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-Melanocyte-Stimulating Hormone and Related Tripeptides: Biochemistry, Antiinflammatory and Protective Effects in Vitro and in Vivo, and Future Perspectives for the Treatment of Immune-Mediated Inflammatory Diseases

Department of Dermatology (T.B., T.A.L., M.B.), University of Münster, Münster, Germany; Wolff Arzneimittel (T.B., C.A.), Bielefeld, Germany; and Department of Internal Medicine (C.M.), University of Münster, Münster, Germany

Correspondence: Address all correspondence and requests for reprints to: Markus Böhm, M.D., Associate Professor Department of Dermatology, University of Münster, Von Esmarch-Strasse 58, D-48149 Münster, Germany. E-mail: bohmm{at}uni-muenster.de

	Abstract

Top Abstract I. Introduction II. Biochemistry of {alpha}-MSH... III. Antiinflammatory and... IV. Antiinflammatory Effects of... V. Therapeutic Potential of... References

 
-MSH is a tridecapeptide derived from proopiomelanocortin. Many studies over the last few years have provided evidence that -MSH has potent protective and antiinflammatory effects. These effects can be elicited via centrally expressed melanocortin receptors that orchestrate descending neurogenic antiinflammatory pathways. -MSH can also exert antiinflammatory and protective effects on cells of the immune system and on peripheral nonimmune cell types expressing melanocortin receptors. At the molecular level, -MSH affects various pathways implicated in regulation of inflammation and protection, i.e., nuclear factor-B activation, expression of adhesion molecules and chemokine receptors, production of proinflammatory cytokines and mediators, IL-10 synthesis, T cell proliferation and activity, inflammatory cell migration, expression of antioxidative enzymes, and apoptosis. The antiinflammatory effects of -MSH have been validated in animal models of experimentally induced fever; irritant and allergic contact dermatitis, vasculitis, and fibrosis; ocular, gastrointestinal, brain, and allergic airway inflammation; and arthritis, but also in models of organ injury. One obstacle limiting the use of -MSH in inflammatory disorders is its pigmentary effect. Due to its preserved antiinflammatory effect but lack of pigmentary action, the C-terminal tripeptide of -MSH, KPV, has been delineated as an alternative for antiinflammatory therapy. KdPT, a derivative of KPV corresponding to amino acids 193–195 of IL-1β, is also emerging as a tripeptide with antiinflammatory effects. The physiochemical properties and expected low costs of production render both agents suitable for the future treatment of immune-mediated inflammatory skin and bowel disease, fibrosis, allergic and inflammatory lung disease, ocular inflammation, and arthritis.

I. Introduction

II. Biochemistry of -MSH and Related Peptides

A. Biosynthesis of -MSH

B. Structure of -MSH and related tripeptides

C. Melanocortin receptors—obligatory structures mediating the inflammatory effects of -MSH and related tripeptides?

III. Antiinflammatory and Protective Spectrum of -MSH

A. Antiinflammatory effects in vitro

B. Antiinflammatory effects in vivo

C. Cytoprotective effects in vitro

D. Protective effects against organ damage

IV. Antiinflammatory Effects of -MSH-Related Tripeptides in Vitro and in Vivo

V. Therapeutic Potential of -MSH-Related Tripeptides in Human Immune-Mediated Inflammatory Diseases

	I. Introduction

Top Abstract I. Introduction II. Biochemistry of {alpha}-MSH... III. Antiinflammatory and... IV. Antiinflammatory Effects of... V. Therapeutic Potential of... References

 
-MSH has fascinated researchers since its discovery and initial characterization as a pigment-inducing (melanotropic) peptide more than 50 yr ago. Enabled with a plethora of biological activities far beyond pigment regulation, the antiinflammatory effects of -MSH have received particular attention in the last few years due to the potential to bring -MSH and related peptides into clinical practice, i.e., to treat human inflammatory disorders with such novel agents (1, 2, 3). This paper summarizes our current knowledge on the immunomodulatory spectrum of -MSH, the parental peptide hormone based on which -MSH tripeptides and derivatives have subsequently been developed. The emphasis of this review is on antiinflammatory effects of -MSH and its derived tripeptides. Because antiinflammatory and protective effects are, however, closely related and often employ similar effector pathways, we included a separate section on the protective spectrum of -MSH in models of cell and tissue injury/toxicity. To facilitate understanding of the text, the basic biochemistry of -MSH and its principal mechanism of action via melanocortin receptors are also described.

	II. Biochemistry of -MSH and Related Peptides

Top Abstract I. Introduction II. Biochemistry of {alpha}-MSH... III. Antiinflammatory and... IV. Antiinflammatory Effects of... V. Therapeutic Potential of... References

 
A. Biosynthesis of -MSH
-MSH is naturally generated from a precursor hormone called proopiomelanocortin (POMC) (4). This approximately 31-kDa protein molecule is the source for several bioactive peptide hormones including ACTH, -, β-, and -MSH, and the endogenous opioids including β-endorphin (Fig. 1A). Proteolytic cleavage of POMC is catalyzed by prohormone convertases (PCs), which are serine proteases of the subtilisin/kexin type. PC1 and PC2 are currently considered the major processing enzymes of POMC, although other members of the PC family, in particular PACE4 and furin convertase, may also process POMC (5). In contrast to ACTH, further processing of -MSH via the action of C-terminal carboxypeptidase, -amidating monooxygenase, and N-acetyltransferase is required for full biological activity of the peptide. ACTH, -, β-, and -MSH are the bona fide melanocortins, a term describing the stimulatory effects of these peptides on pigment cells and cells of the zona fasciculata and glomerulosa of the adrenal gland. As will be outlined below, the natural melanocortins elicit their biological effects via binding to specific surface receptors expressed on target cells. These receptors are distinct from receptors of β-endorphin, which belong to the family of opioid receptors. Although POMC peptides were originally considered as neuropeptides, it is now well established that many peripheral tissues including the skin (6, 7) autonomously express POMC and process it via expression of distinct PCs to POMC-derived peptides. Proinflammatory cytokines as well as corticotropin releasing hormone have been identified as the prototypical stimuli that regulate POMC expression and processing in both central and peripheral tissues (6).

View larger version (26K): [in this window] [in a new window]   FIG. 1. A, Biosynthesis of POMC peptides and natural melanocortins. Posttranslational processing of POMC by PC1 and PC2 (together with its cofactor 7B2) at specific cleavage sites (arrow tips) yields peptide hormones such as ACTH, -MSH, -MSH, and β-endorphin (β-ED) peptides with less-defined functions (β- and -LPH) and fragments (NT, JP, CLIP). LPH, Lipotropic hormone; NT, N-terminal peptide; JP, junctional peptide; CLIP, corticotropin-like intermediate lobe peptide. B, Peptide sequences of the natural melanocortins, the central melanotropic pharmacophor of -MSH, and the -MSH-related C-terminal tripeptides. Structural homologies are depicted in red.

B. Structure of -MSH and related tripeptides

C. Melanocortin receptors—obligatory structures mediating the inflammatory effects of -MSH and related tripeptides?
The natural melanocortins -, β-, and -MSH and ACTH bind to melanocortin receptors (MC-Rs), which are expressed on the cell surface and belong to the superfamily of G protein-coupled receptors with seven transmembrane domains (10, 11). Five MC-R subtypes, MC-1R to MC-5R, have been cloned. They have a sequence homology of 39 to 61% to one another on the amino acid level and bind the natural melanocortin peptides with differential affinity (Table 1). Human MC-1R and MC-4R discriminate poorly between ACTH, whereas -MSH in murine Mc-1r appears more potent than ACTH. MC-2R is selective for ACTH. -MSH is the preferred, though not exclusive, MC-5R ligand, whereas MC-3R is the least selective receptor of the family. The core peptide HFRW binds MC-1R, MC-3R, MC-4R, and MC-5R but with less MC-R subtype specificity than the full length natural melanocortins (12). Ligand stimulation of all MC-Rs leads to activation of adenylate cyclase with increase of intracellular cAMP but other signaling events, e.g., calcium fluxes (13) or activation of MAPKs (14), can also occur depending on the studied cell type.

With regard to MC-1R, it has been shown that this MC-R subtype is expressed not only in melanocytes but also in the majority of nonmelanocytic cutaneous human cell types (7), in mucosal cells of the human gastrointestinal tract (16), and in various cell types of the immune system including human monocytes (17, 18), lymphocytes (19), and neutrophils (20). The majority of antiinflammatory effects of -MSH in vitro have been linked to the detection of MC-1R. It is of note that the antiinflammatory effects of -MSH have been observed in the presence of extremely low, i.e., subpicomolar, concentrations where, based upon the ligand binding affinity of MC-1R, only a few if any receptors would be occupied. It is therefore possible that the antiinflammatory effects of -MSH are mediated not only by MC-Rs but also by additional effector pathways. In fact, previous studies could indeed demonstrate that -MSH potently and selectively reduces surface binding of radiolabeled IL-1β to the T cell subclone EL4–6.1 (21). The latter findings are supported by in vivo findings in rats demonstrating an antagonistic effect of -MSH on the hyperalgesic response induced by IL-1β (22). Further support for a non-MC-R-mediated effector pathway involved in the antiinflammatory action of -MSH comes from ex vivo studies from patients with nonfunctional MC-1R (i.e., individuals with the red hair phenotype) (18) as well as from animal studies using signal-deficient MC-1R mice (recessive yellow e/e mice) (23, 24). However, these findings are complicated by a recent observation demonstrating that recessive yellow e/e mice have a significantly aggravated inflammatory response in a model of inflammatory bowel disease (123).

Whether KPV and its stereoisomers bind to MC-Rs and utilize the identical signaling pathways as the natural ligands is controversial. Early studies using in vitro binding assays and autoradiography in frozen rat brain tissue sections failed to demonstrate replacement of binding of ^[125]NDP-MSH by KPV at concentrations of up to 100 µM (26). Competitive binding analysis of radiolabeled full-length -MSH and KPV in murine B16 melanoma cells furthermore did not reveal any surface binding (27). In addition, KPV even in concentrations up to 1 µM did not compete with radioligand NDP-MSH binding in murine RAW 264.7 macrophages that express MC-1R (28). In the same cell line, KPV failed to increase cAMP levels. Like -MSH, KPV displaced surface binding of radio-labeled IL-1β to the T cell subclone EL4–6.1 and inhibited the hyperalgesic effect of IL-1β in vivo (21, 22). Other more functional in vitro and in vivo studies in the murine system failed to show an involvement of MC-1R, MC-3R, and MC-4R in the antiinflammatory mechanism of KPV and rather suggested an inhibition of IL-1β functions by this peptide (23). On the other hand, intracellular induction of cAMP representing the prototypical signal transduction pathway elicited by -MSH has been observed in murine microglial cells (29). In addition, it has been reported that -MSH, KPV, KPdV, and ACTH have similar pharmacological potency on elicitation of intracellular calcium fluxes as demonstrated in human keratinocytes expressing the MC-1R. Stable transfection of Chinese hamster ovary cells with the MC-1R demonstrated that -MSH and its related C-terminal peptide elevated intracellular calcium (13). Lately, there is evidence that a H⁺-coupled oligopeptide transporter (PepT1) is involved in the antiinflammatory effects of truncated -MSH peptides such as KPV (30). This issue will be discussed in detail in Section IV.

	III. Antiinflammatory and Protective Spectrum of -MSH

Top Abstract I. Introduction II. Biochemistry of {alpha}-MSH... III. Antiinflammatory and... IV. Antiinflammatory Effects of... V. Therapeutic Potential of... References

 
A. Antiinflammatory effects in vitro
-MSH has been found to exert multiple antiinflammatory effects in a variety of in vitro cell culture systems. Table 2 summarizes the majority of antiinflammatory effects of -MSH in vitro.

View this table: [in this window] [in a new window]   TABLE 2. Antiinflammatory effects of -MSH in vitro

1. -MSH, a suppressor of proinflammatory cytokine production.

2. -MSH induces the cytokine suppressor IL-10.
In contrast to the suppressive effects of -MSH on several proinflammatory mediators, the peptide was also identified as an inducer of IL-10, a cytokine with potent immunosuppressive activities. Stimulation of PBMC with -MSH increased both IL-10 mRNA and protein at a concentration of 10^–10 and 10^–12 M (45). Analogous inductive effects were reported in nonimmune cells, e.g., in human epidermal keratinocytes (46). As will be outlined, induction of IL-10 has been demonstrated to be a key mediator of the antiinflammatory effects of -MSH in vivo.

3. -MSH inhibits expression of intercellular adhesion molecules.
Studies on various cell types of human skin including pigment cells, fibroblastic cells, and dermal microvascular endothelial cells as well as murine mast cells have demonstrated that -MSH is capable of suppressing the expression of intercellular adhesion molecule-1 (ICAM-1) induced by proinflammatory stimuli such as IFN-, LPS, or TNF- (47, 48, 49, 50, 51, 52). Other surface molecules modulated by -MSH are CD86 and CD40, which are required for antigen presentation by monocytes and dendritic cells. In LPS-treated human monocytes, -MSH suppressed expression of CD86 but not CD80 (17). In human peripheral blood-derived dendritic cells, -MSH at 10^–12 M likewise down-regulated surface expression of CD86 in nonstimulated cells (53). The modulatory effect of -MSH on another important surface molecule orchestrating immune responses was recently highlighted in an organ model of the human hair follicle. -MSH potently suppressed ectopic MHC class I expression in the constitutively MHC class I-negative hair matrix epithelium of organ-cultured anagen hair bulbs (54).

4. -MSH—a suppressor of proinflammatory noncytokine mediators.
An inhibitory effect of -MSH on prostaglandins (PGs) was demonstrated many years ago. Accordingly, -MSH suppressed PGE synthesis in fetal human lung fibroblasts stimulated with IL-1 (55). The effect of -MSH on PGE synthesis appears to be cell type-specific because TNF--induced PGE₂ production in FM55 melanoma cells but not in HaCaT keratinocytes was blocked by -MSH (56). Induction of inducible NO synthase (iNOS) and release of the gaseous vasodilator nitric oxide (NO) after stimulation of cells with various proinflammatory stressors, e.g., LPS, -IFN, and β-amyloid can also be suppressed by -MSH (29, 36, 57, 58, 59, 60, 61). The immunomodulatory effects of -MSH via NO may be more important in rodent cells than in human monocytic cells, which are known to express only marginal amounts of this gaseous mediator. However, -MSH suppressed in THP-1 cells the IFN-/TNF--mediated production of neopterin, a primate homolog of NO in lower animals (62). Regarding reactive oxygen species, it was recently demonstrated that -MSH inhibits the production of superoxide radicals in rat neutrophils treated with LPS or phorbolester (63). Similarly, -MSH reduced the amount of oxidative burst in HL-60 cells, a human monocytic cell line (44). Although there is no evidence that -MSH is a true radical scavenger by itself, these findings are in accordance with other reports indicating an effect of the peptide on the cellular redox balance as well as on apoptosis pathway, as will be outlined below. Regarding the release of histamine by mast cells, different effects of -MSH have been reported which are probably related to species-specific differences, type of mast cells, and experimental conditions. In murine bone marrow-derived mast cells, -MSH inhibited antigen-induced histamine release along with suppression of other proinflammatory cytokines (38).

5. -MSH modulates lymphocyte activity and proliferation.
Until now, comparatively few studies have investigated the effect of -MSH on lymphocyte function, probably because the overall expression of MC-Rs is low or undetectable in several lymphocyte subsets (19). The detection of -MSH in the immune-privileged microenvironment of the anterior eye chamber and its effect on production of -IFN by antigen-stimulated primed lymph node cells prompted further studies on the effect of -MSH on effector T cells (31). Aqueous humor-treated T cells were capable of suppressing inflammation induced by delayed-type hypersensitivity T cells. The induction of regulatory T cells was mostly pronounced when primed T cells were activated in vitro first in the presence of -MSH, followed by TGF-β₂ (64). The effector T cells produced increased levels of TGF-β₂, whereas their production of -IFN, IL-4, and IL-10 was suppressed (66, 114). The regulatory T cells induced by -MSH exhibited the CD25 and CD4 markers and suppressed the in vitro production of -IFN by other inflammatory T cells. In the human system, -MSH also exhibited modulatory effects on T cells. Cooper et al. (18) could recently demonstrate that -MSH suppresses proliferation of human T lymphocytes stimulated with streptokinase/streptodornase. Streptokinase/streptodornase is a potent bacterial antigen to which most individuals mount a T cell-mediated response. Interestingly, this inhibitory effect of -MSH was independent of the MC-1R genotype which is highly polymorphic, with more than 35 genetic variants being identified (67). In particular, the Arg151Cys, Arg160Trp, and Asp294His variants are associated with red hair and faint skin due to impaired cAMP signaling in melanocytes resulting in an increased phaeomelanin/eumelanin ratio (68, 69). Although a single variant allele leads to a fairer skin, compound heterozygous or homozygous alleles result in red hair. In the study by Cooper et al. (18), however, the suppressive effect of -MSH was similar in activated lymphocytes from donors carrying wild-type MC-1R and in those from donors being compound heterozygous or homozygous for the Arg151Cys, Arg160Trp, and Asp294His variants. Here, it was suggested that -MSH may utilize other signaling pathways than cAMP, i.e., calcium, to maintain its immunosuppressive effect. Of note, and as observed in several other studies addressing the immunomodulating effect of the peptide, -MSH exhibited an unusual dose kinetics, being most effective at 10^–13 M, which cannot be modeled by the known MC-1R ligand affinity or a simple peptide receptor interaction.

6. NF-B—a master regulator of inflammation suppressed by -MSH.
A key molecular mechanism underlying the antiinflammatory effects of -MSH, especially the modulation of proinflammatory cytokine and adhesion molecule expression, appears to be suppression of nuclear factor-B (NF-B) activation. Manna and Aggarwal (70) were the first who reported that -MSH at nanomolar doses inhibits activation of NF-B in a number of cell types and in response to TNF-, IL-1, LPS, okadeic acid, and ceramide. Subsequent studies could confirm this observation in many different cell types using various proinflammatory stimuli (41, 44, 48, 49, 51, 52, 71, 72, 73, 74, 75). Mechanistically, NF-B deactivation by -MSH is mediated by increased levels of cAMP and correlates with inhibition of the degradation of the inhibitory subunit of NF-B, IB. As a consequence, nuclear translocation of the p65 subunit of NF-B is suppressed. However, the precise mechanism by which -MSH releases NF-B from its cytoplasmic anchor protein IB appears to be cell type-specific. In the rat small intestine cell line IEC-6, it was shown that H₂O₂ resulted in NF-B activation, which could be prevented by 100 nM of -MSH (75). The overall IB protein levels were similar in cells treated with H₂O₂ alone and in those treated with H₂O₂ plus -MSH. In contrast, tyrosine phosphorylation of Syk kinase and its downstream target IB were increased by H₂O₂, and these processes were attenuated by -MSH or the Syk kinase inhibitor piceatannol (75). Interestingly, -MSH also restored H₂O₂-induced inhibition of scrape wounding of IEC-6 cells, suggesting a potential of melanocortin peptides in epithelial restitution. Recently, it was reported that -MSH (200 nM) inhibits TNF--induced matrix metalloproteinase (MMP)-13 expression by modulating p38 kinase and NF-B activation in the human chondrosarcoma cell line HTB-94 (76). HTB-24 cells were found to express MC-1R. These findings are interesting with regard to MMP-13-mediated collagen degradation, which could be prevented by melanocortin peptides. Subsequent studies, however, will have to confirm the relevance of these findings in primary human chondrocytes.

B. Antiinflammatory effects in vivo
The antiinflammatory effects of -MSH in vitro have been substantiated in a variety of animal models, mostly in mouse models. In many of these models, systemic or local inflammation is induced by application of endotoxin (LPS), proinflammatory cytokines, or agents known to induce such endogenous proinflammatory mediators. The proinflammatory stimuli are typically given for a short period, usually once or for several days, whereas in other models specific agents such as bleomycin or carbon tetrachloride are administered over prolonged time periods, resulting in chronic inflammation and tissue fibrosis (Table 3).

View this table: [in this window] [in a new window]   TABLE 3. Antiinflammatory in vivoeffects of -MSH in animal models1

1. -MSH in experimentally induced fever and brain inflammation.

In accordance with the inhibitory effect of -MSH on NF-B activation and cytokine production in vitro, -MSH also preserved expression of IB protein and TNF- expression in murine brain after injection of mice with LPS (35, 74, 94). The potent antiinflammatory effects of -MSH in various cell types of the CNS have resulted in attempts to treat experimental autoimmune encephalomyelitis (EAE), a commonly used animal model for multiple sclerosis, with a special -MSH delivery system. EAE is induced in mice by either immunizing susceptible animals with myelin antigens, e.g., myelin basic protein, or by transfer with activated myelin antigen-specific T lymphocytes (adoptive transfer EAE) resulting in paralysis and often demyelinization of the CNS. Using adenovirus-associated, virus-mediated -MSH-transduced proteolipid 139–151-specific T cells, it could be shown that these cells secreted high levels of -MSH and displayed an altered Th1-like cytokine as well as a high frequency of CD4⁺CD25⁺ regulatory T cells (95). Transfer of the -MSH-transduced cells into animals with EAE resulted in decreased inflammatory cell infiltrates within the CNS, higher IL-10 and TGF-β levels, decreased IL-2 and IFN- content, and reduced chemokine expression. Moreover, the -MSH-transduced cells not only suppressed the induction of adoptive transfer EAE but also had preventive effects on active relapse-remitting EAE, indicating a novel therapeutic approach to treat autoimmune diseases of the CNS.

2. Inhibition of systemic inflammation by -MSH.
In models of systemic inflammation, sepsis, and acute respiratory distress, -MSH proved to be a potent agent. Systemic or sc injection of -MSH reduced the circulating levels of IL-1 and TNF- (96). Lipton et al. (97) could further show that in a model of peritonitis/endotoxemia induced by cecal ligation and puncture, systemic -MSH administration (100 µg) improved the survival rate of the mice. Interestingly, the effect of -MSH in this model was similar to systemic administration of the broad-spectrum antibiotic gentamycin, and both -MSH and gentamycin even increased the survival compared with both agents alone. The authors could further show that systemically administered -MSH attenuated the number of white blood cell bronchoalveolar lavage (BAL) fluids of mice exposed to intratracheal endotoxin from Salmonella typhosa (97).

3. -MSH in experimentally induced contact dermatitis and cutaneous vasculitis.
Central, systemic, and topical (sc, epicutaneous) application of -MSH has been evaluated in a variety of inflammatory skin models. Earliest studies focused on irritant agents, e.g., sodium urate crystals, topically applied to shaved skin of rodents resulting in acute contact dermatitis (98). The effect of locally injected -MSH, however, already suggested that the antiinflammatory mechanism of the peptide can be mediated via mechanisms different from activation of centrally expressed MC-Rs. Subsequent studies focused on the characterization of the antiinflammatory efficacy of various routes of -MSH application and on additional models of skin inflammation induced by proinflammatory cytokines and mediators such as IL-1β, IL-6, IL-8, TNF-, platelet-activating factor, and leukotriene B₄ (24, 99, 100, 101, 102, 103, 104, 105). Of note, central administration of -MSH alone was capable of inhibiting skin inflammation induced by local injection of irritants or proinflammatory cytokines, and this effect could be prevented by spinal cord transection supporting the role of descending antiinflammatory neurogenic pathways elicited by -MSH in such models (104).

The effect of -MSH was further characterized in experimental allergic contact dermatitis. Today, epicutaneous sensitization of mice (typically on the ears) with contact allergens such as dinitrofluoro-benzene or oxazalone followed by challenges with these substances is the most commonly used model to study immunosuppressive agents as well as the induction of tolerance in contact dermatitis. Application of -MSH suppressed both the sensitization and elicitation limbs of the cutaneous immune response (106). Later studies using iv administered -MSH (75 µg/kg) extended these findings by demonstrating that the peptide induces hapten-specific tolerance. Importantly, in vivo tolerance induction by -MSH could be abrogated by application of an antibody against the cytokine suppressor IL-10 (107), strongly suggesting that this cytokine is a key player in the molecular mechanism of antiinflammation by -MSH. There is preliminary evidence that -MSH topically applied in a cream may also reduce contact eczema in man (6).

One of the classical models to study vasculitis is the so-called Shwartzman reaction. In the local Shwartzman reaction, mice are primed with sc injections of LPS followed by systemic challenges whereupon perivascular inflammatory cell infiltrates, vasculitis, and hemorrhage develop. A single ip injection of -MSH suppressed this vascular damage and hemorrhage by inhibiting the sustained expression of vascular E-selectin and vascular cellular adhesion molecule-1, two adhesion molecules orchestrating diapedesis and activation of leukocytes, which subsequently leads to hemorrhagic vascular damage (49). The antiinflammatory activity of -MSH in this model is in accordance with the detection of MC-Rs in endothelial cells in vitro in which the peptide also down-regulates adhesion molecule expression.

4. -MSH in experimentally induced organ fibrosis.
There is accumulating evidence that -MSH also has antifibrogenic/antifibrotic effects in animal models of fibrosis. One of the most extensively used models especially for experimental lung fibrosis is the bleomycin model in which this anticancer chemotherapeutic is intratracheally instilled and leads to pulmonary fibrosis within several weeks. The use of this experimental model for fibrosis is emphasized by the well-known side effect of bleomycin in cancer patients in which a scleroderma-like disease of the lung and skin can develop. A cutaneous scleroderma-like model was also established by injecting fibrosis-susceptible mice sc for 3 wk with bleomycin (108). Using this model we could recently demonstrate that 10 µg of coinjected -MSH significantly attenuated skin fibrosis. Histological analysis, immunohistochemistry, real-time RT-PCR, and pepsin digestion with SDS-PAGE of skin samples revealed that -MSH reduced collagen type I amounts compared with bleomycin-alone injected animals (109). Interestingly, this salutary effect of -MSH was associated with increased in vivo levels of sodium dismutase 2 and heme oxygenase-1 (HO-1), two enzymes involved in oxidative stress defense and tissue protection. In vitro, -MSH at doses of 10^–6 to 10^–10 M reduced bleomycin-induced collagen type I ₁/₂ and type III ₁ synthesis in human dermal fibroblasts and up-regulated the expression of the above enzymes (109). The observed antifibrogenic effects of -MSH are in accordance with our previous findings in which 25 µg of -MSH suppressed cutaneous fibrosis induced by repetitive injections of high amounts of TGF-β₁ in newborn mice (110). It is unknown whether -MSH has a physiological role in collagen metabolism because the doses of the peptide used to induce antifibrogenic effect appear supraphysiological. However, fibroblastic cells of human skin express functional MC-1Rs (50, 110), and in vitro collagen synthesis can be reduced at nanomolar amounts of -MSH (109, 110).

Using another -MSH delivery approach, Lee et al. (111) recently showed that -MSH gene therapy reversed an established liver fibrosis induced in mice by administering carbon tetrachloride for a total of 10 wk. After 6 wk of carbon tetrachloride administration, electroporative gene therapy with -MSH in frame with a four-amino acid extension (ACTH 14–17) was started. -MSH attenuated liver fibrosis and reduced hepatic levels of collagen type I ₁, TGF-β₁, and elevated adhesion molecules. Moreover, -MSH gene therapy led to increased MMP1, -2, and -8 expression and/or activity. Collectively, these findings indicate a novel therapeutic approach to treat fibrotic diseases of man with -MSH and related peptides.

5. -MSH and models of experimentally induced arthritis.
It has been known for some time that -MSH has antiinflammatory effects in experimental arthritis. More than 10 yr ago it was shown that repeated administration of 50 µg of -MSH ip twice daily significantly attenuated the clinical and histological signs of adjuvant-induced arthritis in the rat using Mycobacterium tuberculosis. -MSH was similarly effective as 100 mg/kg prednisolone but did not cause significant and progressive weight loss (112). Currently, collagen-induced experimental arthritis is a more commonly used experimental arthritis model in rats and mice, but we are unaware of any study investigating the effect of melanocortins in such models. However, in a rat model of gouty arthritis elicited by intraarticular administration of monosodium urate monohydrate crystals, the MC-3R antagonist SHU9119 blocked the antiinflammatory action of the -MSH precursor and structurally related peptide ACTH (113). Local, but not systemic, administration of very high amounts of ACTH (100 µg) reduced neutrophil migration, arthritis score, joint size, and cytokine levels at doses that did not alter circulating corticosterone. Moreover, the antiinflammatory effect of ACTH was operational in adrenalectomized rats. The precise mechanism of action of -MSH and the relevance of locally expressed MC-Rs, in particular those expressed in the synovia, remains speculative. The observations on the use of SHU9119 in the gouty arthritis model and the presence of functional MC-3Rs on rat knee joint macrophages may suggest an antiinflammatory action of ACTH (and possibly other melanocortins) at the locoregional level.

6. -MSH and experimental ocular inflammation.
One of the most commonly used animal models for human autoimmune inflammatory eye diseases such as a uveitis or retinitis is experimental autoimmune uveitis. Here, uveitis is induced by immunizing mice with human interphotoreceptor retinoid binding protein peptide emulsified with Freund's adjuvant and M. tuberculosis antigen. -MSH (50 µg) given iv 10 and 12 d after immunization suppressed the mean uveitis scores (114). Similarly, iv application of -MSH (250–1000 µg per injection) dose-dependently reduced endotoxin-induced uveitis as determined by the number of infiltrating cells in the anterior chamber and the amounts of protein, NO, TNF-, IL-6, monocyte chemoattractant protein-1, and macrophage inhibitory protein-2 in the aqueous humor (115). The antiinflammatory mechanism of -MSH in these models appears to be linked to induction of regulatory T cells because adoptively transferred T cells generated by -MSH and TGF-β₂ in vitro suppressed experimental autoimmune uveoretinitis (66). It remains to be determined whether -MSH present in the aqueous humor (31) plays a physiological role as an endogenous immunomodulator because the doses of -MSH used in the above studies were supraphysiological.

In another model of corneal trauma and inflammation, -MSH furthermore turned out to act equipotently with corticosteroids. Treatment with -MSH, either topically (10^–8 M) or im (50 mg/kg·d), markedly reduced edema, hyperemia, aqueous protein levels, and aqueous inflammatory cell number (116). In light of the other biological effects of -MSH (e.g., its antimicrobial action) and the simple route of topical application based on this model, MSH peptides may be exploited in future for the treatment of external eye disease.

7. -MSH in experimentally induced airway inflammation.
-MSH was further shown to inhibit allergic airway inflammation in mice. A well-established murine model to investigate the impact of immunomodulators in allergic asthma is ovalbumin-induced airway inflammation model. Accordingly, airway inflammation is induced by aerosol sensitization of ovalbumin followed by subsequent challenges. Microgram doses of ip injected -MSH reduced peribronchial airway inflammation as measured by cell numbers and distribution of leukocyte subpopulations in BAL fluid and the extent of the peribronchial and perivascular inflammatory cell infiltrate of lung sections (117). Of note, levels of both IL-4 and IL-13, two important proallergic cytokines, were suppressed in BAL of allergic mice treated with -MSH. Interestingly and in accordance with the impact of proinflammatory signals on the POMC system in other tissues, endogenous levels of -MSH were rapidly and strongly induced in BAL fluids after aerosol challenges in nonsensitized mice but not in allergic animals. In accordance with the key role of IL-10 in -MSH-mediated suppression of experimental contact dermatitis, the antiinflammatory action of the peptide in allergic airway inflammation was dependent on the presence of IL-10 because IL-10 knockout mice were resistant to treatment with -MSH (117).

8. -MSH in experimentally induced acute pancreatitis.
Acute pancreatitis is a severe human disorder that can be fatal. Using an animal model for experimentally induced acute pancreatitis, it could be shown that -MSH injected ip (50 µg) attenuated cerulein-induced organ inflammation and damage. Cerulein is a potent stimulant of pancreas exocrine secretion when injected sc into fasted rats. -MSH before injection of cerulein reduced plasma amylase levels, pancreatic weight, and inflammation as demonstrated by measurements of myeloperoxidase (MPO) activity and inflammatory cell infiltrates (118). The precise mechanism by which -MSH attenuates this form of experimental acute pancreatitis is unclear. Exocrine secretory epithelia are known to express the MC-5R. Moreover, it was recently shown that MC-2R is expressed in mouse primary islet tissue and in the MIN6 mouse insulinoma cell line (119). Interestingly, ACTH at nanomolar concentration increased insulin secretion in perfusion experiments with MIN6 pseudo-islets and in monolayer cultures. Using a coculture approach of rat PBMC and pancreas islet cells in a transwell system, it was shown that -MSH (50 nM) reduces PMA/ionomycin-induced IL-1β, TNF-, and NO release by PBMC and subsequently attenuates pancreas islet cell apoptosis (61). Functional studies with MC-R knockout animals and expression analysis in human pancreas tissue are needed to clarify the precise role of MC-Rs in the pancreas physiology.

9. -MSH in experimental liver inflammation and colitis.
Chiao et al. (120) originally demonstrated that acute hepatitis induced by LPS and Corynebacterium parvum pretreatment could be prevented by -MSH when given ip 30 min after LPS administration (120). -MSH suppressed systemic NO production, hepatic neutrophil infiltration, and increased hepatic mRNA levels of TNF- and the chemokines IL-8 and monocyte chemoattractant protein-1 (120). The same authors showed expression of MC-1R suggesting that the immunomodulatory effect of -MSH could be related to direct effects on the liver.

Increasing evidence exists that -MSH has potent antiinflammatory activity in experimentally induced colitis. In a mouse model of dextran sodium sulfate (DSS)-induced colitis, 50 µg of -MSH daily profoundly reduced the appearance of fecal blood, inhibited weight loss, and prevented disintegration of the general condition of the animals (121). In a rat model of trinitrobenzene sulfonic acid-induced colitis, ip injection of -MSH likewise reduced the colonic macroscopic lesions compared with untreated ones in both acute and chronic colitis groups (122). Further studies with pharmacological NO donors and cyclooxygenase inhibitors emphasized the role of reduced levels of NO and PGs as important players in the mechanism of antiinflammation by -MSH (122). A modulatory role for -MSH in the gut is underscored by the suppressing effect of the peptide on IL-6 release in ex vivo samples from patients with celiac disease as outlined above (16). Interestingly, the latter authors detected immunostaining for -MSH, MC-1R, and MC-5R in the duodenal mucosa of celiac patients, suggesting the presence of a localized POMC system in the intestinal mucosa. Recently, definitive evidence was provided for an important role of the MC-1R in the regulation of inflammatory responses of the gut using the DSS model of experimental colitis. Maaser et al. (123) examined the inflammatory intestinal response of mice with a frameshift mutation in the MC-1R gene (MC-1Re/e), C57BL/6 wild-type mice, and MC-1Re/e-C57BL/6 bone marrow chimeras. DSS-induced colitis in MC1Re/e mice was aggravated with higher weight loss, and marked histological changes compared with C57BL/6WT, eventually leading to death of all MC1Re/e mice. Similar observations were made in a transmissible murine colitis model induced by Citrobacter rodentium in which infected MC1Re/e mice showed delayed clearance of infection. Aggravation of intestinal inflammation in MC1Re/e mice was not due to lack of hematopoietic cells expressing MC-1R because the course of colitis was similar between MC1Re/e-C57BL/6 bone marrow chimeras and MC1Re/e mice (123). Moreover, the authors could also identify MC-1R expression in murine intestinal epithelia supporting the view that MC-1R may be an important regulator of the mucosal innate host defense (Fig. 2).

View larger version (40K): [in this window] [in a new window]   FIG. 2. Hypothetic role of the melanocortin system in intestinal inflammation. In response to a proinflammatory signal, e.g., bacterial infection, NF-B expression in intestinal epithelial cells is up-regulated leading to an increased expression and release of proinflammatory cytokines such as IL-8 into the basolateral compartment. The increased IL-8 gradient then leads to an enhanced recruitment of neutrophils to the site of inflammation. At the same time, these cells as well as intestinal epithelial cells release -MSH, which binds in an autocrine as well as paracrine fashion to its cognate receptor, MC-1R, with the effect of NF-B down-regulation. This leads to a reduction of proinflammatory cytokine expression and recruitment of leukocytes from the circulating pool of cells.

View this table: [in this window] [in a new window]   TABLE 4. Cytoprotective effects of -MSH in vitro

1. -MSH protects against neuronal cell toxicity.

2. -MSH—a suppressor of apoptosis in nonneuronal cells.
One of the earliest reports definitely linking the protective effect of -MSH with inhibition of apoptosis was the work by Jo et al. (133). Using cyclosporine A as an in vitro model substance to study nephrotoxicity, it was shown that this drug induces expression of the Fas/Fas ligand system in human kidney-2 cells, an immortalized proximal tubular epithelial cell line. One micromole of -MSH reduced cyclosporine A-induced apoptosis and also attenuated the enhanced levels of Fas, Fas ligand, and the Fas-associated protein with death domain.

Recently, our group demonstrated that apoptosis induced by UVB irradiation, the most ubiquitous environmental stressor for the skin, is significantly suppressed by -MSH in a number of cutaneous cell types (134). This antiapoptotic effect of -MSH can be elicited by nanomolar to micromolar doses of the peptide in melanocytes (134, 135) and is linked to reduced amounts of DNA photoproducts, i.e., cyclopyrimidine dimers. Because XPA fibroblasts carrying a gross defect in the nucleotide excision repair do not respond to -MSH with inhibition of UVB-induced apoptosis (134), these data point toward a modulatory effect of -MSH in the DNA repair machinery that is currently under investigation in our laboratory. In light of the discovered protective effect of -MSH on UVB-induced genotoxic stress tetrapeptide, -MSH analogs have been suggested as a novel melanoma preventive strategy (136). Ac-His-D-Phe-Arg-Trp-NH₂, n-pentadecanoyl- and 4-phenylbutyryl-His-D-Phe-Arg-Trp-NH₂ were assessed for their in vitro capacity to stimulate tyrosinase (thus increasing melanogenesis), to reduce UVB-induced apoptosis and release of H₂O₂, and to enhance removal of cyclopyrimidine dimers after UVB exposure. The latter two peptides were more potent than the former or -MSH at 1 nM, and their action could readily be reversed by agouti signaling protein, the physiological antagonist of MC-1R (136).

In accordance with the inhibitory effect of -MSH on UVB-induced apoptosis, it was further shown that the peptide can suppress UVB-induced H₂0₂-, TNF--, and IL-1β-induced cell death (135, 137). These findings create a link between the identified cytoprotective effects of -MSH and the deleterious or cytotoxic effects of proinflammatory cytokines or reactive oxygen species released during inflammatory responses.

D. Protective effects against organ damage
Numerous studies have provided ample evidence for a significant in vivo activity of -MSH and related peptides in various animal models of organ injury and damage (Table 5). In several cases it has become apparent that this protective activity of -MSH is linked to its antiinflammatory action and to common molecular effector pathways, e.g., modulation of NF-B activity. The following section therefore describes in brief the spectrum of -MSH as a protective peptide in vivo with focus on the more recent literature. It should be noted that coverage of the full literature on the protective in vivo effects of melanocortins is beyond the intention of this review. The interested reader is therefore referred to other expert reviews covering specific topics in this broad field (124, 125, 126, 127, 128, 129, 138).

View this table: [in this window] [in a new window]   TABLE 5. Protective effects of -MSH in vivo1

1. -MSH and postlesional repair.

2. -MSH in drug-induced neuro- and ototoxicity.
Like the ACTH-related peptide ORG 2766 (128), -MSH was evaluated for its protective in vivo effect against cisplatin-induced ototoxicity (128, 145, 146, 147). These studies were performed in light of the need for neuroprotective strategies in cancer patients in which cisplatin can lead to severe neuro- and ototoxicity as a limiting side effect. Initial studies with -MSH were uncertain toward a clear-cut protective effect in systemically cisplatin-treated albino guinea pigs due to the existence of responders and nonresponders and also because of a high interanimal variability (145). However, subsequent longitudinal studies with intracochlear administration revealed that sc daily bolus injections of -MSH (75 µg/kg) delay the threshold shift induced by cisplatin (146). In another study using chronically implanted round window electrodes, -MSH was superior to ORG 2766 in the speed and extent of the recovery of the auditory nerve compound action potential threshold (147). Recently, the effect of -MSH was assessed in kainic acid-induced excitotoxicity of the rat representing a model for human temporal lobe epilepsy. Interestingly, the number of viable neurons in the hippocampus and hypothalamus was increased in animals receiving three treatments of -MSH (0.5 mg/kg body weight) after kainic acid administration (148). Moreover, -MSH reduced kainic acid-induced astrocyte excitotoxicity and reduced elevated IL-1β levels in this study. These data are interesting and create a link between epileptogenesis, inflammation, and the neuroprotection by -MSH.

3. -MSH in experimental ischemia.
An increasing number of reports highlight an intriguing protective property of -MSH (and related peptides) in ischemic organ damage. Using brain stem auditory-evoked potential as a first readout for CNS damage, -MSH (1 mg/kg) was shown to improve the recovery of these potentials especially when coadministered before and during the 20-min ischemia (149). Subsequent studies addressing the effect of -MSH on postischemic activation of proinflammatory cytokines demonstrated that the peptide (0.5 mg/kg) given before the start of the ischemia and again 1 h after reperfusion significantly suppressed elevated TNF- levels in the cerebrocortical territory of the middle cerebral artery after transient unilateral occlusion (150). The same authors could show that -MSH likewise suppressed intracerebral TNF- protein after transient global ischemia. Therefore, not only the effect of -MSH on core and brain temperature (151) but also reduced cerebral levels of proinflammatory cytokines appear to be involved in the protective mechanism of -MSH in ischemic brain damage (152). Using NDP-MSH as a related melanocortin peptide, these neuroprotective effects in ischemic brain damage of -MSH could be confirmed in focal cerebral ischemia induced by the vasoconstrictor endothelin-1 in the rat (153) and in global cerebral ischemia in the gerbil (154). Remarkably, in the latter two studies NDP-MSH was effective upon delayed systemic delivery (3 or 9 h after endothelin-1 injection) and induced long-lasting protection (until 67 d after ischemia). Interestingly, the protective effect of NDP-MSH on ischemia-induced inflammatory, apoptotic pathways and hippocampus injury in gerbils could be prevented by HS024, indicating a promising clinical potential of MC-4R agonists as a future therapeutic approach in ischemic stroke (138, 155)

As an extension to the above findings, -MSH was shown to protect against ischemic heart injury as demonstrated in rats sc injected with 40–400 µg/kg of the peptide followed by isolation of hearts 12 h later, perfusion, ischemia for 30 min, and 120-min reperfusion (156). All doses of -MSH reduced infarct size, whereas only at 200 µg/kg of -MSH were coronary flow, aortic flow, and left ventricular developed pressure significantly increased compared with non--MSH-treated animals. These findings are in accordance with earlier findings that revealed beneficial effects of -MSH as well as of ACTH peptides on cardiovascular function and survival (157). Pharmacological blockade experiments using synthetic MC-3R agonists (158), the MC-4R antagonist HS059, and the MC-3R/MC-4R antagonist SHU 9119 (159) indicate that MC-3R mediates the protective effect of -MSH or ACTH (1–24) on myocardial ischemia/reperfusion damage and arrhythmia. These data suggest a potential for MC-3R agonists in the treatment of myocardial infarction. Whether -MSH exerts a physiological or pathophysiological role in myocardial function in man, however, remains unclear. Recently, elevated levels of circulating -MSH have been detected in patients with congestive heart failure New York Heart Association class II, suggesting at least a participation of melanocortins in distinct forms of human heart disease (160).

In at least two other organ systems, -MSH was examined as a protective agent upon ischemia. Given either 30 min before or even 1–2 h after mesenteric ischemia, the peptide (50–100 µg) had salutary effects on intestinal damage, inflammation, and NF-B activation (161, 162). The delayed administration of -MSH, moreover, not only decreased ischemia-induced IL-6 tissue levels but also enhanced expression of HO-1, a guardian of tissue injury (163). The latter observation is in accordance with our data on the up-regulating effect of -MSH on HO-1 in bleomycin-induced skin fibrosis (109). With regard to the kidney, Chiao et al. (164) were the first to report on a protective effect of -MSH in renal damage. Again, not only 25 µg of -MSH during renal ischemia (followed by multiple bolus injections of the peptide after ischemia) but also delaying administration for 6 h reduced ischemia-induced renal dysfunction, reduced tubule necrosis and inflammation, and attenuated ischemia-induced expression of KC/IL-8, ICAM-1 and iNOS (164). Interestingly, the protective effect of -MSH was preserved in ICAM-1 knockout mice, indicating that -MSH protects against ischemia-induced renal damage by neutrophil-independent mechanisms (39). Because -MSH attenuates NO production in activated murine cortical tubule cells, a direct protective effect of -MSH on the kidney parenchyma is likely. This concept is supported by the regulatory effects of -MSH on expression of Fas and Fas ligand (FasL) in ischemic kidney (165). Another interesting observation with regard to the possible mechanism of -MSH against ischemic kidney damage is its up-regulatory effect on the ischemia-induced repression of aquaporin (AQP) 1 and 2 as well as on the sodium transporters Na, K-ATPase, and rat type 1 bumetamide-sensitive Na-K-2Cl cotransporter (166, 167). It will be very interesting to further decipher the exact protective mechanism of -MSH in ischemic kidney injury and to clarify which MC-R subtype in the kidney is involved in this phenomenon.

4. -MSH in experimental nephrotoxicity.
Two other reports further point toward a protective activity of -MSH in the kidney. Using a model of chronic cyclosporine-induced nephropathy, it could be shown that daily ip injection of 50 µg of -MSH reduces apoptosis in the tubules and the interstitium and attenuates tubulointerstitial fibrosis after 48 d of cyclosporine treatment (168). Moreover, -MSH attenuated the cyclosporine-induced expression of the proapoptotic regulator Bax, increased the expression of the antiapoptotic Bcl₂, and reduced TGF-β in the kidney. However, -MSH in this model failed to improve renal function parameters. In another model of drug-induced nephrotoxicity, gentamycin was administered for 7 consecutive days. -MSH (25 µg) was administered daily into the peritoneal cavity. Although -MSH reduced the severity of renal damage as determined by histology, MPO activity, and concentration of renal glutathione levels, it again failed to improve renal functional parameters (169).

5. -MSH and experimental ureteral obstruction.
Recently, -MSH was tested in an animal model for obstructive nephropathy. Using a bilateral ureteral obstruction model, Li et al. (170) showed that iv administration of 50 µg of -MSH (at the onset and 12 h after the obstruction) almost completely prevented the decrease in glomerular filtration rate and strongly reduced tubular cell apoptosis. Analogous with the protective effects of -MSH in renal ischemia, the peptide partially restored the reduced expression of AQP1 and Na-K-ATPase expression.

6. -MSH and experimental acute lung injury.
Finally, there is evidence that melanocortin peptides protect against acute lung injury. Using the renal ischemia-reperfusion model of the mouse, it was demonstrated that iv -MSH (25 µg) not only attenuated NF-B and p38 activation, as well as DNA binding of activator protein 1 (AP1) in the kidney, but also had similar distant protective effects, namely in the lung (171). Most recently, Catania and co-workers (172) further investigated the effect of NDP-MSH in rats exposed to bleomycin instilled into the lungs. Intraperitoneal injection of 100 µg of NDP-MSH reduced bleomycin-induced acute lung injury as determined 8 and 24 h after treatment by reduced interstitial pulmonary edema, less inflammatory cell infiltration, and thinner alveolar walls. NPD-MSH not only attenuated bleomycin-induced IL-6, TNF-, and TGF-β₁ expression but also prevented the up-regulation of genes involved in lung fluid homeostasis, e.g., Na⁺/K⁺-transporting ATPase or epithelial sodium channels. Interestingly, bleomycin treatment resulted in endogenous induction of -MSH in the lung, presumably by monocytes or macrophages (172). These data point toward a clinical potential of -MSH and related peptides in various forms of inflammatory lung disease.

	IV. Antiinflammatory Effects of -MSH-Related Tripeptides in Vitro and in Vivo

Top Abstract I. Introduction II. Biochemistry of {alpha}-MSH... III. Antiinflammatory and... IV. Antiinflammatory Effects of... V. Therapeutic Potential of... References

 
There is clear evidence that KPV has potent antiinflammatory actions in vitro and in vivo although the exact mechanism by which these peptides exert their effects is still poorly understood. Until now most of the studies addressing the antiinflammatory effect of C-terminal tripeptides of -MSH have been performed in vitro and mainly concentrated on the L-form of KPV, leaving it open as to whether other stereoisomers are also effective (Table 6). KPV was shown to reduce production of TNF-, IL-6, and NO induced by proinflammatory stressors (29, 34, 36). Suppression of NO production by RAW 264.7 cells was similarly as effective as full-length -MSH, whereas cyclic KPV derivatives were weaker in their antiinflammatory activity (173). Similar to -MSH, KPV reduced activation of NF-B in human keratinocytes and monocytic cells (72, 174). In the former cell type, KPdV was similarly as effective as KPV in inhibition of TNF--induced NF-B activation. Pharmacological studies in human keratinocytes interestingly revealed an unusual dose-response curve of KPV that extends over six orders of magnitude of dose and which cannot be explained by a simple peptide-receptor interaction (72). Interestingly, the stereoisomer of KPV, KdPV, which previously was shown to lack antipyretic activity in vivo (175), was able to suppress LPS-induced NF-B activation in rat alveolar cells (176). Finally, KPV and KdPV were shown to induce IL-10 in human monocytes at 10^–13 M, albeit to a lesser extent than equimolar amounts of -MSH (45). However, some modulatory effects of -MSH may not be replicated by KPV. We could not detect any cytoprotective effect of KPV on UVB-induced apoptosis in normal human melanocytes (134), suggesting cell type specificity and/or an indispensable role for MC-1R in the modulatory effect of -MSH in this action of the parental neuropeptide. Recent observations from our laboratory further indicate that the structurally related tripeptide KdPT is also capable of suppressing IL-1-mediated inflammatory effects, e.g., IL-1β-induced, but not TNF--induced, NF-B activation and IL-6 and IL-8 expression in human sebocytes at nano- and subnanomolar doses (177).

View this table: [in this window] [in a new window]   TABLE 6. Antiinflammatory effects of -MSH tripeptide analogs and derivatives in vitro

View this table: [in this window] [in a new window]   TABLE 7. Antiinflammatory effects of -MSH tripeptide analogs and derivatives in vivo

	V. Therapeutic Potential of -MSH-Related Tripeptides in Human Immune-Mediated Inflammatory Diseases

Top Abstract I. Introduction II. Biochemistry of {alpha}-MSH... III. Antiinflammatory and... IV. Antiinflammatory Effects of... V. Therapeutic Potential of... References

 
KPV, its stereoisomers, and KdPT are attractive future candidates for pharmaceutical companies that wish to exploit these peptides for the treatment of human immune-mediated inflammatory diseases. At present, evidence exists for the antiinflammatory effects of KPV (Tables 6 and 7), but compared with what is known about -MSH (Tables 2 and 3), more studies are urgently needed for KPV, its stereoisomers, and especially for the -MSH tripeptide derivative KdPT.

The molecular effects underlying the antiinflammatory activity of KPV that have been identified so far are very similar to -MSH and include major effector pathways of inflammation, i.e., suppression of TNF- production, induction of IL-10, and inhibition of NF-B activation. In many immune-mediated inflammatory diseases including inflammatory bowel disease, rheumatoid arthritis, eczema, or allergic asthma, these effector pathways of inflammation are crucially involved in their pathogenesis. Accordingly, antiinflammatory strategies with the so-called "biologics" that target specifically the above effector pathways, e.g., anti-TNF- therapy, have successfully emerged as novel and powerful treatment avenues for such diseases (185). Based on the homology of KPV with -MSH and the homology of KdPT with IL-1β^[193–195], it would only be justified to call these peptides "natural biologics" when used in the future for the treatment of immune-mediated inflammatory diseases.

At present, no toxicity studies of KPV and KPT are available, and thus we do not know the overall safety profile of such tripeptides compared with the melanotropic superpotent -MSH analog NDP-MSH. Previously, NDP-MSH at doses of up to 0.16 mg/kg was injected into humans iv for evaluation of its effect on skin pigmentation. Adverse effects consisted of occasional gastrointestinal upset and facial flushing (186). Several recent studies investigating the in vivo effect of NDP-MSH in humans for pigmentation confirmed no major adverse effects (187, 188, 189). In light of the well-known spectrum of adverse effects encountered with almost all conventional immunosuppressive therapies (e.g., azathioprine, methotrexate, mycophonolate mofetil, cyclosporine, and cyclophosphamide) but also with biologics, the safety profile of -MSH and related tripeptides therefore appears to be high.

Regarding the future safety profile of -MSH and related peptides in man, another biological property of these agents deserves some attention: -MSH and KPV were recently shown to possess antimicrobial activity against Staphylococcus aureus and Candida albicans, two major and representative pathogens (190). This antimicrobial activity of -MSH peptides is linked to an increase in bacterial cAMP content. Moreover, -MSH peptides increased in vitro killing of both pathogens by human neutrophils. The direct and indirect antimicrobial actions of MSH peptides are in marked contrast to virtually all established antiinflammatory and immunosuppressive agents that typically increase the risk for infection during prolonged treatment. It will be interesting to investigate whether the KPV-related KdPT tripeptide has similar antimicrobial actions as -MSH and KPV.

A major advantage of KPV and its stereoisomers appears to be the lack of any melanotropic effect based on the required central message sequence of -MSH to elicit such an effect (8). We are currently unaware of any studies evaluating the effect of KdPT on melanogenesis, but it is unlikely that this peptide has a strong impact on pigmentation.

A definitive future task will also be the design of the most successful routes of administration of -MSH and related tripeptides depending on the targeted immune-mediated inflammatory disease. The half-life of iv administered full-length -MSH is only a few minutes, and thus the duration of the antipyretic effect of -MSH is 1.5 h at most (191). This is probably due to the presence of several serum proteases including aminopeptidase, angiotensin-converting enzyme, prolyl endopeptidase, -chymotrypsin, trypsin, and neutral endopeptidase 24.11 (192, 193, 194, 195, 196). Neutral endopeptidase 24.11 is also expressed by many cell types on the cell surface, thereby directly limiting the biological effects of full-length -MSH at a cellular level (65, 196). Indeed, attempts have been successful to create protease-stable -MSH analogs such as NDP-MSH but with increased potency on pigmentation, while interestingly lacking a definitive effect on experimental fever when injected iv (43). To the best of our knowledge, no data exist on the precise pharmacokinetics of KPV and related tripeptides in blood, and it is even unknown whether such tripeptides are endogenously produced from -MSH, ACTH, POMC, or other precursors. However, it may be speculated that the D-enantiomers of KPV are more stable against peptidase activity than their stereochemical analogs.

On the other hand, the rapid degradation of -MSH in serum may be related to the observed minimal side effects after systemic administration of -MSH analogs in man and will make this peptide and its derived tripeptides especially useful for local delivery in a number of immune-mediated inflammatory diseases. Such diseases include inflammatory skin disorders like eczema, atopic dermatitis, alopecia areata, and several fibrosclerotic disorders (lichen sclerosus, scleroderma, and fibrosing forms of inflammatory alopecia) in which both an antiinflammatory and antifibrogenic effect of a given drug would be embraced. The smaller molecular weight of both KPV and KdPT, below 400 Da compared with -MSH, may here be of particular advantage for the transepithelial delivery of the tripeptides. Disturbance of the skin barrier, as present in atopic eczema, may further enhance the rate of skin absorption of both KPV and KdPT. In other cases, e.g., in the treatment of corneal injury or keratitis, instillations of -MSH and related tripeptides may be possible, whereas in patients with inflammatory bowel diseases creation of slow-release carriers suitable for oral administration of the agents may be desirable. In patients with allergic asthma, aerosolized -MSH or related tripeptides may be envisioned. In patients with inflammatory arthritis, brain inflammation, or uveitis, however, delivery of effective concentrations of -MSH or related tripeptides into inflamed target tissues via nondirect application may be more challenging. As demonstrated already in daily routine practice with pegylated IFNs or biologics, depot preparations of -MSH or related tripeptides may offer a perspective. Previous in vivo studies in guinea pigs using implants containing 4 mg of NDP-MSH could demonstrate a marked and prolonged melanogenic skin response that lasted for 3 months (25). Promising pharmacokinetic observations have recently been made in human volunteers with depot formulations of NDP-MSH (20 mg) for studies on pigmentation (189). The findings suggest that depot formulation of nonmelanotropic -MSH-related tripeptides is likewise possible.

In summary, -MSH and related tripeptides have been shown to possess promising antiinflammatory effects. Compared with the parental neuropeptide, -MSH-related tripeptides are: 1) small and inexpensive molecules, thus suitable for large-scale pharmaceutical production; 2) expected to have no melanogenic effect; 3) through their combined antiinflammatory and antimicrobial effects, have a lower risk for infection compared with conventional immunosuppressive agents; 4) possibly limited in adverse effects, based on the available toxicity and safety data of systemically administered NDP-MSH; and 5) because of their molecular size, have advantages especially for local therapy of several inflammatory disorders. The authors are thus confident that -MSH-related tripeptides will find their way into clinical practice as novel weapons for the treatment of immune-mediated inflammatory diseases.

	Footnotes

 
Disclosure Statement: C.M. and C.A. have nothing to declare. T.B. and T.A.L. are inventors on antiinflammatory tripeptides (PCT/EP02/01323; Europe, USA, Mexico, Canada; Japan, China, Australia, New Zealand). M.B. is an inventor on antioxidative tripeptides (EP070222401; Europe).

This work was supported by grants from the Deutsche Forschungsgemeinschaff (DFG) to M.B. (BO 1075/5-3) and to C.M. and M.B. (MA 2247/3-1).

First Published Online July 8, 2008

¹ T.B. and M.B. contributed equally to this work.

Abbreviations: AP1, Activator protein 1; AQP, aquaporin; BAL, bronchoalveolar lavage; CNS, central nervous system; DNP, dinitrophenol; DRG, dorsal root ganglia; DSS, dextran sodium sulfate; EAE, experimental autoimmune encephalitis; FasL, Fas ligand; HO-1, heme oxygenase-1; ICAM-1, intercellular adhesion molecule-1; IFN, interferon; IB, inhibitory subunit of NF-B; iNOS, inducible NO synthase; KC, keratinocyte-derived chemokine; MC-R, melanocortin receptor; MMP, matrix metalloproteinase; MPO, myeloperoxidase; MW, molecular weight; NDP-MSH, [Nle4,d-Phe7]-MSH; NF-B, nuclear factor-B; NO, nitric oxide; PBMC, peripheral blood mononuclear cells; PC, prohormone convertase; PG, prostaglandin; POMC, proopiomelanocortin.

Received for publication August 14, 2007. Accepted for publication April 28, 2008.

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Top Abstract I. Introduction II. Biochemistry of {alpha}-MSH... III. Antiinflammatory and... IV. Antiinflammatory Effects of... V. Therapeutic Potential of... References

 

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