with a trace amount of TG (149). Subsequently, Metafora et al. (150) demonstrated that a protein similar to UG in the rat prostate showed immunosuppressive and antiinflammatory activity when used in combination with catalytic amounts of TG. Later, rhUG was also found to be an excellent substrate of TG (9). It has also been reported that UG in combination with TG modulates human sperm function (151). Recently, a guinea pig model of ragweed-induced allergic conjunctivitis was used to prove that UG-derived peptides and TG reversed inflammation (152, 153). Most recent reports indicate that UG-derived peptides also suppress sPLA₂ activation by TG (154). The results of these studies show that UG is an excellent substrate of TG (149) and that a combination of UG and TG may yield immunomodulatory and antiinflammatory effects. However, the mechanism by which these two proteins work cooperatively in vivo and, most importantly, how TG mediated polymerization of UG fails to occur in the blood where both proteins are present, remains unclear. Future studies may shed light on these and other aspects of UG-TG interactions.

C. Antichemotactic effects
The first demonstration that UG manifests antichemotactic properties was reported by Schiffmann et al. (155). Subsequently, using an in vitro assay system, it was demonstrated that UG efficiently inhibits both adherence and migration of neutrophils and monocytes induced by formyl-met-leu-phe, a potent chemotactic peptide (156). These results were confirmed by Camussi et al. (157) using UG-derived synthetic peptides. Lesur et al. (158) then demonstrated that UG inhibits PLA₂-mediated fibroblast migration, and UG was found to be a natural inhibitor of neutrophil function in human acute respiratory distress syndrome (159, 160). Although numerous studies have shown that UG is a potent inhibitor of chemotaxis, the molecular mechanism has until now remained unclear.

As indicated above, UG inhibits chemotaxis of monocytes and neutrophils induced by a potent chemoattractant peptide, formyl-met-leu-phe (fMLP) (156). The chemoattraction by fMLP is mediated via a family of G protein-coupled receptors known as formyl peptide receptors (FPRs) (reviewed in Ref.161). Between the two FPR isoforms, FPR and FPR2, fMLP binds to FPR with high affinity, whereas it manifests low affinity binding to FPR2 (FPRL1R in human) (162). Antigen (allergen) exposure in the respiratory system stimulates the expression of acute phase proteins such as serum amyloid A (SAA) (163). The major antigen-presenting dendritic cells (DCs) express FPR2 (164), which promotes SAA-binding on these cells (165). Thus, interaction of SAA with FPR2 on DCs may stimulate chemotactic migration of these antigen-presenting cells to the antigen site, facilitating the processing and presentation of antigens. Recently, it has been shown that the direction of T-helper-2 (T_H2) cell differentiation, which requires input from the DCs, is determined by the cytokine environment at the site of initial antigenic (allergic) activation (166). To determine the molecular mechanism(s) by which UG suppresses allergen-induced T_H2 cytokine production that causes airway inflammation, Ray et al. (167) used UG-knockout (UG-KO) mice to study the expression of genes that are critically important in the differentiation of T_H2 cell lineage. The authors demonstrated that UG binds to FPR2 and that this binding causes inhibition of chemotaxis. Moreover, UG down-regulates SOCS-3 gene expression and STAT-1 activation, which are critical for the differentiation of T_H2 cells. Interactions of UG-derived peptides with the FPR like-1 have recently been reported (168). Most recently, it has been reported that rhUG inhibits adhesion and migration of human endothelial cells in vitro, although it is not known whether this activity is manifested by UG-derived peptides (169). These and other studies are beginning to uncover the immunomodulatory and antichemotactic properties of UG, raising the possibility that UG and UG-derived bioactive peptides have therapeutic potential.

D. Inhibitory effects on platelet aggregation
It has been reported that UG is an excellent substrate of TG or activated blood coagulation factor XIII (XIIIa) (149). Thrombin is an activator of XIII, and thrombin also causes platelet aggregation. Because UG is present in the circulation, it was of interest to determine the effects of UG on thrombin-induced platelet aggregation. Thus, Manjunath et al. (170) carried out experiments in which platelet aggregation was induced by thrombin in the presence and absence of UG. The results showed that UG is a potent inhibitor of platelet aggregation induced by thrombin but not by ADP. Vostal et al. (171) then investigated the role of UG-derived peptides to determine whether these peptides have any effect on platelet aggregation and found that they inhibit ADP-induced platelet aggregation and serotonin secretion. Most recently, Hayashi (172) reported that, whereas activation of platelets by thrombin results in Ca⁺⁺-mobilization, actin filament concentrations and integrin IIbβ3 function, pretreatment of the platelets with recombinant UG before thrombin activation caused inhibition of all of these parameters. This area of UG research has remained poorly developed, although there are potential discoveries to be made with regard to the inhibition of platelet aggregation from the standpoint of prevention of cardiovascular diseases.

E. Growth-stimulatory effects on preimplantation embryos
During early embryonic development, rapid growth of preimplantation embryos occurs in the uterus. Thus, the uterine environment plays a critical role in the development of the conceptus, and uterine proteins have been implicated as key mediators (173). Early investigations in this area focused on the composition of the uterine washings to determine proteins that are secreted by the endometrium. One of these proteins was named "blastokinin" because it stimulated the growth of preimplantation embryos in vitro (1). It was also found that preimplantation embryos at the blastocyst stage do not synthesize detectable amounts of blastokinin (UG) or other uterus-specific proteins (174). Recently, it has been reported that UG may facilitate maternal-fetal communication (Ref.175 ; also reviewed in Ref.176). Thus, the embryo at this stage of development depends solely on the maternal environment to provide proteins necessary for growth and differentiation. Although there is much work devoted to various properties of UG, the growth-stimulating effect was not thoroughly investigated. However, interest in this subject has been rekindled by a recent report by Riffo et al. (177) who showed that UG stimulates the development and cellular proliferation of mouse preimplantation embryos. It is important to note that Daniel and Krishnan (178) reported in 1969 that diapausing embryos of mammals that manifest delayed implantation show accelerated mitotic activity when they were cultured in medium containing blastokinin. Confirmation of these original observations by Daniel and his associates four decades ago (1) seems to justify the first designation "blastokinin." It is expected that future investigations will focus on determining the molecular mechanism(s) by which UG promotes the growth of preimplantation embryos and delineating whether there is UG-mediated maternal-fetal signaling. Perhaps the UG-receptor(s) play a role in this signaling process. If this hypothesis is correct, recombinant UG may find an application in expediting the development of embryos generated by in vitro fertilization.

F. Inhibitory effects on migration and invasion of normal and cancer cells
Although the antiinflamatory properties of UG, at least in part, stem from its ability to inhibit sPLA₂ activity (141, 142) and to bind and sequester proinflammatory lipid mediators (26, 27), its effects on cellular motility and invasiveness remain poorly understood. In 1989, Robinson et al. (179) reported that in cultured rabbit blastocysts UG is transported from the culture media to the interior and proposed the concept of a cell surface transporter for UG. After this discovery, Diaz Gonzalez and Nieto (180) reported that UG binds to microsomal as well as plasma membrane proteins. Using radioactive rhUG, it was demonstrated for the first time that high-affinity UG-binding proteins are expressed on normal cells as well as on cancer cells and that UG acts via these binding proteins to regulate the motility and invasiveness of several cell types (181, 182, 183). In addition, Zhang et al. (184) showed that UG acts via receptor-mediated, autocrine and paracrine pathways to reverse some of the transformed phenotypes in cancer cells such as motility and invasiveness. After this discovery, Burmeister et al. (185) reported a two-receptor pathway for the catabolism of UG in the renal system, and Yoon et al. (186) reported that transfection of lung cancer cells with an adenovirus-UG-cDNA construct suppressed cyclooxygenase-2 (COX-2) gene expression via inhibition of nuclear factor-B (NF-B) activity. More recently, it was found that UG also interacts with lipocalin-1 receptor (187) as well as with fMLP receptor, FPR2 (188). This area of UG research is expected to grow, and future investigations should elucidate the molecular details of the biological effects of UG.

G. Inhibitory effects on tumorigenesis
Tumors arising from tissues that normally express UG infrequently produce this protein (reviewed in Ref.189). Significantly decreased expression of UG-mRNA in lung tumors has been reported (190). Consistent with these results, decreased levels of UG-mRNA expression in cultured cells from non-small cell lung cancers have been reported, and overexpression of UG in these cells modifies the neoplastic potential of these cells (191). Furthermore, overexpression of UG in endometrial cancer cells reversed the transformed phenotype of these cells (184). Cigarette smoking, a major cause of lung cancer, has been reported to reduce UG production in the lungs (192). UG-KO mice appear to be highly susceptible to developing multiorgan invasive tumors. Indeed, the UG-KO mice are highly prone to developing lung tumors when treated with low-dose 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, a potent carcinogen in cigarette smoke (193). In a transgenic mouse model of lung carcinogenesis, a marked decline in the expression of UG was found, which positively correlates with the development of tumorigenesis in this organ (194). Taken together, these results indicate a protective role of UG against carcinogen-induced tumorigenesis. However, much work needs to be done in this area to establish a cause and effect relationship between diminished/absent UG expression and tumorigenesis. The apparent protective role of UG against cancer may stem from its antiinflammatory effects because recent reports indicate that chronic inflammation is a predisposing factor in certain types of cancers (195).

	VII. Uteroglobin-Derived Bioactive Peptides

Top Abstract I. Introduction II. Structural Features of... III. Uteroglobin cDNA and... IV. From Uteroglobin to... V. Transcriptional Regulation of... VI. Biological Properties of... VII. Uteroglobin-Derived... VIII. Uteroglobin-Knockout Mice IX. Uteroglobin Gene... X. Potential Therapeutic... XI. Concluding Remarks and... References

 
One of the most important biological properties of UG is its antiinflammatory effects, which are in part due to its ability to inhibit sPLA₂ activity, as first reported by Levin et al. (141). The antiinflammatory effects of UG may also be augmented by its ability to bind and sequester proinflammatory lipid mediators such as PGs (26, 27). In this respect, the antitumorigenic effect of UG is akin to that of nonsteroidal antiinflammatory drugs (NSAIDs), which like UG, inhibit PG production by inhibiting COX-2.

Although numerous drugs are continuously being developed to control inflammation, glucocorticoids remain the gold standard of antiinflammatory agents. These steroids induce a family of proteins known as lipocortins (196), some of which manifest inhibitory effects on PLA₂ and suppress inflammation (197). Determination of structure-function relationships often provides insight into the biological activities of proteins. Interestingly, it has been reported that UG expression in the lungs is inducible by glucocorticoids (86). Moreover, like lipocortin I (reviewed in Ref.198), UG manifests potent anti-PLA₂ (141, 142), antiinflammatory, and immunomodulatory properties (147, 148). Thus, Miele et al. (199) compared the amino acid sequence of lipocortin-I (also called annexin I) with that of rabbit UG for possible similarities. The results of this comparison identified a region in the -helix-3 of UG (residues 39–47) like that of lipocortin-1 residues 247–255. Synthetic peptides corresponding to these sequences were tested for their sPLA₂-inhibitory and antiinflammatory activities. The results showed that these peptides are potent inhibitors of sPLA₂ activity that manifested strong antiinflammatory activity when tested in a carrageenan-induced model of inflammation. Because of their antiinflammatory effects, these peptide derivatives of UG and lipocortin-1 were called "antiflammins" (199). The amino acid sequences of the antiflammin peptides are provided in Table 2. Since the original report by Miele et al. (199), several antiflammin peptides and their antiinflammatory properties have been described (reviewed in Ref.200). Numerous studies followed this discovery, and whereas most confirmed the results (154, 158, 201, 202, 203, 204, 205) some contradictory reports have been published (206, 207). Although the exact reasons for the negative results are not clearly understood, some of the reports indicated that oxidative damage of the methionine residues in these peptides may have caused their inactivation (208, 209). In addition to their anti-sPLA₂ and antiinflammatory activities, several biological effects of the antiflammin peptides that have pharmacological importance make them candidate drug targets. These effects include inhibition of platelet aggregation (171), adhesion formation after surgery (210), and regulation of the expression of adhesion molecules (206). Moreover, these peptides effectively suppress extraocular inflammation (reviewed in Ref.211). Whereas antiflammin peptides modulate TG activity and regulate the activation of sPLA₂ (152, 153, 154), they also negatively regulate IL-1 action via inhibition of sPLA₂ in T-helper (Th) cells (212).

	VIII. Uteroglobin-Knockout Mice

Top Abstract I. Introduction II. Structural Features of... III. Uteroglobin cDNA and... IV. From Uteroglobin to... V. Transcriptional Regulation of... VI. Biological Properties of... VII. Uteroglobin-Derived... VIII. Uteroglobin-Knockout Mice IX. Uteroglobin Gene... X. Potential Therapeutic... XI. Concluding Remarks and... References

View larger version (68K): [in this window] [in a new window]   FIG. 4. Phenotype of the UG gene-disrupted mice. Top panel, Comparison between a UG-KO mouse (right) and its normal wild-type (WT) littermate (left). A 7-wk-old homozygous KO (UG–/–) that had early-onset disease is compared with its normal WT littermate (UG+/+). Note that the UG-KO mouse is significantly smaller than the WT littermate. Bottom panels, Severe renal glomerular disease in UG-KO mice. Hematoxylin and eosin staining of kidney sections from a WT mouse (A) and its UG-KO littermate (B). Note the heavy deposit of eosinophilic material in the glomeruli of the UG–/– mouse with severe renal disease. C, Photomicrograph of kidney section of a 10-month-old mouse with severe parenchymal fibrosis. D, Photomicrograph of a region of the same mouse kidney shown in panel C, showing renal tubular hyperplasia. Magnification, approximately x403. E, Transmission electron microscopy of the glomerular deposit of a UG–/– mouse with severe renal disease. Magnification, approximately x6,000. F, At x60,000 magnification, the panel E inset shows the presence of long striated fibrillar structures consistent with the presence of collagen (Col) and short diffuse ones consistent with Fn fibrils. G, Fn-immunofluorescence of a kidney section from a WT mouse using murine Fn-antibody. Note the absence of Fn-specific immunofluorescence in the glomeruli, marked "g" of a WT mouse. H, Fn-immunofluorescence of a kidney section from a UG-KO mouse with severe renal disease. Note the intense Fn immunofluorescence over the glomeruli. Mason’s trichrome staining is shown for the kidney sections from WT (I) and UG-KO (J) mice. Note the presence of bluish staining over the glomeruli of the UG–/– mouse kidney section indicating the presence of collagen (original magnification x215). g, Glomerulus; f, fibroblasts; t, tubule. [Reproduced with permission from Z. Zhang et al.: Science 276:1408–1412, 1997 (214 ). Copyright 1997 American Association for the Advancement of Science.]

View larger version (48K): [in this window] [in a new window]   FIG. 5. Renal pathology in UG-KO mice resembles that of the IgAN. Top six panels, Abnormal deposition of IgA and complement C3. A–C, Abnormal IgA immunocomplex deposition in the renal glomeruli of UG gene-disrupted mice, detected by fluorescence microscopy. There is intense immunofluorescence in the glomeruli of the UG–/– (A) and UG+/– (B) mice, indicating heavy deposition of IgA. Such immunofluorescence is lacking in the glomeruli of the UG+/+ littermate (C). Original magnification, x200. D–F, Abnormal complement C3 deposition, detected by immunofluorescence. Both UG–/– (D) and UG+/– (E) mice have readily detectable complement C immunofluorescence in the glomeruli, whereas such depositions are not detectable in the glomeruli of the UG+/+ mouse (F). Original magnification, x400. Bottom eight panels, Histopathological and immunohistochemical analyses of mouse kidney sections. Left, Wild-type (WT); right, antisense-UG (AS-UG). g, Glomerulus. A and B, Hematoxylin and eosin (H & E) staining shows deposition of eosinophilic material in the AS-UG glomerulus (B). C and D, Immunofluorescence using antibody against mouse Fn. The bright Fn-specific fluorescence located mainly in AS-UG glomeruli (D) is undetectable in wild-type glomeruli (C). E and F, Mason’s trichrome staining for collagen (Col) shows positive blue staining in AS-UG glomeruli (F) that is absent from wild-type glomeruli (E). G and H, Immunofluorescence to detect IgA deposition. Although bright IgA-specific immunofluorescence is readily detectable in the AS-UG glomeruli (H), it is undetectable in wild-type glomeruli (G).

View larger version (42K): [in this window] [in a new window]   FIG. 6. UG inhibits proinflammatory cytokine expression and eosinophil infiltration. A, The expression of IL-4 (i), IL-5 (ii), IL-13 (iii), and eotaxin (iv) mRNA was determined by real-time quantitative RT-PCR using total RNA from the lungs of PBS-treated wild-type (WT) mice (bar 1), OVA-sensitized and -challenged WT mice (bar 2), UG-KO mice (bar 3), OVA-sensitized and -challenged UG-KO mice without rhUG treatment (bar 4), and OVA-sensitized UG-KO mice that were pretreated with rhUG (250 µg of rhUG in 200 µl PBS administered iv) 30 min before OVA challenge (bar 5). Asterisks indicate significance at P < 0.05. B, UG-mRNA expression in the lungs of PBS-challenged WT and OVA-sensitized and -challenged WT mice by semiquantitative RT-PCR. GAPDH, Glyceraldehyde-3-phosphate dehydrogenase. C, Total cell counts and number of individual leukocytes per milliliter of bronchoalveolar lavage fluid from PBS (control) and OVA-sensitized and -challenged WT (left) and UG-KO (right) mice and the results from OVA-sensitized and challenged (middle) and OVA-sensitized UG-KO mice treated with rhUG before OVA challenge (extreme right). Values are expressed as the mean ± SD (n = 5 per treatment group). E, Eosinophil; N, neutrophil; L, lymphocyte; M, monocyte. D, Eosinophil infiltration in nonsensitized and unchallenged WT control (frame 1); nonsensitized and unchallenged UG-KO control (frame 2); WT mouse sensitized and challenged with OVA (frame 3); UG-KO mouse sensitized and challenged with OVA (frame 4); and UG-KO mouse sensitized and treated with rhUG before OVA challenge (frame 5). b, Bronchiole. Magnification, x400. [Reproduced with permission from A. K. Mandal et al.: J Exp Med 199:1317–1330, 2004 (26 ). Copyright 2004 The Rockefeller University Press.]

	IX. Uteroglobin Gene Polymorphism(s) in Health and Disease

Top Abstract I. Introduction II. Structural Features of... III. Uteroglobin cDNA and... IV. From Uteroglobin to... V. Transcriptional Regulation of... VI. Biological Properties of... VII. Uteroglobin-Derived... VIII. Uteroglobin-Knockout Mice IX. Uteroglobin Gene... X. Potential Therapeutic... XI. Concluding Remarks and... References

 
A. UG gene polymorphism in allergic and inflammatory diseases
Although UG was first isolated and characterized from the rabbit uterus, many of the clinically relevant studies were focused on the respiratory system. A tetra nucleotide [(ATTT)n] repeat polymorphism in the 5' flanking region of the UG gene has been reported by Stohr and Weber (229). The clinical significance of this polymorphism remained obscure until Zhang et al. (60) reported that a polymorphism in the human UG gene (G38A) is more prevalent in patients with Best disease and asthma. Several subsequent studies showed that this SNP is associated with asthma (62, 63, 64), although one report contradicted these findings (65). Interestingly, in another gene of the Secretoglobin superfamily, UGRP1, a polymorphism in the promoter region was correlated with the susceptibility to asthma (230). Recently, several studies found an inverse relationship between UG levels in the nasal washings and symptoms of rhinitis in allergen-challenged patients with intermittent allergic rhinitis (65, 231, 232, 233, 234, 235). The G38A polymorphism in the UG gene has also been reported in patients with several inflammatory/autoimmune diseases such as lupus erythematosus (236), sarcoidosis (237, 238), and rheumatoid arthritis (239). Although Mehta and Arnold (240) reported a correlation between the SNP in the UG gene and respiratory distress syndrome, Frerking et al. (241) failed to substantiate this claim. Clearly, whereas the results of these studies are important, they require further investigation using large populations so that the significance and clinical relevance of these results can be established.

B. UG gene polymorphism in IgA-nephropathy
Since the report that UG-KO mice develop a disease reminiscent of IgAN (214, 242), several published reports found a correlation between the SNP (G38A) in the UG gene and the progression of IgAN (243, 244, 245, 246, 247). Szelestei et al. (242) studied 110 patients with IgAN, of which 87 patients were followed for up to 3 yr for the progression of the disease. The results showed that the GG genotype of the G38A SNP in the UG gene was more frequent in IgAN patients with progression (odds ratio, 3.5; P < 0.006) compared with the AG+AA genotypes. Moreover, the G allele was found to be more prevalent (odds ratio, 2.6; P < 0.009) in IgAN patients that did not progress as rapidly. The 1/serum creatinine over time plot (in deciliters per milligram per day) was 7-fold steeper in GG patients than the other two genotypes (P = 0.08). The authors proposed that the UG gene contains one or more variants that influence the progression of the disease in patients with IgAN. These results were confirmed by Kim et al. (243) who reported that the G38A SNP may modulate the expression of the UG gene, which adversely affects the disease progression. This study was followed by another report by the same group (244) demonstrating that whereas UG SNP does not cause IgAN, it does adversely affect the progression of the disease. Matsunaga et al. (245) have proposed that low levels of UG due to the SNP may be a predisposing factor in IgAN. Narita et al. (246) studied the genomic DNA from 595 Japanese subjects including 239 IgAN patients, of which 160 had glomerulonephritis, and 196 healthy controls for the G38A SNP. These investigators suggested that the GG genotype can be a genetic marker for rapid disease progression of IgAN to end-stage renal failure with marked proteinuria or high blood pressure. The low levels of serum UG and IgAN have been reviewed by Shijubo et al. (247). However, two reports found no correlation between UG polymorphism and human IgAN (248, 249). It appears that there is now enough interest in this area of research that the results of future investigations will delineate the significance of this polymorphism in health and disease.

	X. Potential Therapeutic Applications of Recombinant Human Uteroglobin

Top Abstract I. Introduction II. Structural Features of... III. Uteroglobin cDNA and... IV. From Uteroglobin to... V. Transcriptional Regulation of... VI. Biological Properties of... VII. Uteroglobin-Derived... VIII. Uteroglobin-Knockout Mice IX. Uteroglobin Gene... X. Potential Therapeutic... XI. Concluding Remarks and... References

 
UG is a multifunctional protein with PLA₂-inhibitory and antiinflammatory activities (reviewed in Ref.227). Early studies in animals indicated that type II cells in the lungs that synthesize surfactant also express UG (103). Tissue-specific expression studies found that UG-mRNA is detectable in various human organs including the lungs (61). Moreover, it is present in the tracheobronchial washings of human neonates (44), and the levels of UG have an inverse relationship with the levels of proinflammatory lipid mediators such as eicosanoids (102). Furthermore, due to its inhibitory effects on PLA₂, which is expressed in the lungs and has the potential to degrade the surfactant phospholipids, UG is likely to play a surfactant-protective role. Neonatal respiratory distress syndrome (NRDS), caused by the deficiency of surfactant, is frequently found in premature neonates and is associated with high mortality. Current treatment includes surfactant replacement. However, a large percentage of the surviving neonates go on to develop a chronic inflammatory disease called bronchopulmonary dysplasia. One of the first clinical trials of rhUG tested its effectiveness in protecting the lung surfactant, a complex mixture of phospholipids and proteins, from degradation by PLA₂ catalysis. The rationale for the therapeutic use of rhUG has been summarized by Pilon (reviewed in Ref.250). Preclinical phase I animal studies showed that administration of rhUG (9, 251) is safe and efficacious (252, 253, 254, 255). These studies provided the basis for a clinical trial of rhUG in neonatal respiratory distress syndrome, and an investigational new drug status was approved by the Food and Drug Administation to conduct a phase I clinical trial to determine safety. Recently, the results of this trial showed that rhUG is safe when administered endotracheally (256, 257). It is anticipated that a phase II trial will be carried out to determine the efficacy of hUG treatment.

	XI. Concluding Remarks and Perspectives

Top Abstract I. Introduction II. Structural Features of... III. Uteroglobin cDNA and... IV. From Uteroglobin to... V. Transcriptional Regulation of... VI. Biological Properties of... VII. Uteroglobin-Derived... VIII. Uteroglobin-Knockout Mice IX. Uteroglobin Gene... X. Potential Therapeutic... XI. Concluding Remarks and... References

 
We have attempted to summarize the work of numerous investigators for a period of four decades. During this time, a secreted protein from the rabbit uterus gave rise to a superfamily of proteins called Secretoglobin. This family continues to add new members while UG remains the most studied. Other proteins in this family may also have important functions. For example, mammaglobin promises to be a good marker for breast cancer. The study of the UG gene structure and its transcriptional regulation has provided insight into the regulation of this gene by steroid as well as nonsteroid hormones. The structural studies on UG protein, the founding member of the Secretoglobin superfamily, continue to yield valuable results including the identification of UG-derived antiinflammatory peptides, antiflammins. The biochemical and biological properties of UG point to its antiinflammatory, antichemotactic, and antimetastatic properties. One of the most important developments is the confirmation of the original observation by Daniel and his colleagues that this protein has growth stimulatory effects on preimplantation embryos, thus justifying the name "blastokinin." Although it appears that UG may have a role in maintaining homeostasis in organs that communicate with the external environment, the relevance of its presence in the circulation still remains poorly understood. UG-KO mice provide a model to determine the physiological role(s) of this protein, and these studies continue at a rapid pace. It is anticipated that gene-targeting other members of the Secretoglobin superfamily will provide new insights. All in all, this area of research has attracted a critical number of investigators, and it is reasonable to expect major advances in the next decade.

	Acknowledgments

 
In this review we have made every effort to cite a comprehensive selection of relevant studies. However, in a review of this magnitude, inadvertent omissions may have occurred. Such omissions do not reflect our judgment on the quality or importance of the work, and we apologize in advance to those authors.

We thank Drs. J. Y. Chou, I. Owens, S. W. Levin, and Aveline Hewetson for critical review of this manuscript and valuable suggestions. We also thank Dr. J. Klug for kindly permitting the reproduction of amino acid sequences of the Secretoglobin superfamily member proteins (see Table 1). We dedicate this review to Drs. Joseph C. Daniel, Jr., and Henning Beier, whose pioneering discoveries provided the ground work for the numerous investigations that followed on UG and other Secretoglobins.

	Footnotes

 
This work was supported in part by the Intramural Research Program of the National Institutes of Health (National Institute of Child Health and Human Development) and by NIH Grant HD-29457.

Disclosure Summary: The authors have nothing to disclose.

First Published Online October 4, 2007

Abbreviations: AA, Arachidonic acid; CC10, Clara cell 10 kDa protein; CCSP, Clara cell secretory protein; COX-2, cyclooxygenase-2; DC, dendritic cell; DP, PGD₂ receptor; ERE, estrogen response element; fMLP, formyl-met-leu-phe; Fn, fibronectin; FPR, formyl peptide receptor; IgAN, IgA nephropathy; KO, knockout; LT, leukotriene; NF-B, nuclear factor-B; PG, prostaglandin; PLA₂, phospholipase A₂(s); rhUG, recombinant human UG; RUSH, Ring-finger motif UG prompter-binding SWI/SNF-related, Helicase; SAA, serum amyloid A; Scgb, Secretoglobin; SMARCA3, SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin subfamily a, member 3; SNP, single nucleotide polymorphism; sPLA₂, soluble PLA₂; TG, transglutaminase; T_H2, T-helper 2; UG, uteroglobin; YY1, Yin Yang-1.

	References

Top Abstract I. Introduction II. Structural Features of... III. Uteroglobin cDNA and... IV. From Uteroglobin to... V. Transcriptional Regulation of... VI. Biological Properties of... VII. Uteroglobin-Derived... VIII. Uteroglobin-Knockout Mice IX. Uteroglobin Gene... X. Potential Therapeutic... XI. Concluding Remarks and... References

 

1. Krishnan RS, Daniel JC 1967 "Blastokinin": inducer and regulator of blastocyst development in the rabbit uterus. Science 158:490–492[Abstract/Free Full Text]
2. Beier HM 1968 Uteroglobin: a hormone-sensitive endometrial protein involved in blastocyst development. Biochim Biophys Acta 160:289–291[Medline]
3. Daniel JC 2000 Discovery and perspectives from the blastokinin era. Ann NY Acad Sci 923:1–8[CrossRef][Medline]
4. Beier HM 2000 The discovery of uteroglobin and its significance for reproductive biology and endocrinology. Ann NY Acad Sci 923:9–24[Medline]
5. Singh G, Katyal SL 1985 Antigenic, molecular and functional heterogeneity of Clara cell secretory proteins in the rat. Biochim Biophys Acta 829:156–163[CrossRef][Medline]
6. Umland TC, Swaminathan S, Furey W, Singh G, Pletcher J, Sax M 1992 Refined structure of rat Clara cell 17kDa protein at 3.0 A resolution. J Mol Biol 224:441–448[CrossRef][Medline]
7. Bernard A, Dumont X, Roels H 1993 The molecular mass and concentrations of protein 1 or Clara cell protein in biological fluids: a reappraisal. Clin Chim Acta 223:189–191[CrossRef][Medline]
8. Bernard AM, Thielmans NO, Lauwerys RR 1994 Urinary protein 1 or Clara cell protein: a new sensitive marker of proximal tubular dysfunction. Kidney Int Suppl 47:S34–S37
9. Mantile G, Miele L, Cordella-Miele E, Singh G, Katyal SL, Mukherjee AB 1993 Human Clara cell 10-kDa protein is the counterpart of rabbit uteroglobin. J Biol Chem 268:20343–20351[Abstract/Free Full Text]
10. Klug J, Beier HM, Bernard AM, Chilton BS, Fleming TP, Lehrer RI, Miele L, Pattabiraman N, Singh G 2000 The uteroglobin/Clara cell protein family: Nomenclature Committee Report. In: Mukherjee AB, Chilton BS, Singh G, DeMayo F, eds. The Uteroglobin/Clara cell protein family. Ann NY Acad Sci 923:348–354[Medline]
11. Bally R, Delettre J 1989 Structure and refinement of the oxidized P21 form of uteroglobin at 1.64A resolution. J Mol Biol 206:153–170[CrossRef][Medline]
12. Nieto A, Ponstingl H, Beato M 1997 Purification and quaternary structure of the hormonally induced protein uteroglobin. Arch Biochem Biophys 180:82–92[CrossRef]
13. Ponstingl H, Nieto A, Beato M 1978 Amino acid sequence of progesterone-induced rabbit uteroglobin. Biochemistry 17:3908–3912[CrossRef][Medline]
14. Popp RA, Foresman KR, Wise D, Daniel JC 1978 Amino acid sequence of a progesterone-binding protein. Proc Natl Acad Sci USA 75:5516–5519[Abstract/Free Full Text]
15. Atger M, Mercier JC, Haze G, Fridlansky F, Milgrom E 1979 N-Terminal sequences of uteroglobin and its precursor. Biochem J 177:985–988[Medline]
16. Buehner M, Beato M 1978 Crystallization and preliminary crystallographic data of rabbit uteroglobin. J Mol Biol 120:337–341[CrossRef][Medline]
17. Mornon JP, Surcouf E, Bally R, Fridlansky F, Milgrom E 1978 X-ray analysis of a progesterone-binding protein (uteroglobin): preliminary results. J Mol Biol 122:237–239[CrossRef][Medline]
18. Mornon JP, Bally R, Fridlansky F, Milgrom E 1979 Characterization of two new crystal forms of uteroglobin. J Mol Biol 127:237–239[CrossRef][Medline]
19. Buehner M, Lifchitz A, Bally R, Mornon JP 1982 Use of molecular replacement in the structure determination of the P21212 and the P21 (pseudo P21212) crystal forms of oxidized uteroglobin. J Mol Biol 159:353–358[CrossRef][Medline]
20. Morize I, Surcouf E, Vaney MC, Epelboin Y, Buehner M, Fridlansky F, Milgrom E, Mornon JP 1987 Refinement of the C222(1) crystal form of oxidized uteroglobin at 1.34 A resolution. J Mol Biol 194:725–739[CrossRef][Medline]
21. Callebaut I, Poupon A, Bally R, Demaret JP, Housset D, Delettre J, Hossenlopp P, Mornon JP 2000 The uteroglobin fold. Ann NY Acad Sci 923:90–112[Medline]
22. Matthews JH, Pattabiraman N, Ward KB, Mantile G, Miele L, Mukherjee AB 1994 Crystallization and characterization of the recombinant human Clara cell 10-kDa protein. Proteins 20:191–196[CrossRef][Medline]
23. Pattabiraman N, Matthews JH, Ward KB, Mantile-Selvaggi G, Miele L, Mukherjee AB 2000 Crystal structure analysis of recombinant human uteroglobin and molecular modeling of ligand binding. Ann NY Acad Sci 923:113–127[Medline]
24. Carlomagno T, Mantile G, Bazzo R, Miele L, Paolillo L, Mukherjee AB, Barbato G 1997 Resonance assignment and secondary structure determination and stability of the recombinant human uteroglobin with heteronuclear multidimensional NMR. J Biomol NMR 9:35–46[CrossRef][Medline]
25. Winkelmann R, Geschwindner S, Haun M, Ruterjans H 1998 Solution structure of the recombinant oxidized rabbit uteroglobin using homonuclear and heteronuclear multidimensional NMR. Eur J Biochem 258:521–532[Medline]
26. Mandal AK, Zhang Z, Ray R, Choi MS, Chowdhury B, Pattabiraman N, Mukherjee AB 2004 Uteroglobin represses allergen-induced inflammatory response by blocking PGD2 receptor-mediated functions. J Exp Med 199:1317–1330[Abstract/Free Full Text]
27. Mandal AK, Ray R, Zhang Z, Chowdhury B, Pattabiraman N, Mukherjee AB 2005 Uteroglobin inhibits prostaglandin F2a receptor-mediated expression of genes critical for the production of pro-inflammatory lipid mediators. J Biol Chem 280:32897–32904[Abstract/Free Full Text]
28. de la Cruz X, Lee B 1996 The structural homology between uteroglobin and the pore-forming domain of colicin A suggests a possible mechanism of action for uteroglobin. Protein Sci 5:857–861[Medline]
29. Beato M 1976 Binding of steroids to uteroglobin. J Steroid Biochem 7:327–334[CrossRef][Medline]
30. Gillner M, Lund J, Cambillau C, Alexandersson M, Hurtig U, Bergman A 1988 The binding of methylsulfonyl-polychloro-biphenyls to uteroglobin. J Steroid Biochem 31:27–33[CrossRef][Medline]
31. Lopez de Haro MS, Perez Martinez M, Garcia C, Nieto A 1994 Binding of retinoids to uteroglobin. FEBS Lett 349:249–251[CrossRef][Medline]
32. Arnemann J, Heins B, Beato M 1977 Purification and properties of rabbit uterus preuteroglobin mRNA. Nucleic Acids Res 4:4023–4036[Abstract/Free Full Text]
33. Arnemann J, Heins B, Beato M 1979 Synthesis and characterization of a DNA complementary to pre-uteroglobin mRNA. Eur J Biochem 99:361–367[CrossRef][Medline]
34. Chandra T, Bullock DW, Woo SL 1981 Hormonally regulated mammalian gene expression: steady-state level and nucleotide sequence of rabbit uteroglobin mRNA. DNA 1:19–26[Medline]
35. Snead R, Day L, Chandra T, Mace Jr M, Bullock DW, Woo SL 1981 Mosaic structure and mRNA precursors of uteroglobin, a hormone-regulated mammalian gene. J Biol Chem 256:11911–11916[Abstract/Free Full Text]
36. Atgcr M, Perricaudet M, Tiollais P, Milgrom E 1980 Bacterial cloning of the rabbit uteroglobin structural gene. Biochem Biophys Res Commun 93:1082–1088[CrossRef][Medline]
37. Chandra T, Woo SL, Bullock DW 1980 Cloning of thc rabbit uteroglobin structural gene. Biochem Biophys Res Commun 95:197–204[CrossRef][Medline]
38. Atger M, Atger P, Tiollais P, Milgrom E 1981 Cloning of rabbit genomic fragments containing the uteroglobin gene. J Biol Chem 256:5970–5972[Abstract/Free Full Text]
39. Menne C, Suske G, Arnemann J, Wenz M, Cato AC, Beato M 1982 Isolation and structure of thc gene for the progesterone-inducible protein uteroglobin. Proc Natl Acad Sci USA 79:4853–4857[Abstract/Free Full Text]
40. Suske G, Wenz M, Cato AC, Beato M 1983 The uteroglobin gene region: hormonal regulation, repetitive elements and complete nucleotide sequence of the gene. Nucleic Acids Res 11:2257–2271[Abstract/Free Full Text]
41. Ray MK, Wang G, Barnish J, Finegold MJ, DeMayo F 1993 Immuno-histochemical localization of mouse Clara cell 10-KD protein using antibodies raised against the recombinant protein. J Histochem Cytochem 44: 919–927
42. Cowan BD, North DH, Whitworth NS, Fujita R, Shumacher EK, Mukherjee AB 1986 Identification of a uteroglobin-like antigen in human uterine washings. Fertil Steril 45:820–823[Medline]
43. Kikukawa T, Cowan BD, Tejada RI, Mukherjee AB 1988 Partial characterization of a uteroglobin-like protein in the human uterus and its temporal relationship to prostaglandin levels in this organ. J Clin Endocrinol Metab 67:315–321[Abstract/Free Full Text]
44. Dhanireddy R, Kikukawa T, Mukherjee AB 1988 Detection of a rabbit uteroglobin-like protein in human neonatal tracheobronchial washings. Biochem Biophys Res Commun 152:1447–1454[CrossRef][Medline]
45. Manyak MJ, Kikukawa T, Mukherjee AB 1988 Expression of a uteroglobin-like protein in human prostate. J Urol 140:176–182[Medline]
46. Aoki A, Pasolli HA, Raida M, Meyer M, Schulz-Knappe P, Mostafavi H, Schepky AG, Znottka R, Elia J, Hock D, Beier HM, Forssmann WG 1996 Isolation of human uteroglobin from blood filtrate. Mol Hum Reprod 2:489–497[Abstract/Free Full Text]
47. Margraf LR, Finegold MJ, Stanley LA, Major A, Hawkins HK, DeMayo FJ 1993 Cloning and tissue-specific expression of the cDNA for the mouse Clara cell 10 kD protein: comparison of endogenous expression to rabbit uteroglobin promoter-driven transgene expression. Am J Respir Cell Mol Biol 9:231–238[Medline]
48. Ray MK, Magdaleno S, O’Malley BW, DeMayo FJ 1993 Cloning and characterization of the mouse Clara cell specific 10 kDa protein gene: comparison of the 5'-flanking region with the human rat and rabbit gene. Biochem Biophys Res Commun 197:163–171[CrossRef][Medline]
49. Nordlund-Moller L, Andersson O, Ahlgren R, Schilling J, Gillner M, Gustafsson JA, Lund J 1990 Cloning, structure, and expression of a rat binding protein for polychlorinated biphenyls. Homology to the hormonally regulated progesterone-binding protein uteroglobin. J Biol Chem 265:12690–12693[Abstract/Free Full Text]
50. Dominguez P 1995 Cloning of a Syrian hamster cDNA related to sexual dimorphism: establishment of a new family of proteins. FEBS Lett 376:257–261[CrossRef][Medline]
51. Sagal RG, Nieto A 1998 Molecular cloning of the cDNA and the promoter of the hamster uteroglobin/Clara cell 10-kDa gene (ug/cc10): tissue-specific and hormonal regulation. Arch Biochem Biophys 350:214–222[CrossRef][Medline]
52. Lopez de Haro MS, Nieto A 1986 Nucleotide and derived amino acid sequences of a cDNA coding for pre-uteroglobin from the lung of the hare (Lepus capensis). Biochem J 235:895–898[Medline]
53. Gutierrez Sagal R, Nieto A 1998 Cloning and sequencing of the cDNA coding for pig pre-uteroglobin/Clara cell 10 kDa protein. Biochem Mol Biol Int 45:205–213[Medline]
54. von der Decken V, Delbruck H, Herrler A, Beier HM, Fischer R, Hoffmann KM 2005 Recombinant bovine uteroglobin at 1.6 A resolution: a preliminary x-ray crystallographic analysis. Acta Crystallograph Sect F Struct Biol Cryst Commun 61:499–502[CrossRef][Medline]
55. Muller-Schottle F, Bogusz A, Grotzinger J, Herrler A, Krusche CA, Beier-Hellwig K, Beier HM 2002 Full-length complementary DNA and the derived amino acid sequence of horse uteroglobin. Biol Reprod 66:1723–1728[Abstract/Free Full Text]
56. Hashimoto S, Nakagawa K, Sueishi K 1996 Monkey Clara cell 10 kDa protein (CC10): a characterization of the amino acid sequence with an evolutional comparison with humans, rabbits, rats, and mice. Am J Respir Cell Mol Biol 15:361–366[Abstract]
57. Singh G, Katyal SL, Brown WE, Phillips S, Kennedy AL, Anthony J 1988 Amino-acid and cDNA nucleotide sequences of human Clara cell 10 kDa protein. Biochim Biophys Acta [Erratum (1989) 1007:243] 950:329–337
58. Wolf M, Klug J, Hackenberg R, Gessler M, Grzeschik KH, Beato M, Suske G 1992 Human CC10, the homologue of rabbit uteroglobin: genomic cloning, chromosomal localization and expression in endometrial cell lines. Hum Mol Genet 1:371–378[Abstract/Free Full Text]
59. Hay JG, Danel C, Chu CS, Crystal RG 1995 Human CC10 gene expression in airway epithelium and subchromosomal locus suggest linkage to airway disease. Am J Physiol 268:L565–L575
60. Zhang Z, Zimonjic DB, Popescu NC, Wang N, Gerhard DS, Stone EM, Arbour NC, DeVries HG, Scheffer H, Gerritsen J, Colle’e JM, Ten Kate LP, Mukherjee AB 1997 Human uteroglobin gene: structure, subchromosomal localization, and polymorphism. DNA Cell Biol 16:73–83[Medline]
61. Peri A, Cordella-Miele E, Miele L, Mukherjee AB 1993 Tissue-specific expression of the gene coding for human Clara cell 10-kD protein, a phospholipase A2-inhibitory protein. J Clin Invest 92:2099–2109[Medline]
62. Laing IA, Goldblatt J, Eber E, Hayden CM, Rye PJ, Gibson NA, Palmer LJ, Burton PR, Le Souef PN 1998 A polymorphism of the CC16 gene is associated with an increased risk of asthma. J Med Genet 35:463–467[Abstract/Free Full Text]
63. Laing IA, Hermans C, Bernard A, Burton PR, Goldblatt J, Le Souef PN 2000 Association between plasma CC16 levels, the A38G polymorphism, and asthma. Am J Respir Crit Care Med 161:124–127[Abstract/Free Full Text]
64. Choi M, Zhang Z, Ten Kate LP, Colle’e JM, Gerritsen J, Mukherjee AB 2000 Human uteroglobin gene polymorphisms and genetic susceptibility to asthma. Ann NY Acad Sci 923:303–306[Medline]
65. Candelaria PV, Backer V, Laing IA, Porsbjerg C, Nepper-Christensen S, de Klerk N, Goldblatt J, Le Souef PN 2005 Association between asthma-related phenotypes and the CC16 A38G polymorphism in an unselected population of young adult Danes. Immunogenetics 57:25–32[CrossRef][Medline]
66. Sengler C, Heinzmann A, Jerkic SP, Haider A, Sommerfeld C, Niggemann B, Lau S, Forster J, Schuster A, Kamin W, Bauer C, Laing I, LeSouef P, Wahn U, Deichmann K, Nickel R 2003 Clara cell protein 16 (CC16) gene polymorphism influences the degree of airway responsiveness in asthmatic children. J Allergy Clin Immunol 111:515–519[CrossRef][Medline]
67. Mansur AH, Fryer AA, Hepple M, Strange RC, Spiteri MA 2002 An association study between the Clara cell secretory protein CC16 A38G polymorphism and asthma phenotypes. Clin Exp Allergy 32:994–999[CrossRef][Medline]
68. Ni J, Kalf-Suske M, Gentz R, Schageman J, Beato M, Klug J 2000 All human genes of the uteroglobin family are localized on chromosome 11q12.2 and form a dense cluster. Ann NY Acad Sci 293:25–42[CrossRef]
69. Heyns W, De Moor P 1977 Prostatic binding protein: a steroid binding protein secreted by rat prostate. Eur J Biochem 78:221–230[CrossRef][Medline]
70. Lea OA, Petrusz P, French FS 1979 Prostatein: a major secretory protein of the rat ventral prostate. J Biol Chem 254:6196–6202[Free Full Text]
71. Chen C, Schilling K, Hiipakka RA, Huang IY, Liao S 1982 Prostate -protein. Isolation and characterization of the polypeptide components and cholesterol binding. J Biol Clem 257:116–121
72. Parker M, Needham M, White R 1982 Prostatic steroid binding protein: gene duplication and steroid binding. Nature 298:92–94[CrossRef][Medline]
73. Heyns W, Peeters B, Mous J, Rombauts W, De Moor P 1978 Purification and characterisation of prostatic binding protein and its subunits. Eur J Biochem 89:181–186[Medline]
74. Watson MA, Fleming TP 1996 Mammaglobin, a mammary-specific member of the uteroglobin gene family, is overexpressed in human breast cancer. Cancer Res 56:860–865[Abstract/Free Full Text]
75. Fleming TP, Watson MA 2000 Mammaglobin, a breast-specific gene, and its utility as a marker for breast cancer. Ann NY Acad Sci 923:78–89[Medline]
76. Molloy MP, Bolis S, Herbert BR, Ou K, Tyler MI, van Dyk DD, Willcox MD, Gooley AA, Williams KL, Morris CA, Walsh BJ 1997 Establishment of the human reflex tear two-dimensional polyacrylamide gel electrophoresis reference map: new proteins of potential diagnostic value. Electrophoresis 18:2811–2815[CrossRef][Medline]
77. Lehrer RI, Xu G, Abduragimov A, Dinh NN, Qu XD, Martin D, Glasgow BJ 1998 Lipophilin, a novel heterodimeric protein of human tears. FEBS Lett 432:163–167[CrossRef][Medline]
78. Lehrer RI, Nguyen T, Zhao C, Ha CX, Glasgow BJ 2000 Secretory lipophilins: a tale of two species. Ann NY Acad Sci 923:59–67[Medline]
79. Morgenstern JP, Griffith IJ, Brauer AW, Rogers BL, Bond JF, Chapman MD, Kuo MC 1991 Amino acid sequence of Fel dI, the major allergen of the domestic cat: protein sequence analysis and cDNA cloning. Proc Natl Acad Sci USA 88:9690–9694[Abstract/Free Full Text]
80. Mukherjee AB, Chilton BS 2000 The uteroglobin/Clara cell protein family. Vol 923. New York: New York Academy of Sciences; 1–358
81. Peri A, Cowan BD, Bhartiya D, Miele, Nieman LK, Nwaeze IO, Mukherjee AB 1994 Expression of Clara cell 10-kD gene in the human endometrium and its relationship to ovarian menstrual cycle. DNA Cell Biol 13:495–503[Medline]
82. Muller H, Beato M 1980 RNA synthesis in rabbit endometrial nuclei. Hormonal regulation of transcription of the uteroglobin gene. Eur J Biochem 112:235–241[Medline]
83. Shen XZ, Tsai MJ, Bullock DW, Woo SL 1983 Hormonal regulation of rabbit uteroglobin gene transcription. Endocrinology 112:871–876[Abstract/Free Full Text]
84. Kopu HT, Hemminki SM, Torkkeli TK, Jänne OA 1979 Hormonal control of uteroglobin secretion in rabbit uterus: inhibition of uteroglobin synthesis and messenger ribonucleic acid accumulation by oestrogen and anti-oestrogen administration. Biochem J 180:491–500[Medline]
85. Kay E, Feigelson M 1972 An estrogen modulated protein in rabbit oviductal fluid. Biochim Biophys Acta 271:436–441[Medline]
86. Savouret J-F, Loosfelt H, Atger M, Milgrom E 1980 Differential hormonal control of a messenger RNA in two tissues. J Biol Chem 255:4131–4136[Free Full Text]
87. Lopez de Haro MS, Nieto A 1985 Glucocorticoids induce the expression of the uteroglobin gene in rabbit foetal lung explants cultured in vitro. Biochem J 225:255–258[Medline]
88. Savouret JF, Milgrom E 1983 Uteroglobin: a model for the study of progesterone action in mammals. DNA 2:99–104[Medline]
89. Cato AC, Beato M 1985 The hormonal regulation of uteroglobin gene expression. Anticancer Res 5:65–72[Medline]
90. Loosfelt H, Atger M, Misrahi M, Guiochon-Mantel A, Meriel C, Logeat F, Benarous R, Milgrom E 1986 Cloning and sequence analysis of rabbit progesterone-receptor complementary DNA. Proc Natl Acad Sci USA 83:9045–9049[Abstract/Free Full Text]
91. Misrahi M, Atger M, d’Auriol L, Loosfelt H, Meriel C, Fridlansky F, Guiochon-Mantel A, Galibert F, Milgrom E 1987 Complete amino acid sequence of the human progesterone receptor deduced from cloned cDNA. Biochem Biophys Res Commun 143:740–748[CrossRef][Medline]
92. Beier HM, Bohn H, Muller W 1975 Uteroglobin-like antigen in the male genital tract secretions. Cell Tissue Res 165:1–11[Medline]
93. Suske G, Wenz M, Cato ACB, Beato M 1983 The uteroglobin gene region: hormonal regulation, repetitive elements and complete nucleotide sequence of the gene. Nucleic Acids Res 11:2257–2271[Abstract/Free Full Text]
94. Atger M, Milgrom E 1977 Progesterone-induced messenger RNA. Translation, purification, and preliminary characterization of uteroglobin mRNA. J Biol Chem 252:5412–5418[Free Full Text]
95. Loosfelt H, Fridlansky F, Savouret JF, Atger M, Milgrom E 1981 Mechanism of action of progesterone in the rabbit endometrium. Induction of uteroglobin and its messenger RNA. J Biol Chem 256:3465–3470[Free Full Text]
96. Kumar NM, Chandra T, Woo SL, Bullock DW 1982 Transcriptional activity of the uteroglobin gene in rabbit endometrial nuclei during early pregnancy. Endocrinology 111:1115–1120[Abstract/Free Full Text]
97. Atger M, Savouret JF, Milgrom E 1980 Synthesis, purification and characterization of a DNA complementary to uteroglobin messenger RNA. J Steroid Biochem 13: 1157–1162
98. Bailly A, Atger M, Atger P, Cerbon MA, Alizon M, Vu Hai MT, Logeat F, Milgrom E 1983 The rabbit uteroglobin gene. Structure and interaction with the progesterone receptor. J Biol Chem 258:10384–10389[Abstract/Free Full Text]
99. Warembourg M, Tranchant O, Atger M, Milgrom E 1986 Uteroglobin messenger ribonucleic acid: localization in rabbit uterus and lung by in situ hybridization. Endocrinology 119:1632–1640[Abstract/Free Full Text]
100. Levey IL, Daniel Jr JC 1976 Isolation and translation of blastokinin mRNA. Biol Reprod 14:194–201[Abstract]
101. Bullock DW, Woo SLC, O’Malley BW 1976 Uteroglobin messenger RNA: translation in vitro. Biol Reprod 15:435–443[Abstract]
102. Peri A, Dubin NH, Dhanireddy R, Mukherjee AB 1995 Uteroglobin gene expression in the rabbit uterus throughout gestation and in the fetal lung. Relationship between uteroglobin and eicosanoid levels in the developing fetal lung. J Clin Invest 96:343–353[Medline]
103. Guy J, Dhanireddy R, Mukherjee AB 1992 Surfactant-producing rabbit pulmonary alveolar type II cells synthesize and secrete an antiinflammatory protein, uteroglobin. Biochem Biophys Res Commun 189:662–669[CrossRef][Medline]
104. DeMayo FJ, Damak S, Hansen TN, Bullock DW 1991 Expression and regulation of the rabbit uteroglobin gene in transgenic mice. Mol Endocrinol 5:311–318[Abstract/Free Full Text]
105. DeMayo FJ, Finegold MJ, Hansen TN, Stanley LA, Smith B, Bullock DW 1991 Expression of SV40 T antigen under control of rabbit uteroglobin promoter in transgenic mice. Am J Physiol 261:L70–L76
106. Perl A-KT, Wert SE, Loudy DE, Shan Z, Blair PA, Whitsett JA 2005 Conditional recombination reveals distinct subsets of epithelial cells in trachea, bronchi, and alveoli. Am J Respir Cell Mol Biol 33:455–462[Abstract/Free Full Text]
107. Bailly A, Le Page C, Rauch M, Milgrom E 1986 Sequence-specific DNA binding of the progesterone receptor to the uteroglobin gene: effects of hormone, antihormone and receptor phosphorylation. EMBO J 5:3235–3241[Medline]
108. Cato AC, Geisse S, Wenz M, Westphal HM, Beato M 1984 The nucleotide sequences recognized by the glucocorticoid receptor in the rabbit uteroglobin gene region are located far upstream from the initiation of transcription. EMBO J 3:2771–2778[Medline]
109. Theveny B, Bailly A, Rauch C, Rauch M, Delain E, Milgrom E 1987 Association of DNA-bound progesterone receptors. Nature 329:79–81[CrossRef][Medline]
110. Jantzen K, Fritton HP, Igo-Kemenes T, Espel E, Janich S, Cato AC, Mugele K, Beato M 1987 Partial overlapping of binding sequences for steroid hormone receptors and DNaseI hypersensitive sites in the rabbit uteroglobin gene region. Nucleic Acids Res 15:4535–4552[Abstract/Free Full Text]
111. Hagen G, Wolf M, Katyal SL, Singh G, Beato M, Suske G 1990 Tissue- specific expression, hormonal regulation and 5'-flanking gene region of the rat Clara cell 10 kDa protein: comparison to rabbit uteroglobin. Nucleic Acids Res 18:2939–2946[Abstract/Free Full Text]
112. Klug J, Beato M 1996 Binding of YY1 to a site overlapping a weak TATA box is essential for transcription from the uteroglobin promoter in endometrial cells. Mol Cell Biol 16:6398–6407[Abstract/Free Full Text]
113. Arias J, Hernandez A, Barron A, Castro I 2001 Expression of TCF, TPF/YY1, and the Sp family transcription factors in rabbit endometrium throughout pregnancy. Arch Med Res 32:263–267[CrossRef][Medline]
114. Gordon S, Akopyan G, Garban H, Bonavida B 2006 Transcription factor YY1: structure, function and therapeutic implications in cancer biology. Oncogene 25:1125–1142[CrossRef][Medline]
115. Suske G, Lorenz W, Klug J, Gazdar AF, Beato M 1992 Elements of the rabbit uteroglobin promoter mediating its transcription in epithelial cells from the endometrium and lung. Gene Expr 2:339–352[Medline]
116. Misseyanni A, Klug J, Suske G, Beato M 1991 Novel upstream elements and the TATA-box region mediate preferential transcription from the uteroglobin promoter in endometrial cells. Nucleic Acids Res 19:2849–2859[Abstract/Free Full Text]
117. Hagen G, Muller S, Beato M, Suske G 1992 Cloning by recognition site screening of two novel GT box binding proteins: a family of Sp1 related genes. Nucleic Acids Res. 20:5519–5525
118. Dennig J, Hagen G, Beato M, Suske G 1995 Members of the Sp transcription factor family control transcription from the uteroglobin promoter. J Biol Chem 270:12737–12744[Abstract/Free Full Text]
119. Hagen G, Muller S, Beato M, Suske G 1994 Sp1-mediated transcriptional activation is repressed by Sp3. EMBO J 13:3843–3851[Medline]
120. Slater EP, Redeuihl G, Theis K, Suske G, Beato M 1990 The uteroglobin promoter contains a noncanonical estrogen responsive element. Mol Endo 4:604–610[Abstract/Free Full Text]
121. Scholz A, Truss M, Beato M 1998 Hormone-induced recruitment of Sp1 mediates estrogen activation of the rabbit uteroglobin gene in endometrial epithelium. J Biol Chem 273:4360–4366[Abstract/Free Full Text]
122. Garcia C, Calvo E, Nieto A 2007 The transcription factor SOX17 is involved in the transcriptional control of the uteroglobin gene in rabbit endometrium. J Cell Biochem 102:665–679[CrossRef][Medline]
123. Daniel JC, Jetton AE, Chilton BS 1984 Prolactin as a factor in the uterine response to progesterone in rabbits. J Reprod Fert 72:443–452[Abstract/Free Full Text]
124. Chilton BS, Mani SK, Bullock DW 1988 Servomechanism of prolactin and progesterone in regulating uterine gene expression. Mol Endocrinol 2:1169–1175[Abstract/Free Full Text]
125. Rider V, Bullock DW 1988 Progesterone-dependent binding of a trans-acting factor to the uteroglobin promoter. Biochem Biophys Res Commun 156:1368–1375[CrossRef][Medline]
126. Rider V, Peterson CJ 1991 Activtion of uteroglobin gene expression by progesterone is modulated by uterine-specific promoter-binding proteins. Mol Endocrinol 5:911–920[Abstract/Free Full Text]
127. Kleis-SanFrancisco S, Hewetson A, Chilton BS 1993 Prolactin augments progesterone-dependent uteroglobin gene expression by modulating promoter-binding proteins. Mol Endocrinol 7:214–223[Abstract/Free Full Text]
128. Hayward-Lester A, Hewetson A, Beale EG, Oefner PJ, Doris PA, Chilton BS 1996 Cloning, characterization and steroid-dependent posttranscriptional processing of RUSH-1 and β, two uteroglobin promoter-binding proteins. Mol Endocrinol 10:1335–1349[Abstract/Free Full Text]
129. Hewetson A, Hendrix EC, Mansharamani M, Lee VH, Chilton BS 2002 Identification of the RUSH consensus-binding site by cyclic amplification and selection of targets: demonstration that RUSH mediates the ability of prolactin to augment progesterone-dependent gene expression. Mol Endocrinol 16:2101–2112[Abstract/Free Full Text]
130. Li WI, Chen CL, Chou JY 1989 Characterization of a temperature-sensitive β-endorphin-secreting transformed endometrial cell line. Endocrinology 125:2862–2867[Abstract/Free Full Text]
131. Mukherjee AB, Murty LC, Chou JY 1993 Differentiation and uteroglobin gene expression by novel rabbit endometrial cell lines. Mol Cell Endocrinol 94:R15–R22
132. Sheridan PL, Schorpp M, Voz ML, Jones KA 1995 Cloning of an SNF/SWI2-related protein that binds specifically to the SPH motifs of the SV40 enhancer and to the HIV-1 promoter. J Biol Chem 270:4574–4587
133. Braun H, Suske G 1998 Combinatorial action of HNF3 and Sp family transcription factors in the activation of the rabbit uteroglobin/CC10 promoter. J Biol Chem 273:9821–9828[Abstract/Free Full Text]
134. Ray MK, Magdaleno SW, Finegold MJ, DeMayo FJ 1995 cis-Acting elements involved in the regulation of mouse Clara cell-specific 10-kDa protein gene. J Biol Chem 270:2689–2694[Abstract/Free Full Text]
135. Ray MK, Chen C-Y, Schwartz RJ, DeMayo FJ 1996 Transcriptional regulation of a mouse Clara cell-specific protein (mCC10) gene by the NKx transcription factor family members thyroid transcription factor 1 and cardiac muscle-specific homeobox protein (CSX). Mol Cell Biol 16:2056–2064[Abstract/Free Full Text]
136. Barnes PJ 2006 How corticosteroids control inflammation. Quintiles Prize Lecture 2005. Br J Pharmacol 148:245–254[CrossRef][Medline]
137. Volovitz B, Nathanson I, DeCastro G, Kikukawa T, Mukherjee AB 1988 Relationship between leukotriene C4 and uteroglobin-like protein in nasal and tracheobronchial mucosa of children. Implications in acute respiratory illness. Int Arch Allergy Appl Immunol 86:420–425[Medline]
138. Makino S, Zaragoza DB, Mitchell BF, Robertson S, Olson DM 2007 Prostaglandin F2 and its receptor as activators of human decidua. Semin Reprod Med 25:60–68[CrossRef][Medline]
139. Egarter CH, Husslein P 1992 Biochemistry of myometrial contractility. Baillieres Clin Obstet Gynaecol 6:755–769[CrossRef][Medline]
140. Baulieu EE 1995 The combined use of prostaglandin and antiprogestin in human fertility control. Adv Prostaglandin Thromboxane Leukot Res 23:55–62[Medline]
141. Levin SW, Butler JD, Schumacher UK, Wightman PD, Mukherjee AB 1986 Uteroglobin inhibits phospholipase A2 activity. Life Sci 38:1813–1819[CrossRef][Medline]
142. Singh G, Katyal SL, Brown WE, Brown WE, Kennedy AL, Singh U, Wong-Chong ML 1990 Clara cell 10kDa protein (CC10) comparison of structure and function of uteroglobin. Biochim Biophys Acta 1039:348–355[CrossRef][Medline]
143. Murakami M, Kudo I 2003 Cellular arachidonate-releasing functions of various phospholipase A2s. Adv Exp Med Biol 525:87–92[Medline]
144. Mariniello L, Porta R 2005 Transglutaminases as biotechnological tools. Prog Exp Tumor Res 38:174–191[Medline]
145. Lorand L, Graham RM 2003 Transglutaminases: crosslinking enzymes with pleotropic functions. Nat Rev Mol Cell Biol 4:140–156[CrossRef][Medline]
146. Mukherjee AB, Laki K, Agrawal AK 1980 Possible mechanism of success of an allotransplantation in nature: mammalian pregnancy. Med Hypotheses 6:1043–1055[CrossRef][Medline]
147. Mukherjee AB, Ulane RE, Agrawal AK 1982 Role of uteroglobin and transglutaminase in masking the antigenicity of implanting rabbit embryos. Am J Reprod Immunol 2:135–141[Medline]
148. Mukherjee DC, Agrawal AK, Manjunath R, Mukherjee AB 1983 Suppression of epididymal sperm antigenicity in the rabbit by uteroglobin and transglutaminase in vitro. Science 219:989–991[Abstract/Free Full Text]
149. Manjunath R, Chung SI, Mukherjee AB 1984 Crosslinking of uteroglobin by transglutaminase. Biochem Biophys Res Commun 121:400–407[Medline]
150. Metafora S, Peluso G, Persico P, Ravagnan G, Esposito C, Porta R 1989 Immunosuppressive and anti-inflammatory properties of a major protein secreted from the epithelium of the rat seminal vesicles. Biochem Pharmacol 38:121–131[CrossRef][Medline]
151. Luconi M, Muratori M, Maggi M, Pecchioli P, Peri A, Manchi M, Filimberti E, Forti G, Baldi E 2000 Uteroglobin and transglutaminase modulate human sperm functions. J Androl 21:676–688[Abstract]
152. Sohn J, Kim TI, Yoon YH, Kim JY, Kim SY 2003 Novel transglutaminase inhibitors reverse the inflammation of allergic conjunctivitis. J Clin Invest 111:121–128[CrossRef][Medline]
153. Miele L 2003 New weapons against inflammation: dual inhibitors of phospholipase A2 and transglutaminase. J Clin Invest 111:19–21[CrossRef][Medline]
154. Moreno JJ 2006 Effects of antiflammins on transglutaminase and phospholipase A2 activation by transglutaminase. Int Immunopharmacol 6:300–303[CrossRef][Medline]
155. Schiffmann E, Geetha V, Pencev D, Warabi H, Mato J, Hirata F, Brownstein M, Manjunath R, Mukherjee A, Liotta L, Terranova VP 1983 Adherence and regulation of leukotaxis. Agents Actions Suppl 12:106–120[Medline]
156. Vasanthakumar G, Manjunath R, Mukherjee AB, Warabi H, Schiffmann E 1988 Inhibition of phagocyte chemotaxis by uteroglobin, an inhibitor of blastocyst rejection. Biochem Pharmacol 37:389–394[CrossRef][Medline]
157. Camussi G, Tetta C, Bussolino F, Baglioni C 1990 Antiinflammatory peptides (antiflammins) inhibit synthesis of platelet-activating factor, neutrophil aggregation and chemotaxis, and intradermal inflammatory reactions. J Exp Med 171:913–927[Abstract/Free Full Text]
158. Lesur O, Bernard A, Arsalane K, Lauwerys R, Begin R, Cantin A, Lane D 1995 Clara cell protein (CC-16) induces a phospholipase A2-mediated inhibition of fibroblast migration in vitro. Am J Respir Crit Care Med 152:290–297[Abstract]
159. Geerts L, Jorens PG, Willems J, De Ley M, Slegers H 2001 Natural inhibitors of neutrophil function in acute respiratory distress syndrome. Crit Care Med 29:1920–1924[CrossRef][Medline]
160. Booke M, Van Aken H 2001 Neutrophils in acute respiratory distress syndrome: upregulated, uninhibited, or even both. Crit Care Med 29: 2031 (Commentary)
161. Le Y, Murphy PM, Wang JM 2002 Formyl-peptide receptors revisited. Trends Immunol 23:541–548[CrossRef][Medline]
162. Liang TS, Wang JM, Murphy PM, Gao JL 2000 Serum amyloid A is a chemotactic agonist at FPR2, a low-affinity N-formylpeptide receptor on mouse neutrophils. Biochem Biophys Res Commun 270:331–335[CrossRef][Medline]
163. Buyukozturk S, Gelincik AA, Genc S, Kocak H, Oneriyidogan Y, Erden S, Dal M, Colakoglu B 2004 Acute phase reactants in allergic airway disease. Tohoku J Exp Med 204:209–213[CrossRef][Medline]
164. Lee HY, Kang HK, Jo EJ, Kim JI, Lee YN, Lee SH, Park YM, Ryu SH, Kwak JY, Bae YS 2004 Trp–Lys–Tyr–Met–Val–Met stimulates phagocytosis via phospho-lipase D-dependent signaling in mouse dendritic cells. Exp Mol Med 36:135–144[Medline]
165. Gao JL, Murphy PM 1993 Species and subtype variants of the N-formyl peptide chemotactic receptor reveal multiple important functional domains. J Biol Chem 268:25395–25401[Abstract/Free Full Text]
166. Seki Y, Inoue H, Nagata N, Hayashi K, Fukuyama S, Matsumoto K, Komine O, Hamano S, Himeno K, Inagaki-Ohara K, Cacalano N, O’Garra A, Oshida T, Saito H, Johnston JA, Yoshimura A, Kubo M 2003 SOCS-3 regulates onset and maintenance of T(H)2-mediated allergic responses. Nat Med 9:1047–1054[CrossRef][Medline]
167. Ray R, Zhang Z, Lee YC, Gao JL, Mukherjee AB 2006 Uteroglobin suppresses allergen-induced TH2 differentiation by down-regulating the expression of serum amyloid A and SOCS-3 genes. FEBS Lett 580:6022–6026[CrossRef][Medline]
168. Kamal AM, Hayhoe RP, Paramasivam A, Cooper D, Flower RJ, Solito E, Perretti M 2006 Antiflammin-2 activates the human formyl-peptide receptor like 1. Scientific World Journal 6:1375–1384[Medline]
169. Antico G, Lingen MW, Sassano A, Melby J, Welch RW, Fiore S, Pilon AL, Miele L 2006 Recombinant human uteroglobin/CC10 inhibits the adhesion and migration of primary human endothelial cells via specific and saturable binding to fibronectin. J Cell Physiol 207:553–561[CrossRef][Medline]
170. Manjunath R, Levin SW, Kumaroo KK, Butler JD, Donlon JA, Horne M, Fujita R, Schumacher UG, Mukherjee AB 1987 Inhibition of thrombin-induced platelet aggregation by uteroglobin. Biochem Pharmacol 36:741–746[CrossRef][Medline]
171. Vostal JG, Mukherjee AB, Miele L, Shulman NR 1989 Novel peptides derived from a region of local homology between uteroglobin and lipocortin-1 inhibit platelet aggregation and secretion. Biochem Biophys Res Commun 165:27–36[CrossRef][Medline]
172. Hayashi Y 2003 Recombinant protein 1/Secretoglobin 1A1 participates in the actin polymerization of human platelets. Clin Chim Acta 335:147–155[CrossRef][Medline]
173. Bazer FW 1975 Uterine protein secretions: relationship to development of the conceptus. J Anim Sci 41:1376–1382[Abstract/Free Full Text]
174. Beier HM, Maurer RR 1975 Uteroglobin and other proteins in rabbit blastocyst fluid after development in vivo and in vitro. Cell Tissue Res 159:1–10[Medline]
175. Herrler A, von Wolff M, Beier HM 2002 Proteins in the extraembryonic matrix of preimplantation rabbit embryos. Anat Embryol (Berl) 206:49–55[CrossRef][Medline]
176. Herrler A, von Rango U, Beier HM 2003 Embryo-maternal signalling: how the embryo starts talking to its mother to accomplish implantation. Reprod Biomed Online 6:244–256[Medline]
177. Riffo M, Gonzalez KD, Nieto A 2007 Uteroglobin induces the development and cellular proliferation of the mouse early embryo. J Exp Zool Part A Ecol Genet Physiol 307:28–34[Medline]
178. Daniel Jr JC, Krishnan RS 1969 Studies on the relationship between uterine fluid components and the diapausing state blastocysts from mammals having delayed implantation. J Exp Zool 172:267–282[CrossRef][Medline]
179. Robinson DH, Kirk KL, Benos DJ 1989 Macromolecular transport in rabbit blastocysts: evidence for a specific uteroglobin transport system. Mol Cell Endocrinol 63:227–237[CrossRef][Medline]
180. Diaz Gonzalez K, Nieto A 1995 Binding of uteroglobin to microsomes and plasmatic membranes. FEBS Lett 361:255–258[CrossRef][Medline]
181. Kundu GC, Mantile G, Miele L, Cordella-Miele E, Mukherjee AB 1996 Recombinant human uteroglobin suppresses cellular invasiveness via a novel class of high-affinity cell surface binding site. Proc Natl Acad Sci USA 93:2915–2919[Abstract/Free Full Text]
182. Kundu GC, Mandal AK, Zhang Z, Mantile-Selvaggi G, Mukherjee AB 1998 Uteroglobin (UG) suppresses extracellular matrix invasion by normal and cancer cells that express the high affinity UG-binding proteins. J Biol Chem 273:22819–22824[Abstract/Free Full Text]
183. Kundu GC, Zhang Z, Mantile-Selvaggi G, Mandal A, Yuan CJ, Mukherjee AB 2000 Uteroglobin binding proteins: regulation of cellular motility and invasion in normal and cancer cells. Ann NY Acad Sci 923:234–248[Medline]
184. Zhang Z, Kundu GC, Panda D, Mandal AK, Mantile-Selvaggi G, Peri A, Yuan CJ, Mukherjee AB 1999 Loss of transformed phenotype in cancer cells by overexpression of the uteroglobin gene. Proc Natl Acad Sci USA 96:3963–3968[Abstract/Free Full Text]
185. Burmeister R, Boe IM, Nykjaer A, Jacobsen C, Moestrup SK, Verroust P, Christensen EI, Lund J, Willnow TE 2001 A two-receptor pathway for catabolism of Clara cell secretory protein in the kidney. J. Biol Chem 276:13295–13301[CrossRef]
186. Yoon JM, Lim JJ, Yoo CG, Lee CT, Bang YJ, Han SK, Shim YS, Kim YW 2005 Adenovirus-uteroglobin suppresses COX-2 expression via inhibition of NF-B activity in lung cancer cells. Lung Cancer 48:201–209[CrossRef][Medline]
187. Zhang Z, Kim SJ, Chowdhury B, Wang J, Lee YC, Tsai PC, Choi M, Mukherjee AB 2006 Interaction of uteroglobin with lipocalin-1 receptor suppresses cancer cell motility and invasion. Gene 369:66–71[CrossRef][Medline]
188. Ray R, Zhang Z, Lee YC, Gao JL, Mukherjee AB 2006 Uteroglobin suppresses allergen-induced TH2 differentiation by down-regulating the expression of serum amyloid A and SOCS-3 genes. FEBS Lett 580:6022–6026[CrossRef][Medline]
189. Linnoila RI, Szabo E, Demayo F, Witschi H, Sabourin C, Malkinson A 2000 The role of CC10 in pulmonary carcinogenesis: from a marker to tumor suppression. Ann NY Acad Sci 923:249–267[Medline]
190. Jensen SM, Jones JE, Pass H, Steinberg SM, Linnoila RI 1994 Clara cell 10 kDa protein mRNA in normal and atypical regions of human respiratory epithelium. Int J Cancer 58:629–637[Medline]
191. Szabo E, Goheer A, Witschi H, Linnoila RI 1998 Overexpression of CC10 modifies neoplastic potential in lung cancer cells. Cell Growth Differ 9:475–485[Abstract]
192. Shijubo N, Itoh Y, Yamaguchi T, Shibuya Y, Morita Y, Hirasawa M, Okutani R, Kawai T, Abe S 1997 Serum and BAL Clara cell 10 kDa protein (CC10) levels and CC10-positive bronchiolar cells are decreased in smokers. Eur Respir J 10:1108–1114[Abstract]
193. Yang Y, Zhang Z, Mukherjee AB, Linnoila RI 2004 Increased susceptibility of mice lacking Clara cell 10-kDa protein to lung tumorigenesis by 4- (methylnitrosamino)-1-(3-pyridyl)-1-butanone, a potent carcinogen in cigarette smoke. J Biol Chem 279:29336–29340[Abstract/Free Full Text]
194. Hicks SM, Vassallo JD, Dieter MZ, Lewis CL, Whiteley LO, Fix AS, Lehman-McKeeman LD 2003 Immunohistochemical analysis of Clara cell secretory protein expression in a transgenic model of mouse lung carcinogenesis. Toxicology 187:217–228[CrossRef][Medline]
195. De Marzo AM, Platz EA, Sutcliffe S, Xu J, Gronberg H, Drake CG, Nakai Y, Isaacs WB, Nelson WG 2007 Inflammation in prostate carcinogenesis. Nat Rev Cancer 7:256–269[CrossRef][Medline]
196. Flower RJ 1988 Lipocortin and mechanism of action of glucocorticoids. Br J Pharmacol 94:987–1015[Medline]
197. Di Rosa M, Flower RJ, Hirata F, Parente L, Russo-Marie F 1984 Anti-phospholipase proteins. Prostaglandins 28:441–442[CrossRef][Medline]
198. Flower RJ, Rothwell NJ 1994 Lipocortin-1: cellular mechanisms and clinical relevance. Trends Pharmacol Sci 15:71–76[CrossRef][Medline]
199. Miele L, Cordella-Miele E, Facchiano A, Mukherjee AB 1988 Novel anti-inflammatory peptides from the region of highest similarity between uteroglobin and lipocortin I. Nature 335:726–730[CrossRef][Medline]
200. Miele L 2000 Antiflammins. Ann NY Acad Sci 293:128–140
201. Moreno JJ 2000 Antiflammin peptides in the regulation of inflammatory response. Ann NY Acad Sci 923:147–153[Medline]
202. Iatenti A, Doyle PM, Hardy GN, Simpkin DS, DiRosa M 1990 Anti-inflammatory effects of vasocortin and nonapeptide fragments of uteroglobin and lipocortin I (antiflammins). Agents Actions 29:48–49[CrossRef][Medline]
203. Mize NK, Buttery M, Ruis N, Leung I, Cormier M, Daddona P 1997 Antiflammin 1 peptide delivered non-invasively by iontophoresis reduces irritant-induced inflammation in vivo. Exp Dermatol 6:181–185[CrossRef][Medline]
204. Zouki C, Ouellet S, Filep JG 2000 The anti-inflammatory peptides, antiflammins, regulate the expression of adhesion molecules on human leukocytes and prevent neutrophil adhesion to endothelial cells. FASEB 14:572–580[Abstract/Free Full Text]
205. Facchiano A, Cordella-Miele E, Miele L, Mukherjee AB 1991 Inhibition of pancreatic phospholipase A2 activity by uteroglobin and antiflammin peptides: possible mechanism of action. Life Sci 48:453–464[CrossRef][Medline]
206. Marki F, Pfeilschifter J, Rink H, Wiesenberg I 1990 ‘Antiflammins’: two nonapeptide fragments of uteroglobin and lipocortin I have no phospholipase A2-inhibitory and anti-inflammatory activity. FEBS Lett 264:171–175[CrossRef][Medline]
207. Hope WC, Patel BJ, Bolin DR 1991 Antiflammin-2 (HDMNKVLDL) does not inhibit phospholipase A2 activities. Agents Actions 34:77–80[CrossRef][Medline]
208. Tetta C, Camussi G, Bussolino F, Herrick-Davis K, Baglioni C 1991 Inhibition of the synthesis of platelet-activating factor by anti-inflammatory peptides (antiflammins) without methionine. J Pharmacol Exp Ther 257:616–620[Abstract/Free Full Text]
209. Ye JM, Wolfe JL 1996 Oxidative degradation of antiflammin 2. Pharm Res 13:250–255[CrossRef][Medline]
210. Rodgers KE, Girgis W, Campeau JD, diZerega GS 1997 Reduction of adhesion formation by intraperitoneal administration of anti-inflammatory peptide 2. J Invest Surg 10:31–36[Medline]
211. Chan CC, Tuaillon N, Li Q, Shen DE 2000 Therapeutic applications of antiflammin peptides in experimental ocular inflammation. Ann NY Acad Sci 923:141–146[Medline]
212. Moreno JJ 2006 Effects of antiflammins on transglutaminase and phospholipase A2 activation by transglutaminase. Int Immunopharmacol 6:300–303[CrossRef][Medline]
213. Stripp BR, Lund J, Mango GW, Doyen KC, Johnston C, Hultenby K, Nord M, Whitsett JA 1996 Clara cell secretory protein: a determinant of PCB bioaccumulation in mammals. Am J Physiol 271:L656–L664
214. Zhang Z, Kundu GC, Yuan CJ, Ward JM, Lee EJ, DeMayo F, Westphal H, Mukherjee AB 1997 Severe fibronectin-deposit renal glomerular disease in mice lacking uteroglobin. Science 276:1408–1412[Abstract/Free Full Text]
215. Zheng F, Kundu GC, Zhang Z, Ward J, DeMayo F, Mukherjee AB 1999 Uteroglobin is essential in preventing immunoglobulin A nephropathy in mice. Nat Med 5:1018–1025[CrossRef][Medline]
216. Zhang Z, Kundu GC, Zheng F, Yuan CJ, Lee E, Westphal H, Ward J, DeMayo F, Mukherjee AB 2000 Insight into the physiological function(s) of uteroglobin by gene-knockout and antisense-transgenic approaches. Ann NY Acad Sci 923:210–233[Medline]
217. Hynes RO 1985–1986 Fibronectins: a family of complex and versatile adhesive glycoproteins derived from a single gene. Harvey Lect 81:133–152
218. Cederholm B, Wieslander J, Bygren P, Heinegard D 1988 Circulating complexes containing IgA and fibronectin in patients with primary IgA nephropathy. Proc Natl Acad Sci USA 85:4865–4868[Abstract/Free Full Text]
219. Lee YC, Zhang Z, Mukherjee AB 2006 Mice lacking uteroglobin are highly susceptible to developing pulmonary fibrosis. FEBS Lett 580:4515–4520[CrossRef][Medline]
220. Ray R, Choi M, Zhang Z, Silverman GA, Askew D, Mukherjee AB 2005 Uteroglobin suppresses SCCA gene expression associated with allergic asthma. J Biol Chem 280:9761–9764[Abstract/Free Full Text]
221. Chen LC, Zhang Z, Myers AC, Huang SK 2001 Cutting edge: altered pulmonary eosinophilic inflammation in mice deficient for Clara cell secretory 10-kDa protein. J Immunol 167:3025–3028[Abstract/Free Full Text]
222. Hung CH, Chen LC, Zhang Z, Chowdhury B, Lee WL, Plunkett B, Chen CH, Myers AC, Huang SK 2004 Regulation of TH2 responses by the pulmonary Clara cell secretory 10-kd protein. J Allergy Clin Immunol 114:664–670[CrossRef][Medline]
223. Ray R, Zhang Z, Lee YC, Gao JL, Mukherjee AB 2006 Uteroglobin suppresses allergen-induced TH2 differentiation by down-regulating the expression of serum amyloid A and SOCS-3 genes. FEBS Lett 580:6022–6026[CrossRef][Medline]
224. Watson TM, Reynolds SD, Mango GW, Boe IM, Lund J, Stripp BR 2001 Altered lung gene expression in CCSP-null mice suggests immunoregulatory roles for Clara cells. Am J Physiol Lung Cell Mol Physiol 281: L1523–L1530
225. Reynolds SD, Reynolds PR, Snyder JC, Whyte F, Paavola KJ, Stripp BR 2007 CCSP regulates cross talk between secretory cells and both ciliated cells and macrophages of the conducting airway. Am J Physiol Lung Cell Mol Physiol 293:L114–L123
226. Yoshikawa S, Miyahara T, Reynolds SD, Stripp BR, Anghelescu M, Eyal FG, Parker JC 2005 Clara cell secretory protein and phospholipase A2 activity modulate acute ventilator-induced lung injury in mice. J Appl Physiol 98:1264–1271[Abstract/Free Full Text]
227. Mukherjee AB, Kundu GC, Mantile-Selvaggi G, Yuan CJ, Mandal AK, Chattopadhyay S, Zheng F, Pattabiraman N, Zhang Z 1999 Uteroglobin: a novel cytokine? Cell Mol Life Sci 55:771–787[CrossRef][Medline]
228. Miele L, Cordella-Miele E, Mukherjee AB 1987 Uteroglobin: structure, molecular biology, and new perspectives on its function as a phospholipase A2 inhibitor. Endocr Rev 8:474–490[Abstract/Free Full Text]
229. Stohr H, Weber BH 1994 (ATTT)n-tetranucleotide repeat polymorphism in the 5'-flanking region of the UGB gene. Hum Mol Genet 3:2086[Medline]
230. Niimi T, Munakata M, Keck-Waggoner CL, Popescu NC, Levitt RC, Hisada M, Kimura S 2002 A polymorphism in the human UGRP1 gene promoter that regulates transcription is associated with an increased risk of asthma. Am J Hum Genet 70:718–725[CrossRef][Medline]
231. Benson M, Jansson L, Adner M, Luts A, Uddman R, Cardell LO 2005 Gene profiling reveals decreased expression of uteroglobin and other anti-inflammatory genes in nasal fluid cells from patients with intermittent allergic rhinitis. Clin Exp Allergy 35:473–478[CrossRef][Medline]
232. Johansson S, Keen C, Stahl A, Wennergren G, Benson M 2005 Low levels of CC16 in nasal fluid of children with birch pollen-induced rhinitis. Allergy 60:638–642[CrossRef][Medline]
233. Fritz SB, Terrell JE, Conner ER, Kukowska-Latallo JF, Baker JR 2003 Nasal mucosal gene expression in patients with allergic rhinitis with and without nasal polyps. J Allergy Clin Immunol 112:1057–1063[CrossRef][Medline]
234. Benson M, Fransson M, Martinsson T, Naliai AT, Uddman R, Cardell LO 2007 Inverse relation between nasal fluid Clara cell protein 16 levels and symptoms and signs of rhinitis in allergen-challenged patients with intermittent allergic rhinitis. Allergy 62:178–183[Medline]
235. de Burbure C, Pignatti P, Corradi M, Malerba M, Clippe A, Dumont X, Moscato G, Mutti A, Bernard A 2007 Uteroglobin-related protein 1 and Clara cell protein in induced sputum of patients with asthma and rhinitis. Chest 131:172–179[CrossRef][Medline]
236. Menegatti E, Nardacchione A, Alpa M, Agnes C, Rossi D, Chiara M, Modena V, Sena LM, Roccatello D 2002 Polymorphism of the uteroglobin gene in systemic lupus erythematosus and IgA nephropathy. Lab Invest 82:543–546[CrossRef][Medline]
237. Iannuzzi MC 2004 Clara cell protein in sarcoidosis: another job for the respiratory tract protector? Am J Respir Crit Care Med 169:143–144[Free Full Text]
238. Janssen R, Sato H, Grutters JC, Ruven HJ, du Bois RM, Matsuura R, Yamazaki M, Kunimaru S, Izumi T, Welsh KI, Nagai S, van den Bosch JM 2004 The Clara cell 10 adenine38guanine polymorphism and sarcoidosis susceptibility in Dutch and Japanese subjects. Am J Respir Crit Care Med 170:1185–1187[Abstract/Free Full Text]
239. Goronzy JJ, Matteson EL, Fulbright JW, Warrington KJ, Chang-Miller A, Hunder GG, Mason TG, Nelson AM, Valente RM, Crowson CS, Erlich HA, Reynolds RL, Swee RG, O’Fallon WM, Weyand CM 2004 Prognostic markers of radiographic progression in early rheumatoid arthritis. Arthritis Rheum 50:43–54[CrossRef][Medline]
240. Mehta NM, Arnold JH 2005 Genetic polymorphisms in acute respiratory distress syndrome: new approach to an old problem. Crit Care Med 33:2443–2445[CrossRef][Medline]
241. Frerking I, Sengler C, Gunther A, Walmrath HD, Stevens P, Witt H, Landt O, Pison U, Nickel R 2005 Evaluation of the –26G>A CC16 polymorphism in acute respiratory distress syndrome. Crit Care Med 33:2404–2406[CrossRef][Medline]
242. Szelestei T, Bahring S, Kovacs T, Vas T, Salamon C, Busjahn A, Luft FC, Nagy J 2000 Association of a uteroglobin polymorphism with rate of progression in patients with IgA nephropathy. Am J Kidney Dis 36:468–473[Medline]
243. Kim YS, Kang D, Kwon DY, Park WY, Kim H, Lee DS, Lim CS, Han JS, Kim S, Lee JS 2001 Uteroglobin gene polymorphisms affect the progression of immunoglobulin A nephropathy by modulating the level of uteroglobin expression. Pharmacogenetics 11:299–305[CrossRef][Medline]
244. Lim CS, Kim SM, Oh YK, Kim YS, Chae DW, Han JS, Kim S, Lee JS, Yoon HJ 2007 Association between the Clara cell secretory protein (CC16) G38A polymorphism and the progression of IgA nephropathy. Clin Nephrol 67:73–80[Medline]
245. Matsunaga A, Numakura C, Kawakami T, Itoh Y, Kawabata I, Masakane I, Suzuki T, Suzuki M, Goto T, Itoh K, Hayasaka K 2002 Association of the uteroglobin gene polymorphism with IgA nephropathy. Am J Kidney Dis 39:36–41[Medline]
246. Narita I, Saito N, Goto S, Jin S, Omori K, Sakatsume M, Gejyo F 2002 Role of uteroglobin G38A polymorphism in the progression of IgA nephropathy in Japanese patients. Kidney Int 61:1853–1858[CrossRef][Medline]
247. Shijubo N, Kawabata I, Sato N, Itoh Y 2003 Clinical aspects of Clara cell 10- kDa protein/uteroglobin (secretoglobin 1A1). Curr Pharm Des 9:1 139–149[Medline]
248. Coppo R, Chiesa M, Cirina P, Peruzzi L, Amore A; European IgACE Study Group 2002 In human IgA nephropathy uteroglobin does not play the role inferred from transgenic mice. Am J Kidney Dis 40:495–503[CrossRef][Medline]
249. Yong D, QingQing W, Hua L, Yang LX, QingLing Z, Ying H, QiaoJing Q, HanChao S 2006 Association of uteroglobin G38A polymorphism with IgA nephropathy: a meta-analysis. Am J Kidney Dis 48:1–7[CrossRef][Medline]
250. Pilon AL 2000 Rationale for the development of recombinant human CC10 as a therapeutic for inflammatory and fibrotic disease. Ann NY Acad Sci 923:280–299[Medline]
251. Miele L, Cordella-Miele E, Mukherjee AB 1990 High level bacterial expression of uteroglobin, a dimeric eukaryotic protein with two interchain disulfide bridges in its natural quaternary structure. J Biol Chem 265:6427–6435[Abstract/Free Full Text]
252. Chandra S, Davis JM, Drexler S, Kowalewska J, Chester D, Koo HC, Pollack S, Welch R, Pilon A, Levine CR 2003 Safety and efficacy of intratracheal recombinant human Clara cell protein in a newborn piglet model of acute lung injury. Pediatr Res 54:509–515[CrossRef][Medline]
253. Miller TL, Shashikant BN, Melby JM, Pilon AL, Shaffer TH, Wolfson MR 2005 Recombinant human Clara cell secretory protein in acute lung injury of the rabbit: effect of route of administration. Pediatr Crit Care Med 6:698–706[CrossRef][Medline]
254. Shashikant BN, Miller TL, Welch RW, Pilon AL, Shaffer TH, Wolfson MR 2005 Dose response to rhCC10-augmented surfactant therapy in a lamb model of infant respiratory distress syndrome: physiological, inflammatory, and kinetic profiles. J Appl Physiol 99:2204–2211[Abstract/Free Full Text]
255. Miller TL, Shashikant BN, Pilon AL, Pierce RA, Shaffer TH, Wolfson MR 2007 Effects of recombinant Clara cell secretory protein (rhCC10) on inflammatory-related matrix metalloproteinase activity in a preterm lamb model of neonatal respiratory distress. Pediatr Crit Care Med 8:40–46[CrossRef][Medline]
256. Levine CR, Gewolb IH, Allen K, Welch RW, Melby JM, Pollack S, Shaffer T, Pilon AL, Davis JM 2005 The safety, pharmacokinetics, and anti-inflammatory effects of intratracheal recombinant human Clara cell protein in premature infants with respiratory distress syndrome. Pediatr Res 58:15–21[CrossRef][Medline]
257. Welty SE 2005 CC10 administration to premature infants: in search of the "silver bullet" to prevent lung inflammation. Pediatr Res 58:7–9[CrossRef][Medline]
258. Nicholls A 1993 GRASP: graphical representation and analysis of surface properties. New York: Columbia University
259. Ni J, Kalff-Suske M, Gentz R, Schageman J, Beato M, Klug J 2000 All human genes of the uteroglobin family are localized on chromosome 11q12.2 and form a dence cluster. Ann NY Acad Sci 923:25–42[Medline]

This article has been cited by other articles:

				E. Backstrom, U. Lappalainen, and K. Bry Maternal IL-1{beta} Production Prevents Lung Injury in a Mouse Model of Bronchopulmonary Dysplasia Am. J. Respir. Cell Mol. Biol., February 1, 2010; 42(2): 149 - 160. [Abstract] [Full Text] [PDF]

				E. Ventura, F. Sassi, S. Fossati, A. Parodi, W. Blalock, E. Balza, P. Castellani, L. Borsi, B. Carnemolla, and L. Zardi Use of Uteroglobin for the Engineering of Polyvalent, Polyspecific Fusion Proteins J. Biol. Chem., September 25, 2009; 284(39): 26646 - 26654. [Abstract] [Full Text] [PDF]

				S. G. Remington, J. M. Crow, and J. D. Nelson Secretoglobins: Lacrimal Gland-Specific Rabbit Lipophilin mRNAs Invest. Ophthalmol. Vis. Sci., July 1, 2008; 49(7): 2856 - 2862. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) A correction has been published Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints, Permissions and Rights Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mukherjee, A. B. Articles by Chilton, B. S. Search for Related Content PubMed PubMed Citation Articles by Mukherjee, A. B. Articles by Chilton, B. S. Pubmed/NCBI databases Substance via MeSH