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Department of Pathology (A.S.), University of Tennessee, Memphis, Tennessee 38163; and Department of Medicine (J.W.), Southern Illinois University, Springfield, Illinois
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Abstract |
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 Top Abstract I. IntroductionII. Structure of the...III. Skin as a...IV. Skin as a...V. Molecular and Structural...VI. Regulation of Cutaneous...VII. Regulation of Cutaneous...VIII. Final Comments and...References |
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-MSH,
and ß-endorphin. Demonstration of the corresponding receptors in the
same cells suggests para- or autocrine mechanisms of action. These
findings, together with the demonstration of cutaneous production of
numerous other hormones including vitamin D3, PTH-related
protein (PTHrP), catecholamines, and acetylcholine that share
regulation by environmental stressors such as UV light, underlie a role
for these agents in the skin response to stress. The endocrine
mediators with their receptors are organized into dermal and epidermal
units that allow precise control of their activity in a
field-restricted manner. The skin neuroendocrine system communicates
with itself and with the systemic level through humoral and neural
pathways to induce vascular, immune, or pigmentary changes, to directly
buffer noxious agents or neutralize the elicited local reactions.
Therefore, we suggest that the skin neuroendocrine system acts by
preserving and maintaining the skin structural and functional integrity
and, by inference, systemic homeostasis.
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I. Introduction |
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TopAbstractI. IntroductionII. Structure of the...III. Skin as a...IV. Skin as a...V. Molecular and Structural...VI. Regulation of Cutaneous...VII. Regulation of Cutaneous...VIII. Final Comments and...References |
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Over the last decade, it has become increasingly apparent that
the skin, particularly the epidermis, has powerful metabolic and
endocrine capabilities (11, 12). For example, the skin synthesizes
vitamin D, which enters the circulation and, upon activation, exerts
profound metabolic and endocrine effects (13, 14). Resident skin cells
also synthesize and release the hormones parathyroid hormone-related
protein (PTHrP) (15), POMC-derived MSH, ACTH, and ß-endorphin
peptides (5, 16, 17), the CRH and urocortin peptides (18, 19), the
neurotransmitters catecholamines and acetylcholine (20, 21), and
precursors to biogenic amines (9, 21, 22, 23). While production of some of
these factors is not constitutive, it does respond to specific
inductive stimuli. The skin is also a site for activation of steroid
hormones such as the conversion of testosterone to
5-dihydrotestosterone or to estradiol, or the conversion of
T4 to T3 (4, 11, 12). These
locally generated hormones and neurotransmitters can act in a paracrine
or autocrine fashion. Moreover, the presence of numerous nerve endings
and a rich vascular network provide additional mechanisms for the
expression of neuroendocrine functions, e.g., transmission
of regulatory signals to the global or central systems via the vascular
system, or through the afferent neural network.
This emerging concept, of skin as a neuroendocrine organ, is a relatively new addition to the field of cutaneous biology; it combines concepts from immunology, endocrinology, and neurobiology to unravel the multidirectional communications between brain, the endocrine and immune systems, and peripheral organs (24, 25, 26, 27, 28). In this regard, the skin has a unique role because of its location, size, and relative functional diversity. Moreover, cutaneous signals sent to neuroendocrine centers may play modulatory roles, although peripheral intraorgan or intersystemic communications are also necessary to maintain global and local homeostasis.
We will presently review evidence on the production of hormones and neurotransmitters by the skin and on the expression of the corresponding receptors. Cutaneous regulation of neuroendocrine communication will be analyzed and its function discussed within the context of organ homeostasis. Data on the experimental characterization of receptors for neurohormones in skin cells will be reviewed, including regulation of expression, ligand production, and characterization of signal transduction pathways. Pertinent data will be included with the understanding that the mere presence of a substance in a culture system of skin cells does not necessarily imply that the substance has physiological relevance in vivo. Special attention will be given to intraorgan communication and to the potential systemic or central effects of skin-produced factors acting on sensory nerves, or skin-activated circulating cells, or through direct release into the circulation as neurohormones or mediators. This review will end by setting the stage for future basic and clinical research.
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II. Structure of the Skin |
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TopAbstractI. IntroductionII. Structure of the...III. Skin as a...IV. Skin as a...V. Molecular and Structural...VI. Regulation of Cutaneous...VII. Regulation of Cutaneous...VIII. Final Comments and...References |
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type expressed
in mouse epidermis and hair follicle and the sparse, mostly Tß
cells expressed in human epidermis (7). All of the dermal components
are of mesodermal origin, with the exception of nerves and specialized
sensory receptors that develop from the ectoderm (1, 3, 4, 7, 29). The
dermal cellular populations include
fibroblasts/fibrocytes/myofibroblasts, adipocytes,
monocytes/macrophages, mast cells, Langerhans cells, T lymphocytes,
dendrocytes, smooth muscle cells, and vascular and lymphatic
endothelial cells. Fibrocytes arise by differentiation of stellate
mesenchymal cells present in the primordial dermis, whereas adipocytes
differentiate from subdermal mesenchymal cells that surround newly
formed blood vessels. Macrophages, mast cells, Langerhans cells, and
dendrocytes migrate to the skin from the bone marrow. Formation of the adnexal structures results from precise mesenchymal epithelial interactions producing down growth of primordial adnexal structures to reach the reticular dermis and subcutis (1, 3, 4, 29, 30, 31). The multidirectional interaction between cells of ectodermal and mesodermal origin results in a cohesive unified skin structure that, nevertheless, maintains a degree of heterogeneity expressed by marked regional differences (1, 4, 29).
In the context of this review it must be noted that brain, peripheral nervous system, retina, and medulla of adrenal gland are also of ectodermal origin, whereas olfactory epithelium and olfactory nerves, anterior lobe of hypophysis, and epithelial elements of the mammary gland all derive from the outer epithelium (29). Mesodermal structures include the immune system, endothelium of blood vessels, adrenal cortex, and gonadal epithelium and stroma (7, 29). These embryologic associations may determine the potential capability for resident skin cells to produce molecules similar to their close or distant relatives. Thus, cellular lineage may predict neuroendocrine functional activity.
B. Anatomy and histology
The skin is composed of two main compartments: the epidermis with
the adnexal epithelial structures and the dermis with the nonepithelial
elements of adnexa (1, 2, 3, 4). While not a skin component, the subcutaneous
fat is closely related to the skin anatomically and functionally.
Structure and thickness of both epidermis and dermis vary according to
anatomic location; thus, the average thickness of the epidermis is 0.1
mm, but in the acral areas is up to 1.6 mm thick. The latter regions
contain thick cornified and granular layers and numerous eccrine units
and nerve endings but lack folliculosebaceous-apocrine units. In
contrast, facial skin contains numerous vellus follicles with prominent
sebaceous glands; skin in the axilla and groins is characterized by
numerous apocrine glands, back skin has very thick reticular dermis,
and scalp skin contains large terminal hair follicles routed deep into
the subcutaneous fat. In furry animals, terminal hair follicles cover
most of the body, serving as insulating cover and as touch organs
(30, 31, 32).
The basal membrane zone separates the epidermis and epithelial adnexal structures from the dermis. Beneath the basement membrane is a thin zone of adventitial dermis that comprises the papillary dermis, between the epidermal folds and the periadnexal dermis surrounding adnexal structures. The papillary dermis is characterized by thin collagen bundles interspersed with elastic fibers, frequent fibrocytes, abundant matrix, and a rich vascular network composed predominantly of capillaries. The reticular dermis is composed predominantly of thick collagen bundles and elastic fibers and a lower concentration of stromal matrix, with comparatively fewer fibrocytes; there are also blood vessels, and adipocytes that extend upward from the subcutaneous fat.
The skin immune system is composed of resident, recruited, and recirculating cell populations (7). The resident population is constitutively expressed in the skin under physiological conditions. This is represented by keratinocytes, fibroblasts, vascular and lymphatic endothelial cells, mast cells, tissue macrophages (histiocytes), T lymphocytes, and dendritic cells. The recruited population comprises monocytes, basophilic, neutrophilic, and eosinophilic granulocytes, as well as mast cells and T and B lymphocytes. The recirculating cell population is represented by dendritic cells, natural killer cells, and T lymphocytes. Recruited or recirculating cells reach the skin via circulation.
The vasculature is arranged into a superficial (subpapillary) plexus, located in the upper reticular dermis, and a deep plexus positioned in the lower reticular dermis (1, 2, 3, 4). These plexuses are connected by communicating blood vessels, which are most numerous in the upper dermis and around folliculosebaceous and eccrine units. The vascular network provides rich capillary supply for the dermal papillae and periadnexal dermis. A lymphatic network accompanies the vascular bed, although it is a functionally separate entity.
The skin contains an extensive neural network represented by cholinergic and adrenergic nerves and by myelinated and unmyelinated sensory fibers (1, 3, 4, 33, 34). The autonomic nerves supply arterioles, glomus bodies, hair erector muscles, and apocrine and eccrine glands. The terminal endings of sensory fibers are either surrounded by histologically distinctive structures, such as Pacini and Meissner’s corpuscles, Ruffini organs, Merkel disks, and mucocutaneous end organs, or supply directly individual Merkel cells. A rich network of free sensory endings surround and penetrate hair follicles, pilosebaceous units, eccrine and apocrine glands, papillary dermis, and epidermis. The sensory and autonomic networks do show regional differences according to anatomic sites and also have topographical specificity by distributing into well defined areas called dermatomes. The torso, extremities, posterior scalp, and neck are supplied by sensory nerves arising from dorsal root ganglia of the spinal cord, whereas face, most of the scalp, and upper anterior neck are innervated by trigeminal nerve branches.
C. Physiology (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 30, 31, 32, 33, 34, 35)
The most important function of the skin, determined by its
location at the interface between external and internal environments,
is that of physical barrier. This is established in the epidermis by a
precisely regulated gradient of keratinocyte differentiation stages,
which forms a highly impermeable protein-lipid layer at the outer-most
segment. This layer prevents the destruction of living keratinocytes by
environmental factors and reduces or minimizes water evaporation,
maintaining a liquid environment to preserve skin structural integrity
in the face of frequent mechanical trauma. The epidermal pigmentary
system protects the skin against the damaging effect of solar radiation
in humans and, in conjunction with the follicular pigmentary system,
determines hair and skin color that play an important role in social
communication and camouflage in many mammalian species. The epidermal
and dermal immune elements provide defense against biological insults,
and they are also involved in the integration of the response to
foreign and self-antigens through interactions with the central immune
system. Immune responses are involved in the reaction to viral or
microbial infections, or to cancer development; dysregulated immune
responses may be pathogenic in autoimmune diseases.
The adnexal organs are epidermally derived structures that extend into dermis and subcutis. Their functional role is pleiotropic by participating in the formation of hair shafts from hair follicle, serving protective, thermoregulatory, and sensory (touch) functions, as well as being involved in social communication. The secretion of eccrine, apocrine, and sebaceous glands is important for thermoregulation, for preservation of the integrity of the physical barrier, for regulation of electrolyte balance, and for secretion of the pheromones and odorant-affecting behavior. The dermis, in addition to its structural role, is involved in mechanical protection and thermoregulation via its rich vascular network. The skin also provides the sensory reception for touch, pressure, vibration, temperature, pain, and pleasure through a neural network comprised of specialized receptors and free nerve endings. Finally, the skin, as a regulator of metabolism, transforms various hormones and can also inactivate potentially harmful substances of exogenous or endogenous origin.
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III. Skin as a Target for Neuroendocrine Signals |
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.
Clinical observations made in diverse endocrine disorders associated
with cutaneous changes also confirm that the skin is a target for
hormones, neurohormones, and neurotransmitters (3, 4, 5, 6, 12, 16, 17, 18, 19, 20, 21, 35, 36, 37, 38). That the skin is also a target of neural responses is
supported by studies showing neural contributions to the etiology and
clinical manifestations of inflammatory skin diseases and vitiligo
(3, 4, 33, 34, 38, 39).
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CRH and urocortin have a recognized role in skin pathophysiology through their actions on the skin immune system (5, 40, 48, 55, 56, 57, 58, 59). Thus, in the periphery, CRH can act as a proinflammatory agent (48, 55, 56) and, together with urocortin, induces degranulation of mast cells (48, 57). However, antiinflammatory effects have been also demonstrated in models of tissue injury, e.g., in thermally injured skin where local injection of CRH has an antiedema effect independent of hypothalamus-pituitary-adrenal (HPA) axis function, and in doxorubicin-induced eye lid inflammation that is reduced in severity by pretreatment of the eyelid with CRH (58, 59, 60). In addition, CRH has antinociceptive activity and accelerates wound healing (58, 59, 60). CRH and urocortin also inhibit proliferation of keratinocytes (51) and either stimulate or inhibit melanoma cell proliferation depending on culture conditions (Refs. 46, 49 and A. Slominski and B. Zbytek, unpublished data).
B. Melanocortin receptors (MC-R)
The membrane-bound G protein-coupled melanocortin receptors of
type 1, 2, and 5 (MC1-R, MC2-R, MC5-R) have been identified in the skin
(5, 8, 17, 61, 62, 63, 64, 65, 66, 67, 68, 69). MC1-R was detected in melanocytes, keratinocytes,
sebocytes, fibroblasts, endothelial cells, Langerhans cells, and dermal
immune cells, while MC5-R was detected in the epithelial cells of
eccrine, apocrine, and sebaceous glands (5, 8, 17, 61, 62, 63, 64). Although
expression of the MC2-R gene has been detected in human and mouse skin
(65, 66), precise cell compartment(s) assignment will require further
testing; possible expression sites include adipocytes, keratinocytes,
and melanocytes (63, 64, 65, 66). The MC receptors are activated by ACTH, and
by -, ß- and -MSH; ligand affinity varies according to
receptor type and mammalian species (5, 8, 17, 61, 70). Signal
transduction through MC1-R, MC2-R, and MC5-R has been linked to
activation of adenylate cyclase (5, 8, 17, 61, 67, 68, 69).
The best recognized phenotypic effect of the POMCderived ACTH and
MSH peptides is the stimulation of melanogenesis and its switching from
pheo- to eumelanogenesis (5, 8, 16, 17, 61, 67, 68, 69, 70, 71, 72), which can also be
documented clinically (3, 4, 5, 8, 67, 72). There is a general agreement
that ACTH, -MSH, and ß-MSH have the strongest melanogenic activity
(8, 16, 67, 68, 69). -MSH peptides have low intrinsic melanogenic
activity in human normal melanocytes and rodent malignant melanocytes
(70, 71), similar to findings in frog and lizard melanophores (8, 67, 68, 73). However, it is possible that selected -MSH peptides such as
2 and 3 could still modulate pigmentation indirectly, modifying
cellular responses to the other melanotropins (71). Studies in cultured
normal and malignant melanocytes show that MSH and ACTH, acting via
cAMP-dependent pathways (5, 8, 16, 17, 61, 67, 68, 69, 72, 74, 75, 76, 77, 78, 79),
stimulate the expression and activity of enzymatic, structural, and
regulatory proteins involved in melanogenesis (5, 8, 67, 68, 69). Depending
on species and cellular genotype, MSH and ACTH can inhibit or stimulate
proliferation of malignant melanocytes (8, 67, 68, 69, 72, 74, 75, 76, 77, 78).
However, most authors agree that in normal human melanocytes, ACTH and
MSH act as stimulators of cell proliferation (8, 69, 79), dendrite
production (5, 8, 67, 68, 69, 74), and melanocyte migration (8) and
decrease expression of intercellular adhesion molecule-1 (ICAM-1) (80).
Epidermal, adnexal, vascular, and dermal structures represent
additional targets for POMC peptides (5, 17, 35, 61, 62, 63, 64). Thus, -MSH
can modify proliferation and differentiation of keratinocytes as well
as their immune activity and regulate activity of dermal fibroblast (5, 17, 64, 81, 82). In endothelial cells, -MSH may play a crucial role
decreasing their adherence and the transmigration of inflammatory
cells, a prerequisite step for immune and inflammatory reactions.
-MSH and ACTH have strong immunomodulating activity in the skin that
results in an overall immunosuppressive effect (5, 17, 64, 82). For
example, -MSH acts as antagonist to interleukin-1 (IL-1) suppressing
production of proinflammatory cytokines while it induces production of
the immunosuppressive cytokine IL-10. -MSH is also capable of
suppressing accessory molecule expression on antigen-presenting cells
and may thereby serve as one of the signals responsible for anergy or
tolerance induction (17, 64, 82).
In addition to the regulation of hair pigmentation, -MSH and ACTH
have other actions on adnexal structures (5, 17, 35, 62, 83, 84). For
example, in mink and mice, ACTH acts as inducer of anagen development
(85, 86), whereas in mouse anagen skin it induces premature onset of
catagen (83). ACTH and -MSH also influence sebaceous gland function
(35, 84): -MSH specifically stimulates sebum secretion and
lipogenesis in cutaneous sebaceous glands, enhancing wax and sterol
ester biosynthesis, and stimulating production and release of female
sex attractant odors and of male aggression-promoting pheromones (by
specialized preputial glands) (35). -MSH and perhaps ACTH may be
important in overall rodent skin thermoregulation, by preventing
overwetting of hairs, and in behavior regulation through its action on
nonspecialized and specialized sebaceous glands (35, 84). It is likely
that MSH and ACTH peptides also affect function of human sebaceous
glands.
C. Opioid receptors
µ-Opioid receptors, which bind with high-affinity
ßendorphin, were detected in cultured human epidermal
keratinocytes (87). Further investigations using in situ
hybridization and immunocytochemistry on skin biopsy specimens showed
that the receptors are localized to keratinocytes in the epidermis and
outer root sheath of the hair follicles, to the peripheral epithelial
cells in sebaceous glands, and to the secretory component in sweat
glands (87). The related 
opioid receptor that binds enkephalins
with high affinity has also been detected in human and mouse epidermal
keratinocytes (88). Met-enkephalin has been shown to inhibit
proliferation of mouse epidermal keratinocytes in vivo, in a
circadian pattern (88), and both met- and leu-enkephalins can inhibit
differentiation of human keratinocytes in vitro (89). In
addition, ß-endorphin and enkephalins have antinociceptive and
immunomodulatory properties (7, 24, 25, 27, 28).
D. GH receptor (GH-R)
The GH-R has been detected in human and rodent skin in epidermis,
hair follicle, eccrine glands, dermal fibroblasts, adipocytes, and in
Schwann and muscle cells (90, 91, 92, 93). Transcription of the GH-R gene has
also been detected in cultured human melanocytes (91). These findings
suggest that epidermal, adnexal, and dermal cell populations can be
direct targets for GH. For example, GH can stimulate differentiation of
rat sebocytes and modify melanocyte proliferation (94, 95). However,
the phenotypic effects could also arise from an indirect effect such as
the stimulation of cutaneous cells to produce insulin growth factor-1
(IGF-1).
The cutaneous phenotypic effects of GH have been thoroughly described in patients with acromegaly, whose skin thickness increases considerably and acquires a doughy texture (1, 2, 3, 36, 37, 68). This effect is accompanied by increased fibroblasts activity and dermal glycosaminoglycans deposition that promotes water retention (96). Additional cutaneous signs of acromegaly are acanthosis nigricans, hypertrichosis with exception of the beard region, hyperpigmentation, eccrine and apocrine hyperhidrosis, increased sebum secretion, growth of pedunculated fibromas, and thickening and hardening of the nails (1, 2, 3, 36, 37, 68). Transgenic mice overexpresssing GH show skin overgrowth with increased dermal thickness, significant dermal fibrosis, and replacement of subcutaneous adipose tissue by fibrous tissue (97).
E. PRL and LH/CG receptors (LH/CG-R)
Receptors for the pituitary hormones PRL, LH, and human CG (hCG)
are also expressed in the skin (98, 99, 100, 101, 102, 103). PRL receptors have been
localized in rat epidermal and follicular keratinocytes by in
situ hybridization (98) and in ovine dermal papilla fibroblasts
and follicular keratinocytes with a radioligand binding assay (99). PRL
binding sites exhibiting high affinity for the ligand were identified
in membrane preparation from mink skin; the highest concentration of
binding sites was found during the winter fur growth cycle (100). PRL
stimulation of cultured human keratinocytes proliferation has been
linked to the expression of high-affinity PRL binding sites on the cell
surface (101). PRL can directly and indirectly modulate the hair
growth, shedding, and molting cycle of furry animals, whereas in humans
hyperprolactinemia has been associated with hirsutism (3, 31, 104, 105, 106). It has also been proposed that PRL participates in the
regulation of sebaceous gland activity, since acne vulgaris can be
associated with idiopathic hyperprolactinemia in the absence of altered
androgen concentrations (3, 106). PRL has potent immunomodulatory
properties (107), suggesting that it can also regulate functions in the
skin immune system.
Normal human skin also contains the mRNAs for the LH/CG-R and a 66-kDa protein capable of binding 125I-hCG (102). These receptors were detected in the epidermis, inner and outer root sheaths of the anagen hair follicle, sebaceous glands, and eccrine glands (103). Testing for expression of FSH receptors in normal human skin found it to be below the level of detectability (103).
F. Neurokinin receptors (NK-R)
Expression of the G protein-coupled neurokinin receptors NK-1R,
NK-2R, and NK-3R has been reported in human and rodent skin (38, 108);
however, others have detected only NK1-R in extracts from human skin
(109). Either substance P (SP) or neurokinins A and B (NKA and NKB)
could activate these receptors, through signal transduction pathways
involving adenylate cyclase and phospholipases C and A2 (33, 34, 38).
Human and rodent keratinocytes and endothelial cells express NK-1R to
NK-3R, and mast cells, fibroblasts, and Langerhans cells express NK-1R
(38). Activation of these receptors stimulates proliferation of
keratinocytes, fibroblasts, and endothelial cells and
neovascularization (4, 7, 33, 34, 38, 108, 109, 110, 111, 112, 113). NKA and SP stimulate
mast cells release of histamine and tumor necrosis factor- (TNF),
and keratinocyte and endothelial cell function with production and
release of proinflammatory cytokines, and expression of adhesion
molecules (7, 33, 34, 38, 108, 109, 110, 111, 112, 113, 114, 115). SP stimulates hair growth in
rodents (116).
G. Calcitonin gene-related peptide receptor (CGRP-R)
There is functional evidence that the G protein-coupled receptor
CGRP-R is expressed in skin cells (3, 4, 7, 33, 38, 108, 110, 111, 112, 113, 114, 117, 118, 119, 120). CGRP is a potent vasodilator of small and large vessels, at
least partly through direct activation of arteriolar smooth muscle cell
receptors. CGRP also increases vascular permeability, producing dermal
edema through indirect activation of mast cells or through stimulation
of nitric oxide (NO) production by endothelial cells with consequent
vasodilatation (4, 33, 38, 108, 114). CGRP stimulates endothelial cell,
keratinocyte, and melanocyte proliferation (117, 119). Stimulation of
keratinocyte proliferation has been linked to direct activation of
adenylyl cyclase activity (117), and CGRP induces keratinocyte
production and release of promelanogenic factors (120). CGRP modifies
the activity of the skin immune system (7, 38, 110, 111, 112, 113, 114, 118).
H. Vasoactive intestinal peptide receptor (VIP-R)
VIP-Rs are present in skin, and their activity is linked to G
protein-coupled stimulation of adenylyl cyclase activity with cAMP
production (3, 4, 7, 33, 38, 108, 110, 111, 112, 113, 117, 118). VIP biding sites
have been characterized in malignant human melanocytes (121), where VIP
stimulates cAMP production (122).VIP also stimulates keratinocyte
proliferation and sweat production (4, 38, 117). Peptide
histidine-methionine (PHM) and GH releasing factor (GFR) have
stimulatory effects on keratinocyte cAMP production and cell
proliferation, thought to be mediated through the VIP-R (38, 117).
Indirectly, VIP also participates in the wheal and flare reaction
through the activation of mast cells histamine release, or through
NO-induced vasodilatation (3, 4, 7, 33, 38, 108, 111, 112).
I. Neurotrophin (NT) receptors
Both human and rodent skin express transmembrane receptor proteins
of the tyrosine kinase (Trk) and p75 pan-neurotrophin (p75NTR)
families, which show high and low affinity for neuron growth factor
(NGF), respectively (33, 38, 108, 123, 124, 125, 126, 127, 128, 129, 130, 131). The high-affinity
receptors for NGF and NT4 include TrkA and TrkB; TrkC serves as a
high-affinity receptor for NT3, which also binds, but with low
affinity, to TrkA and TrkB. The receptors for the Trk family and for
p75NTR are expressed in epidermal and follicular keratinocytes,
epidermal melanocytes, specialized dermal fibroblasts, mast cells,
immunocytes, and cutaneous nerves (7, 33, 38, 108, 123, 124, 125, 126, 127, 128, 129, 130). NGF
stimulates melanocyte dendrite formation and prolongs melanocyte
survival after UV damage (123, 124). NGF and other neurotrophins can
regulate keratinocyte proliferation and differentiation (123, 125, 128, 129, 130), functions that in the mouse appear to be coordinated with
the hair cycle (128). Lastly, NGF and other neurotrophins can act as
mast cells secretagogs and can modulate dermal fibroblasts and dermal
immune cells function (7, 33, 38, 108, 123, 124, 125, 126, 127, 128, 129, 130). NGF and neurotrophins
may have a physiological role in hair cycle and hair follicle
morphogenesis (128, 129, 130, 132), whereas NGF may protect human
keratinocytes from UVB-induced apoptosis (125).
J. Miscellaneous neuropeptide receptors
Somatostatin is known to affect skin immune functions and basal
secretion of histamine and, thus, immune cells and keratinocytes
probably express the corresponding receptors (38, 110, 111, 112, 133).
Similarly, the inhibition of cAMP production by neuropeptide Y (NPY) in
human keratinocytes, the stimulation of keratinocyte DNA synthesis by
bombesin, and the acceleration of skin wound healing by TSH (12, 33, 38, 110, 111, 112, 117) suggest that specific receptors for these hormones
may be also expressed in skin. There are, in fact, data showing that
the gene coding for the TSH receptor is expressed in adipocytes and
fibroblasts (134). Receptors for bombesin and somatostatin have been
shown in dermal fibroblasts (33, 38, 111, 112).
K. PTH and PTH-related protein (PTHrP) receptors
Dermal fibroblasts express class 1 PTH/PTHrP receptors, which
respond to PTH or the PTHrP signal by increasing cAMP, production of
cytokines and keratinocyte growth factor (KGF) (135, 136); however, the
same receptor is not detected in keratinocytes (135, 137, 138, 139).
Nevertheless, PTHrP has direct epidermal biological activity
stimulating keratinocyte proliferation and differentiation both
in vitro and in vivo, and hair follicle formation
(15, 140, 141). The keratinocyte intracellular activation pathway
differs from that stimulated by class I receptors; PTHrP, while
producing intracellular calcium accumulation and protein kinase C
stimulation, does not stimulate adenylate cyclase; instead it activates
the phospholipase C pathway (138, 139, 142, 143). These PTH/PTHrP class
II keratinocyte receptors have been partially characterized and found
to also respond to PTH (138, 139, 143). PTHrP can indirectly regulate
functional activity of the epidermis through the stimulation of KGF
production by dermal fibroblasts (136). Furthermore, PTHrP can play a
role during wound healing, helping restore epidermal homeostasis (144).
Studies on the PTHrP knockout mouse model, and in mice overexpressing
the peptide in the skin, document an important role of PTHrP on
epidermal function and hair formation (15, 141).
L. Vitamin D receptor (VDR)
Receptors for the active form of vitamin D [1,25-dihydroxyvitamin
D (1,25-(OH)2D or calcitriol] are expressed in
human and rodent epidermal and follicular keratinocytes (13, 145, 146, 147, 148, 149, 150, 151).
In the mouse, hair cycle-dependent VDR expression has been reported: it
is stronger in mid and late anagen and in catagen and weaker in the
telogen and early anagen phases of hair growth (146). VDRs serve as
targets mediating calcitriol induction of keratinocyte differentiation
and inhibition of cell proliferation (13, 148). Because of these
properties, vitamin D derivatives are being used therapeutically
(topically) in psoriasis (3, 13, 14). The presence of alopecia in some
forms of vitamin D-resistant rickets with decreased expression of VDR
in dermal papilla cells indicates a role in hair growth (13, 150). Some
authors have identified VDRs in human melanocytes and observed a
modulatory effect of 1,25-(OH) 2D on
melanogenesis (8, 151). This observation has not been confirmed
universally (152). Skin immune cells may also express VDRs because of
the finding of constitutive immunosuppressive activity for 1,25-(OH)
2D (153). Patients with mutations of VDR present
with hypocalcemia, rickets, and significant cutaneous involvement
expressed as sparse body hair and, sometimes, total alopecia that
includes the eyebrows and eyelashes (150). In the latter subjects, VDR
gene mutations result in premature stop signals or abnormal DNA binding
and marked resistance to calcitriol therapy (150). Experiments
performed on mice treated with topical calcitriol show normal hair
regrowth after chemotherapy-induced alopecia (147).
M. Glucocorticoid and mineralocorticoid receptors
Glucocorticoid receptors (GRs) are members of the superfamily of
trans-acting transcriptional factors and are widely
expressed in all skin compartments (3, 4, 12, 31, 154, 155, 156, 157). More
specifically, GRs are expressed in epidermal and follicular
keratinocytes, epithelial cells of eccrine and apocrine glands,
sebocytes, melanocytes, immune cells of epidermis and dermis, dermal
fibroblasts, and smooth muscle (154, 155, 156, 157); activation of these
receptors regulates or modulates specific functions in the
corresponding cells. The role of glucocorticoids is best emphasized by
the skin changes associated with hypercortisolism (3, 36, 37). In such
states there are alterations in body fat distribution, general atrophy
of the skin, impairment of wound healing, easy bruisability, mild
acanthosis nigricans, acne, hirsutism, and alopecia. A glucocorticoid
direct inhibitory effect on hair growth has been well documented in
animal models (31). It must also be emphasized that glucocorticoids,
whether administered topically or orally, are potent drugs used
in the treatment of inflammatory skin diseases (3).
Most recently, mineralocorticoid receptors (MRs) have been detected in keratinocytes of the epidermis and hair follicle and in sweat and sebaceous glands of human skin (158). The same cutaneous structures also expressed 11ß-hydroxysteroid dehydrogenase (11HSD), which converts glucocorticoids to their inactive metabolites, thereby allowing the binding of aldosterone to MRs at much lower prevailing levels (158, 159).
N. Androgen and estrogen receptors
Sex steroid receptors belong to the superfamily of
trans-acting transcriptional factors, similar to
glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) (36, 68). They are widely distributed in all skin compartments, and their
density and expression level vary depending on anatomic site and gender
(3, 4, 12, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173). The well recognized androgen effects on hair
growth and sebaceous gland functions are related to expression of the
corresponding androgen receptors (ARs) in epithelial cells of those
adnexal structures and in specialized dermal papilla fibroblasts that
regulate hair morphogenesis (161, 162, 163, 164, 165). ARs are also expressed in other
adnexal structures, in epidermal keratinocytes and melanocytes, dermal
fibroblasts, and resident and circulating cells of the skin immune
system (3, 4, 12, 31, 160, 161, 162, 163, 164, 165, 169). Similar to ARs, estrogen
receptors (ERs) are also expressed in the epidermal, adnexal, and
dermal compartments of the skin (3, 4, 12, 166, 167, 168, 170, 171, 172, 173). ERs
have been detected variably, depending on the sensitivity method and
presence or absence of pathology, in epithelial cells of epidermis,
hair follicle, sebaceous, eccrine and apocrine glands, in melanocytes,
and in dermal fibroblasts. Thus, both estrogens and androgens regulate
hair growth, sebaceous gland function, proliferation and
differentiation of epithelial cells of the epidermis and adnexa,
functional activity of dermal fibroblasts and fibrocytes, wound
healing, and skin immune cells activity. There are also data showing
that androgens and estrogens can modulate proliferation and
melanogenesis in cultured melanocytes (169, 170, 171). Lastly, transgenic
male mice overexpressing GH show overgrowth of the skin that is
androgen dependent, e.g., it is not observed in females or
in castrated males (97).
Clinical signs of androgen excess include acne, hirsutism, and androgenic alopecia (3, 36, 37, 163, 164). Acne results from follicular hyperkeratinization, increased sebum production, and from the release of lipases and proinflammatory mediators by Propionicum acnes. In these conditions, androgens [mainly dihydrotestosterone (DHT) and to a lesser degree testosterone] mediate the increased sebum production and follicular hyperkeratinization (3, 37, 163, 164). Hirsutism and androgenic alopecia are associated with increased production of DHT within the dermal papilla of androgen-responsive hair follicles of the face, chest, genital skin, and scalp (3, 12, 31, 37, 163). Conversely, in males with androgen deficiency, the skin remains thin and fine; sebaceous and apocrine glands and sexual hair follicles remain dormant; beard, axillary, and pubic hair do not develop and neither does androgenic alopecia; and there is also a general decrease in skin pigmentation (3, 37, 163). Increased estrogen levels, for example during pregnancy, can lead to hyperpigmentation of nipples, areolae, genital skin, and facial skin (3). The latter, known as melasma, is exacerbated by sun exposure (3). In addition, preexisting nevi and ephelides darken, and telangiectasia, spider angioma, and palmar erythema may develop (3, 37).
The presence of actual ERs in malignant melanocytes has been questioned (174). However, studies with normal cultured melanocytes have demonstrated both the presence of receptors and phenotypic effects on cell proliferation (171). Nevertheless, the reports are truly conflicting as regards the estrogen effect on melanogenesis. Thus, while some have reported stimulation of tyrosinase activity and melanin synthesis by estrogens (170), others have shown an opposite inhibitory effect (171). These contradictory results indicate the need for additional work on the role of estrogens in melanocyte functions.
O. Thyroid hormone receptors
The skin is a recognized target for T3 (3, 4, 12, 31, 36, 37, 157, 164, 175, 176). This hormone is involved in the
process of epidermal differentiation and increases its responsiveness
to growth factors. It also participates in the function of sebaceous,
eccrine, and apocrine glands, in hair growth, and in the production of
proteo- and glycosaminoglycans by dermal fibroblasts. All of these
effects are probably mediated by interactions with the specific thyroid
hormone receptors (TRs) that serve as transcriptional regulators. In
fact, thyroid hormone receptors (c-erb-A) were detected by RT-PCR in
human skin (177), and c-erbAß and c-erbA mRNAs were detected in
dermal fibroblasts, consistent with T3 binding to
fibroblast nuclear extracts (178). Since T3 may
have an inhibitory effect on melanogenesis in malignant melanocytes, it
is likely that TR is also expressed in melanocytes (179).
A potential role for thyroid hormones in the regulation of skin function is suggested by its changes in hyper- and hypothyroidism (3, 36, 37). In the former, the skin changes include erythema, palmoplantar hyperhidrosis, acropathy, and infiltrative dermopathy. Graves’ disease also may be associated with generalized pruritus, chronic urticaria, alopecia areata, vitiligo, and diffuse skin pigmentation. In hypothyroidism, the skin is cool, dry with pasty appearance; the epidermis is thin and hyperkeratotic; alopecia may develop, and there is diffuse myxedema. In contrast to the pretibial myxedema present in hyperthyroidism, the generalized myxedema of hypothyroidism is reversible with thyroid hormone therapy (37).
P. Cholinergic receptors
Grando and associates (20, 180, 181, 182) found that human
keratinocytes express both nicotinic and muscarinic receptors in a
differentiation-dependent manner. Specifically, human keratinocytes
were found to express the 3, 5, 6, 7, ß1, ß2, and ß4
nicotinic receptor subunits (20, 180, 181). Immunocytochemistry studies
further showed that the number and subunit composition varies according
to stage of epidermal keratinocyte differentiation (20, 181). The
nicotinic receptors on keratinocytes represent functional ion channels
mediating the influx of Na+ and
Ca+2, and the efflux of K+,
being thus essential for keratinocyte viability (20, 180, 181).
Activation of nicotinic receptors stimulates keratinocyte motility and
differentiation (20, 180, 181).
Muscarinic receptors of several subtypes have been detected in vitro and in vivo in epidermal keratinocytes (20, 181, 182). The subtypes expressed include the m1, m3, m4, and m5 types, with both timing and level of expression being dependent on keratinocyte differentiation stage (20, 181, 182). Muscarinic receptors have been characterized also in malignant human melanocytes (183, 184), and there is strong evidence for their expression in normal melanocytes (Grando et al., unpublished observation).
Q. Adrenergic receptors
Radioligand binding studies have shown cutaneous adrenergic
receptors, with epidermal keratinocytes and eccrine epithelial cells
expressing predominantly the ß2 adrenoreceptors (4, 21, 185, 186, 187).
In situ binding assays have further identified 1-
adrenoreceptors in the epidermis (188). Stimulation of ß-adrenergic
receptors in epidermal keratinocytes results in increased cAMP
production, calcium influx, and stimulation of keratinocyte
differentiation (3, 4, 21, 187). ß-Receptors are expressed in
inflammatory cells of the dermis (185), thus explaining the
ß2-adrenoreceptor agonists inhibition of proinflammatory TNF
release (189). - And ß-adrenoreceptors are expressed in dermal
blood vessels, and their activation induces vasoconstriction and
decreases vascular permeability (4, 190, 191). Since the melanoma cell
phenotype can be modified by adrenergic agonists, it is possible that
normal mammalian melanocytes may express adrenergic receptors, similar
to pigment cells of other vertebrates (8, 66, 192). The ß1, ß2, and
ß3 adrenoceptors are also present on adipocytes (193).
R. Glutamate receptors
Immunocytochemical studies performed on rat skin
demonstrated the presence of the G protein-coupled metabotropic
receptors of the ionotropic glutamate-gated ion channels such as the
N-methyl-D-aspartate (NMDA) and
-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) types of
glutamate receptors in basal epidermal keratinocytes (194). In addition
to receptor expression, the specific glutamate transporters have been
also detected. Thus, EAAC1 was found in basal keratinocytes, GLT-1 in
suprabasal keratinocytes, and the AMPA-type receptor clustering
protein, GRIP, in basal keratinocytes (194). In the same rat model,
epidermal expression levels of the NMAD receptor and the EAAC1
glutamate transporter were significantly related to wound healing and
embryogenesis. Cultured human keratinocytes have shown expression of
mRNAs for the NMDAR1 subunit and for GRIP (194).
S. Serotonin receptors
The potential presence of serotonin receptors in the skin is
suggested by the local effects of serotonin, e.g.,
pro-edema, vasodilatory, proinflammatory, and pruritogenic (3, 4, 34, 115, 195, 196). In mouse skin, serotonin-induced vascular permeability
is mediated by the activation of 5-hydroxytryptamine type 1 (HT1) and
HT2 receptors (197). The pruritogenic effect of serotonin may be
mediated through direct activation of HT3 receptors or indirectly
through mast cells (7, 27, 34, 198). Cutaneous expression of 5-HT2A
receptors was detected in unmyelinated axons at the dermal-epidermal
junction and in the nerve endings of Pacinian corpuscles (199). Because
of serotonin proinflammatory activity, it is likely that cells of the
skin immune system will also express the HT receptors generally found
in the immune cells (7, 27). Such mechanism would explain the
initiation of T celldependent contact sensitivity by serotonin
released from human platelets (200), and also the release of
prostaglandin E2 from rat skin in
vitro (201). Since serotonin can stimulate epidermal keratinocyte
proliferation in organ culture, these cells may also express HT
receptors (202).
T. Histamine receptors
After its release from mast cells, basophils, and platelets,
histamine has pleiotropic phenotypic effects in the skin through
interactions with H1, H2,
and H3 receptors (3, 7, 115, 203). Histamine’s
most prominent cutaneous effects are on the local vascular and immune
systems, supporting the use of antihistamine drugs for the treatment of
pruritus, urticaria, and angioedema (3, 7, 115, 195). Histamine
receptors are expressed in the dermal compartment on immunocytes,
endothelial cells, blood vessels, smooth muscle, fibroblasts, and nerve
endings (3, 7, 115, 195, 203), whereas in the epidermis,
H1 and H2 receptors are
expressed on keratinocytes (204, 205, 206, 207). Epidermal melanocytes express
H2 receptors (208). Activation of keratinocyte
H2 receptors affect proliferation and
differentiation via activation of the adenylate cyclase/phospholipase C
pathway with associated increases in intracellular calcium levels (204, 205). In the same cell system, activation of the
H1 receptor enhances UVB-induced IL-6 production
(206), whereas H1 receptor antagonists inhibit
ICAM-1 expression (207). Activation of the H2
receptors on melanocytes stimulates melanogenesis (208). Thus, both the
dermal and epidermal compartments are clear targets for histamine,
regulating cellular functions not directly connected with the
previously described proinflammatory effects of this mediator. Of great
interest is the proposed role for the mast cell as a coordinator of
immune, neural, and endocrine activity on the central level and
peripheral organs (115, 203); in this context the cutaneous actions of
histamine through specific receptors would also be addressed at
coordinating the local cutaneous neuroendocrine system responses (203).
U. Miscellaneous receptors
A number of studies suggest that epidermal keratinocytes express
purinoreceptors that, when activated by adenosine or adenine
nucleotides, will stimulate cAMP and IP3 production, respectively (209, 210). Purinoreceptor activation inhibits keratinocyte proliferation
(211). Functionally active adrenomedullin receptors (AM-R), which are
G-protein linked and coupled to adenylyl cyclase activity, have been
identified in epithelial cells of epidermis, hair follicle, sebaceous
and eccrine glands, and in melanoma cells (212). AM binding sites have
been characterized in cultured keratinocytes and in melanoma cells; in
the latter system AM stimulates DNA synthesis (212). Calcium sensing
receptors identical to those found in the parathyroid glands have been
identified in cultured normal human keratinocytes (213). There is also
experimental data suggesting the existence of receptors for
L-tyrosine and L-DOPA (214), since both
L-tyrosine and L-DOPA can act as regulators of
melanogenesis (10, 23), and L-DOPA can suppress lymphocyte
activity (215). Finally, the modulatory effect of melatonin on
keratinocyte proliferation and inhibition of melanogenesis suggests
that melatonin receptors are expressed also in mammalian skin
(216, 217, 218). Nevertheless, the evidence is based solely on the detection
of melatonin binding sites, while specific receptors for melatonin
remain to be characterized. In lower vertebrates, skin melatonin
receptors are well characterized, and melatonin is recognized to play
an important role in skin pigmentation, acting as a lightening agent
(8, 67, 68).
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IV. Skin as a Source of Hormones and Neurotransmitters |
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TopAbstractI. IntroductionII. Structure of the...III. Skin as a...IV. Skin as a...V. Molecular and Structural...VI. Regulation of Cutaneous...VII. Regulation of Cutaneous...VIII. Final Comments and...References |
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. Neuropeptides released by cutaneous
nerve endings or produced by skin are listed in Table 3. The production of vitamin D is covered
separately because it is synthesized in the skin, and its systemic
effects have been well characterized.
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In the skin, PTHrP is highly expressed in the granular layer of the epidermis and outer root sheath of the hair follicle and at much lower levels in basal keratinocytes and melanocytes (15, 220). Pathologically, PTHrP is frequently expressed in squamous carcinomas and in their corresponding cutaneous form (15, 143). Expression of PTHrP has also been reported in metastatic melanoma (221, 222). In addition, during wound healing PTHrP is produced by granulation tissue cells that include myofibroblasts and infiltrating macrophages (144). It is of interest that PTHrP is the main cause for the syndrome of humoral hypercalcemia of malignancy (HHM) and that it is produced predominantly by squamous cell tumors (223). However, cutaneous squamous cell carcinomas, which have a high incidence of about 39/100,000, may have resulted in only a few documented cases of HHM (223). The reason for this discrepancy is unclear but may be related to lower levels of expression, release of mostly inactive fragments, or of inability of PTHrP molecules to cross the basement membranes and reach the systemic circulation (219). Presumably, such a barrier is broken in some cases of advanced squamous cell carcinoma of the skin that develop hypercalcemia. HHM associated with increased serum levels of PTHrP has also been described in metastatic human melanoma (221); and, in at least one case, clear evidence is provided that melanoma cells themselves have been the source of PTHrP (222). The reported patient had no signs of bone metastases, and PTHrP immunoreactivity was detected in melanoma cells on autopsy specimens but not in a biopsy specimen of the melanoma obtained before onset of hypercalcemia (222).
B. Hypothalamic and pituitary hormones
1. CRH and related urocortin peptide. The skin is one of the
organs producing all the peptides hormones that are central components
of the HPA, the main mediator of the systemic response to stress (5, 6, 9, 16, 17, 18, 19, 25, 28, 36, 56). Among the hormones involved in this classic
neuroendocrine pathway are hypothalamic CRH and, more recently, the
related peptide urocortin (18, 19). In the skin, CRH gene expression
has been detected in cultured human keratinocytes and melanocytes with
actual production of the peptide, as shown by RIA and RP-HPLC;
furthermore, the CRH antigen has been localized in situ to
epidermis, hair follicle, nerve bundles, and dermal blood vessels (18, 42, 43, 44, 46, 49). In mouse skin, which does not express the CRH gene,
high concentrations of CRH have been detected by RIA, and chemical
identification of CRH was documented by RP-HPLC analysis (44, 46).
Since the CRH immunoreactivity was localized to epidermal and
follicular keratinocytes and in nerve bundles (43, 44), it was
postulated that CRH is imported to the mouse skin by cutaneous nerve
endings (43, 44, 46); alternatively, mouse skin could express a related
gene, with high homology to CRH (46).
We recently observed expression of the urocortin gene in mouse skin and also detected the actual urocortin peptide (19). Urocortin tissue levels were highest in telogen skin and decreased progressively during hair cycle to the lowest level in late anagen (19). This pattern is opposite to the hair cycle-associated production of CRH as determined in the same model (44). Expression of the urocortin gene has also been documented in whole human skin, human keratinocytes, human melanocytes, and in hamster melanoma cells (19). Similar to CRH, expression of urocortin peptide was detected in situ in the epidermis, hair follicle, sweat glands, melanocytic nevi, smooth muscle, and wall of blood vessels (19). The reported expression of CRH and urocortin in lymphocytes (224, 225) strongly suggests that cells of the skin immune system may also contribute to the cutaneous pool of those peptides. Therefore, the hormone products that initiate HPA activation at the central level are also readily available in the skin.
2. POMC. There is a large body of data documenting expression of POMC gene in whole human and rodent skin and in cultured skin cells that include keratinocytes, melanocytes, dermal fibroblasts, and endothelial cells, Langerhans cells, monocytes/macrophages, T lymphocytes, and leukocytes (5, 16, 17, 64, 83).
a. Human skin.
The POMC peptides ACTH, -MSH,
and ß-MSH and ß-endorphin peptides have been detected by
immunocytochemistry in normal and pathological melanocytes,
keratinocytes, Langerhans cells, and mononuclear dermal inflammatory
cells (5, 17, 226, 227). Studies with RP-HPLC and Western blotting in
cultured human melanocytes and keratinocytes showed multiple forms of
those peptides such as ACTH 1–10, acetyl-ACTH 1–10, ACTH 1–17, ACTH
1–39, desacetyl--MSH, -MSH, and ß-endorphin (5, 17, 228, 229, 230).
Human dermal endothelial cells and fibroblasts did not only produce,
but also released, -MSH and ACTH immunoreactivity into the medium
(17, 64, 82, 108, 231). The other POMC peptide, ß-MSH, was detected
by immunocytochemistry in human skin in epidermal and follicular
keratinocytes, malignant keratinocytes, melanoma cells, and dermal
inflammatory mononuclear cells (5). 3-MSH has also been detected in
keratinocytes, melanoma cells, neutrophils, and in nerve endings (5, 232).
b. Rodent skin.
ACTH, -MSH, and ß-MSH antigens were
detected in epidermal and follicular keratinocytes of mouse skin (5, 17, 83), and ACTH and -MSH were also detected in nerve bundles and
smooth muscle; ß-endorphin has been identified only in the sebaceous
glands (5, 83). Cultured murine and hamster melanoma cells expressed
the ACTH, -MSH, ß-endorphin, and 3-MSH antigens (5, 16).
As regards the POMC gene expression, the transcription of shorter and
longer POMC mRNA forms has been identified in epidermal and dermal
cells (5, 17). This pattern was accompanied by translation of a 30-kDa
POMC precursor and its subsequent processing to ACTH, -MSH, ß-MSH,
ß-endorphin, and 3-MSH peptides (5, 17). Detection of the
processing enzymes PC1 and PC2 convertases in human and rodent skin
indicates that processing of POMC in skin is similar to that in the
hypothalamus and pituitary (17, 108 232A ). It must be noted that one
group has reported only 80% homology between the human cutaneous POMC
mRNA and its pituitary counterpart (233); however, subsequent analysis
of the reported sequence by others showed contamination with murine
pituitary POMC cDNA (234).
Therefore, the information above is convincing evidence of POMC
peptide production in the skin and its processing to -MSH, ACTH, and
ß-endorphin-related peptides. Definition of local production of other
products of POMC processing will require additional research.
3. Other pituitary hormones. Studies with in vitro systems have shown that human dermal fibroblasts express PRL mRNA 150 kb longer than the pituitary form (235). However, the fibroblasts synthesized and secreted PRL peptide, immunologically and electrophoretically identical to pituitary PRL (235). The data are also consistent with earlier observations of PRL production by normal human connective tissue (236), and with detection of PRL immunoreactivity in sweat glands (237, 238). Expression of the human GH gene has also been detected by RT-PCR in cultured dermal fibroblasts (239); human endothelial cells express the PRL gene (240); and human immune cells produce both PRL and GH (25, 241, 242, 243). Our most recent studies indicate restricted expression of GH gene in the dermal compartment, that failed to detect production of PRL mRNA in whole human skin (243A ). Therefore, actual GH and PRL production by the main cutaneous cell compartments has yet to be determined.
C. Neuropeptides and neurotrophins
1. Enkephalins. Met-enkephalins (Met-E) and leu-enkephalins
(Leu-E), which are products of the larger protein precursor
proenkephalin A (PEA) (36, 68), are also produced by mammalian skin
(88, 244, 245, 246, 247, 248, 249). Met-E immunoreactivity has been detected in normal
human skin and is increased in areas affected by psoriasis (88, 244, 245). The corresponding antigen is located in epidermal keratinocytes
and in inflammatory infiltrate components such as T lymphocytes,
macrophages, and leukocytes. Met-E has been also detected in the
keratinocytes of basal, spinous, and granular layers of human and
murine epidermis (88, 245, 250). The detection of PEA mRNA in lesional
psoriatic skin further supports local production of the Met-E peptide
(244). The cellular source expressing PEA could be mesenchymal dermal
cells (248, 249) or immune cells including mast cells (24, 25), since
regulated PEA mRNA expression and production of final enkephalin
peptides has been detected in rodent skin mesenchymal cells (249), and
circulating immune cells express the PEA gene (251). The Met-E peptide
has been also detected in epidermal Merkel cells and Langerhans cells
(246, 247). Upon further review of the data, it appears that cell type
and conditions necessary for expression of the PEA gene remain to be
determined. Similar research is needed to determine the cellular source
of pro-dynorphin-related peptides, the presence of which has been
reported in mammalian skin (252).
2. Nonopioid neuropeptides. Mammalian skin expresses a variety
of neuropeptides that include tachykinins SP and NKA, CGRP, VIP, NPY,
somatostatin (SOM), galanin, atrial natriuretic peptide (ANP), peptide
histidine methionine/peptide histidine-isoleucinamide (PHM/PHI),
bradykinin, cholecystokinin (CKK), and gastrin-releasing peptide (GRP)
(4, 7, 33, 34, 38, 108, 109, 110, 111, 112, 113, 114). In normal human skin, the most abundant
of these peptides are SP, CGRP, VIP, and NPY, although detectable but
lower levels of NKA, SOM, and ANP are also present. Neuropeptides are
synthesized by nerve cells and released predominantly by unmyelinated
afferent C fibers characterized as C-polymodal nociceptors (C-PNN) and
by small myelinated A-fibers (33, 34, 38, 108). To a lesser extent,
autonomic efferent nerves also release the neuropeptides (4, 33, 34).
In general, nerves penetrating into the epidermis contain SP, NKA, and
CGRP, whereas those innervating dermal structures contain SP, CGRP,
VIP, and NKA (33). The neuropeptides are synthesized in dorsal root
ganglia, where they are processed and sorted in the Golgi network and
then migrate, within dense core vesicles through retrograde axonal
transport, to nerve endings in the skin (34). The skin concentration of
neuropeptides varies by anatomical site, reflecting, probably, regional
differences in innervation (4, 33, 253). It is generally accepted that
afferent or efferent nerves are the main source for the cutaneous
neuropeptides listed above.
An additional source of cutaneous neuropeptides is their synthesis and secretion by resident and circulating skin cells, present in inflamed or even normal skin (4, 7, 24, 25, 27, 28, 38, 110, 111, 115, 254, 255). For example, Merkel cells express antigens that are recognized by antibodies against CGRP, SP, NKA, VIP, PHI, NPY, SOM, and galanin (38, 111, 112, 255). Likewise, Langerhans cells express CGRP, SP, GRP, VIP, SOM, and NKA antigens (110, 254). It remains to be tested whether expression of those antigens is connected to actual transcription and translation of the corresponding genes. Several immunocytochemical studies have reported the presence of VIP, SOM, SP, CGRP, NPY, and NKA in dermal and epidermal immune cells from skin affected with psoriasis, urticaria pigmentosa, allergic dermatitis, and, in some cases, uninvolved normal skin (4, 7, 38, 110, 111, 254, 255). NPY has been additionally detected in epidermal and follicular keratinocytes of normal skin and SOM in basal epidermal keratinocytes of atopic dermatitis skin (38, 133, 254). Thus, skin cells definitively can produce neuropeptides; however, the conditions necessary for such production and the precise identity of the producing cells remain to be defined.
3. Neurotrophins. The skin can produce the neurotrophins NGF, NT-3, NT-4, and brain-derived neurotrophic factor (BDNF) (7, 123, 124, 125, 128, 129, 130, 256, 257, 258). NGF is synthesized and secreted by keratinocytes, Merkel cells, and dermal fibroblasts and mast cells (7, 123, 128, 256, 257, 258). In human skin, production of NT3 has been detected in dermal fibroblasts (124), whereas in the mouse it is more widely expressed since NT3 is found in epidermal and follicular keratinocytes of developing skin, and in adult animals it is detected in keratinocytes of hair follicle and DP fibroblasts (128, 129, 130). Hair follicle keratinocytes can synthesize NT4 and NGF (128, 129, 130), and dermal Schwann cells can synthesize NGF, NT-3, and NT-4. Locally produced neurotensin can induce mast cell degranulation (203). It may be speculated that the pleomorphism of neurotrophin cutaneous expression could be related to their significance in regeneration, a functional capability vital for the maintenance of homeostasis.
D. Neurotransmitters/neurohormones
1. Acetylcholine. Cultured human keratinocytes can synthesize,
secrete, and degrade acetylcholine (180, 181, 259). Keratinocyte
acetylcholine is synthesized by choline acetyltransferase from acetyl
coenzyme A and choline; in turn, acetylcholine is hydrolyzed by
acetylcholinesterase to acetate and choline. Activities of both
enzymes, choline acetyltransferase and acetylcholinenesterase, have
been detected and characterized in homogenates of cultured
keratinocytes. Immunolocalization studies have shown that choline
acetyltransferase is consistently present in all layers of the human
epidermis, while acetylcholinesterase is restricted to basal
keratinocytes (180, 181, 259). Acetylcholinesterase activity has been
also detected in situ in epidermal melanocytes (260).
In addition to local synthesis, acetylcholine is also released by
cholinergic nerve endings supplying dermal structures (34).
2. Catecholamines. The human epidermis has the capability to synthesize the catecholamines dopamine, norepinephrine, and epinephrine (21, 22, 187, 261, 262, 263), which is consistent with previous findings of phenylethanolamine-N-methyl transferase immunoreactivity in human epidermal keratinocytes (264). The synthetic activity of cutaneous catecholamines resides predominantly in keratinocytes that express biopterin-dependent tyrosine hydroxylase and phenylethanolamine-N-methyl transferase (21, 187, 261, 262). Catecholamine production takes place in human and rodent melanoma cells (265, 266), which suggests that normal melanocytes may also produce catecholamines (267). Catecholamines can be inactivated directly in the epidermis by the enzymes monoamine oxidase (MAO) and by catechol-methyl transferase, the enzyme already characterized in keratinocytes and melanocytes (187, 268, 269). L-Tyrosine, a precursor for both catecholamines and for melanin, is also synthesized in human keratinocytes and melanocytes from L-phenylalanine by phenylalanine hydroxylase (20, 21, 187, 262, 270). Moreover, phenylalanine hydroxylase and tyrosine hydroxylase activities are dependent on the cofactor 6BH4, which is also synthesized and recycled by human keratinocytes and melanocytes (21, 22, 187, 261). Lymphocytes may also represent an additional source of catecholamines (271). It has been proposed that L-tyrosine and its hydroxylation product L-DOPA would have hormone- and neurotransmitter-like roles (23, 214, 272), with melanocytes being the main site of cutaneous L-DOPA production through the tyrosine hydroxylase activity of tyrosinase (8, 273). L-DOPA produced by melanocytes can, in fact, be released into the extracellular environment. As for norepinephrine, an important cutaneous source is its dermal release from adrenergic nerve fibers (4, 33, 34).
3. Other neurohormones. Serotonin may be also synthesized in the mammalian skin, since rodent mast cells can synthesize serotonin, although this property is not shared by human mast cells (7, 27, 115, 195). Serotonin has also been detected in Merkel cells and human melanocytes and melanoma cells (266, 274, 275). In rodent skin serotonin can be transformed into N-acetylserotonin (NAS), and the responsible enzyme arylalkylamine N-acetyltransferase, together with its gene, are correspondingly expressed (196, 276, 277). In hamster skin NAS can be further metabolized to melatonin and 5methoxytryptamine (278). Finally, the neurotransmitters glutamate and aspartate have been detected by immunocytochemistry in epidermal keratinocytes and in dermal and epidermal dendritic immunocytes (279).
E. Thyroid hormones
Human skin may be an extrathyroid site of conversion of
T4 into the more active T3
(12, 280, 281, 282). This metabolic transformation would occur in the
epidermal keratinocytes through the action of type 2 deiodination
pathway (280, 281), with efficiency inversely related to the serum
T4 (12). The human epidermis is also the site of
T3 deiodination to 3,3'-diiodothyronine (12).
More recent data suggest, however, that at least rodent skin expresses
only deiodinase type 3, which catalyzes the 5-deiodination of thyroid
hormones (283, 284, 285). Since the cutaneous expression of three
deiodinases in rodent skin changes during embryonal development, this
area needs to be reexamined with modern methods, as it applies to human
skin (284, 285).
F. Sex steroid hormones
The skin can transform the steroids dehydroepiandrosterone (DHEA)
and its sulfate (DHEA-S) into active androgens and estrogens (4, 160, 286, 287, 288). Specifically, enzymatic activity corresponding to
3ß-hydroxysteroid dehydrogenase/
5–4 isomerase (3ß-HSD) has
been localized to the sebaceous glands and, to a lesser degree, in hair
follicles, epidermis, and eccrine glands, while 17ß-hydroxysteroid
dehydrogenase (17ß-HSD) has been localized to follicular and
epidermal keratinocytes (287, 288, 289, 290, 291). 3ß-HSD converts DHEA into
4-androstenedione, and 5-androstene-3ß,17ß-diol into testosterone,
while 17ß-HSD converts DHEA into 5-androstene-3ß,17ß-diol,
4-androstenedione into testosterone, and androstanedione into DHT (4, 36, 160). Testosterone is also converted into DHT through the action of
a 5-reductase, detected in dermal and dermal papilla fibroblasts,
follicular and epidermal keratinocytes, and sebaceous and apocrine
glands (4, 160, 164, 286, 289, 290, 291, 292, 293, 294, 295, 296, 297). There are two isozymic forms of
the 5-reductase, but the skin expresses predominantly the type I in
a highly specific cellular and regional distribution (290, 291, 292, 293, 294, 295, 296).
Nevertheless, cutaneous expression of 5-reductase type 2 has been
also reported, but at much lower levels; this form has been
immunodetected in hair follicles of human scalp (295, 296). The skin
immune system can also convert DHEA into 5-androstene-3ß,17ß-diol
and into 5-androstene-3ß,7ß,17ß-triol. Cutaneous conversion of
testosterone into estradiol is mediated by an aromatase expressed in
dermal fibroblasts and adipocytes, but not in keratinocytes (4).
However, in keratinocytes 17ß-HSD can transform 17ß-estradiol into
estrone or estrone into 17ßestradiol (286).
G. Other steroid hormones
The presence of 17ß-HSD indicates that skin can dehydrogenate
pregnenolone into progesterone, although the reaction does not proceed
in cultured keratinocytes (286). The skin expresses genes for
cytochromes P450SCC, P450c17, and P450c21 (66). Immunocytochemistry
localization of the antigens for cytochrome P450SCC and P450C17 showed
the former in epidermal keratinocytes and eccrine glands and the latter
in epidermal and follicular keratinocytes, and in sebaceous and eccrine
glands (102). These findings, together with the expression of the ACTH
and of the MC2-R gene, suggest that the skin could potentially
synthesize glucocorticoids (66). In fact, early studies have shown that
whole human skin can metabolize progesterone (PROG) (4), while human
keratinocytes can transform DOC into 5-dihydro-DOC (286). We have
recently reported that skin-derived malignant melanocytes can indeed
metabolize exogenous PROG to DOC, corticosterone, and 18OHDOC, and that
it can also metabolize DOC to corticosterone and 18OHDOC (Fig. 1) (298). A more physiological
preparation, whole skin from the rat, can transform PROG into DOC and
metabolize DOC to corticosterone-like and to
11-dehydrocorticosterone-like molecular species (Fig. 2) (299).
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V. Molecular and Structural Basis for the Organizational Integration of Neuroendocrine Elements of the Skin |
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TopAbstractI. IntroductionII. Structure of the...III. Skin as a...IV. Skin as a...V. Molecular and Structural...VI. Regulation of Cutaneous...VII. Regulation of Cutaneous...VIII. Final Comments and...References |
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). The
well characterized exocrine function is performed by the adnexal
structures that comprise eccrine, apocrine, and sebaceous glands and
hair follicles. These are important in strengthening the epidermal
barrier, in thermoregulation, and in the defense against microorganisms
(3, 4, 7, 11). Formation of the hair shaft together with the secretions
of eccrine, apocrine, and sebaceous glands also plays an important role
in social communication. Furthermore, at least in furry animals, the
skin plays an important role in behavioral regulation, ascribed to the
exocrine activity of the specialized and nonspecialized sebaceous
glands that produce and secrete odorants and pheromones (35).
|
). These units are composed of cells of
epithelial, neural crest, mesenchymal, and bone marrow origin that form
the epidermal, dermal, and adnexal structures (cf. Figure 3
). As listed
in Tables 1 and 2, these cutaneous cells and adnexal structures can
concomitantly produce hormones and express the corresponding receptors
(see Section III), indicating that the predominant
mechanisms of interaction within the different cutaneous compartments
are auto- and paracrine in nature. For example, the common skin
stressor, UV radiation, stimulates epidermal production and secretion
of the POMC-derived MSH and ACTH peptides. In turn, these peptides
interact with MC receptors on melanocytes, keratinocytes, and
Langerhans cells (LC) to modify their functional activity and
increase cutaneous melanin pigmentation (5, 9, 17, 64) and also
generate local antiinflammatory and immunosuppressive effects (17, 64, 108). Immunosuppression, mediated predominantly by -MSH, is
expressed as functional antagonism to IL-1, down-regulation of
accessory molecules expression on antigen presenting cells, and
stimulation of IL-10 secretion (17, 64, 82, 108). At the dermal level
these immunosuppressive effects include modulation of local cytokine
production, and inhibition of endothelial cells expression of adhesion
molecules necessary for inflammatory cells transmigration through the
capillary network (7, 17, 64, 82, 108). Dermally produced -MSH and
ACTH modify hair pigmentation and sebaceous gland function, whereas
ACTH modifies hair growth (5, 16, 35, 61, 83, 86). Cutaneously produced
CRH and urocortin affect epidermal proliferation of keratinocytes and
melanocytes (18, 19, 46, 51), and in the dermis these peptides can
modify local immune responses and act as vasodilators and mast cell
segregators (40, 48, 56, 57, 58, 59, 60, 203).
|
As regards sex hormones actions, testosterone by itself, or after conversion to DHT in keratinocytes and dermal fibroblasts modifies hair growth and sebaceous glands function (4, 163, 164). Dermally produced estradiol (4) can affect function of adnexal structures and the wound healing process (172, 173).
As discussed in the section on the vitamin D receptor, the active vitamin D3 metabolite 1,25-(OH)2D3 inhibits keratinocytes proliferation and stimulates their differentiation via interaction with the VDR (13, 14). Evidence for the epidermal conversion of vitamin D into 1,25-(OH) 2D3 (301) would further support local (auto- and paracrine) mechanisms of action. PTHrP produced in the epidermis and hair follicle has a similar effect on keratinocytes through interaction with a receptor different from the classic class 1 PTH/PTHrP receptor (15, 302). Both vitamin 1,25-(OH) 2D3 and PTHrP can affect hair growth (13, 14, 15, 302).
Notwithstanding their overwhelming local action, hormones produced in the skin can also enter superficial and deep vascular dermal plexuses, or vessels supplying adnexal structures, with long distance effects. Such a true endocrine role is most apparent in the case of hormones and cytokines produced in the dermis that have rather free access, by diffusion to local capillary vessels. Limiting factors for this diffusion are the distance between production site and vasculature, adhesiveness to the extracellular matrix, and local rate of degradation. In contrast, epidermally produced hormones and cytokines must penetrate the basement membrane (BM) before traversing the extracellular matrix (EM) of the papillary dermis; therefore, the permeability barrier and the adhesiveness to the BM and EM limit their access to the most superficial capillary vessels. An example of the relative restriction posed by the dermal-epidermal junction is the rarity of patients showing systemic effect (hypercalcemia) from cutaneous PTHrP, a hormone produced abundantly in the epidermis (15, 302). Still, epidermally produced vitamin D (14), urocanic acid (303, 304), and, perhaps, PTHrP do enter the systemic circulation and are able to modify the functional activity of distant organs, providing evidence for endocrine effects by factors produced in the epidermis. Urocanic acid produced in the stratum corneum of the epidermis can also enter the systemic circulation and have immunosuppressive effects (4, 123, 303, 304). As mentioned above, epidermal PTHrP may play predominantly para- or autocrine roles (15, 141). It could, however, have a distant effect after release by pathological conditions (skin cancer) (222, 223).
Cutaneous neuroendocrine elements are therefore tightly organized and
arranged into epidermal and dermal endocrine units, as determined by
the physical separation between those compartments (Figs. 4 and 5). These units, which become fully
expressed in a field-restricted stress-dependent manner, have broad
bidirectional communications. This is accomplished through soluble
factors able to penetrate the basement membrane and, also, through
sensory nerve endings connecting epidermis and dermal structures (Figs. 4 and 5). Sensory nerve fibers provide anterograde or retrograde
transmission of impulses through axon reflexes with release of
neuropeptides at epidermal or dermal nerve endings (33, 34, 38). The
latter intracutaneous communication mechanism represents therefore a
high-speed and extremely specific connection for the transfer of
information, sensed externally or internally, to specific target cells.
Target cell activation may then be mediated by neuropeptides (cf. Table 3 and Section IV.C) synthesized and released
predominantly by the unmyelinated C fibers described as C-polymodal
nociceptors (C-PNN), or by myelinated A-fibers (33, 34, 38). There
are specific roles for each of the different neuropeptides released by
afferent nerve endings in the functional regulation of epidermal
barrier properties, skin immune activity, vascular activity, hair
growth, and adnexal functions. Those topics, as well as their mechanism
of action, have been discussed in comprehensive reviews on the subject
(5, 7, 33, 34, 38, 56, 110, 111, 112, 128, 203). It is apparent from
neuroimmunocytochemistry studies that nerve subpopulations containing
different neuropeptides, such as SP, NKA, CGRP, VIP, SOM, NPY, PHM,
enkephalins, CRH, and - and -MSH, do enter cutaneous structures.
The presence of this neural network with fibers penetrating all the
vital layers of the epidermis and branching into dermal structures,
adnexa, Merkel cells, epidermal Langerhans cells, melanocytes, and
dermal mast cells provides, therefore, the support for a dual role for
those cells, as effectors and regulators (33, 34, 38, 110, 114, 115, 118, 119, 128, 203, 300, 305, 306, 307, 308, 309, 310, 311, 312, 313). Within this local branching neural
network, disturbances of local homeostasis expressed as production of
chemical mediators can be sensed in a specific manner and transmitted
to local subunits to counteract noxious stimuli or protect against
further damage. The neural branches can be also activated directly by
neurohormones and bioactive peptides produced locally, such as
histamine, eicosanoids, or NO (33, 34, 38, 112, 203, 312, 314); or, by
physicochemical agents such as changes in pH, cation, and free radical
concentration (cf. Ref. 34). Indirect neural modulation may be provided
by the cytokine networks that modify the chemical environment
surrounding the nerve endings. As compared with this neural mechanism,
humoral communication, dependent on local diffusion, results in a much
slower response.
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The bidirectional interaction between skin elements and local neural network is perhaps best illustrated by the changes in murine skin during the hair cycle, which are dependent on appropriate dermal and adnexal innervation (128, 300, 311). In this process, the hair cycle-associated tissue remodeling is accompanied by a tightly regulated sprouting and regression of specific afferent and efferent nerve fibers that form a neural and neurotransmitter network. Its cutaneous expression is highly specific and tightly determined by the actual phase of the hair cycle (128, 300, 311).
The epidermal and dermal endocrine units with their bidirectional
communication pathways, which proceed via soluble mediators or via
antidromic axon reflexes through the nerve branches that link both
compartments, combine to form the skin neuroendocrine organization
(Fig. 5). In general, this neuroendocrine organization functions to
coordinate the epidermal and dermal changes necessary for reinforcing
the physical barrier and maintaining its structural integrity. To
implement these objectives, it modulates sensory reception, melanin
pigment production and distribution, activity of the local immune
system, vascular functions, thermoregulation, exocrine secretion, and
metabolic transformation of prohormones or hormones into other
molecules of different biological activity.
The skin neuroendocrine system is thus continuously sensing
environmental components and, when activation threshold levels are
reached, a reaction is triggered with production of specific biological
factors. Some of these factors may be released to the extracellular
compartment to activate sensory nerve endings, directly enter the
circulation, or activate circulating immune cells. The sum of these
actions sets the optimal mode for dealing with deleterious
environmental changes (Fig. 6). Humoral
signals that could directly enter the circulation include cytokines and
hormones and vitamin D3. The latter represents a
marker for a cutaneous action in response to an environmental component
(UV-B), which results in well defined systemic effects on calcium
homeostasis (14). An analogous example in amphibians is the skin
regulation of pituitary function through TRH and skin peptide
tyrosine-tyrosine (SPPY) (315, 316). Environmental factor(s) determine
concentrations of TRH and SPPY in frog skin, which are higher than in
any neuroendocrine organ; skin TRH reaches the pituitary to stimulate
production and release of PRL and -MSH, while SPPY inhibits
production of -MSH (315, 316). In mammals, there are other local
hormonal factors that could potentially enter systemic circulation
after UV radiation exposure or in pathological conditions. Among those
are POMC-derived -MSH and ß- endorphin (5, 9, 108, 230),
met-enkephalin (245), PTHrP (15, 302), or DHT, estradiol, and
T3 (4, 11, 12). Skin cytokines can also directly
affect the functional activity of distant immune and nonimmune organs
(7, 11, 17, 27, 108), whereas circulating cytokines are known to affect
hypothalamo-pituitary axis function (24, 25, 26, 27, 28). Thus, IL-1, IL-6,
interferons, and TNF can access brain and pituitary to up-regulate
production and release of selected hypothalamic and pituitary hormones.
Cytokines may have similar action on the regulation of adrenal
gland function (28, 317). Intermediates of melanogenesis
L-DOPA and products of its metabolism in the melanocytes
might also have systemic effects when, under pathological conditions,
they are released into the circulation (10, 23, 318).
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, which can stimulate leptin production by adipose tissue in the
deep dermis and/or subcutis (319, 320). In this manner, small amounts
of cutaneous cytokines could affect feeding behavior and energy balance
(319). Another example is the activation of skin immune cells that can
enter the circulation and have distant immunological or regulatory
effect (7, 27).
Similar to the humoral model of communication in the cutaneous
endocrine system, with potential cytokine-mediated stimulation of the
HPA axis, the cutaneous neural signaling system could also activate
central nervous system pathways. The latter connections have the
advantages of being more rapid with higher specificity (Fig. 6). Thus,
changes in the skin physicochemical environment generated by physical,
chemical, or biological trauma, UV radiation, or local disease
processes could be sensed by afferent nerve ending, and thence
transmitted via the spinal cord to the brain. However, before the
information is sent to the brain, it may be modulated by the local
cutaneous neuroendocrine units through the direct activation of nerve
receptors by neurohormones and neurotransmitters, or by neuropeptides
(cf. Tables 2 and 3), histamine, eicosanoids, NO, and other
proinflammatory mediators (5, 7, 27, 33, 34, 108, 113, 203, 314).
Alternatively, stress released cytokines and proinflammatory biological
modifiers could affect signal type and neural sensor availability
through indirect mechanisms, e.g., activation of other cells
to produce and release factors activating afferent receptors. In this
context, mast cells, melanocytes, Langerhans cells, and Merkel cells
could be particularly important because of their close contact with
nerve endings (33, 34, 110, 111, 119, 203, 305, 306, 307, 308). Secondary changes
in hydrogen ions, cations, free radical and NO concentrations or
eicosanoids produced by cytokine-activated keratinocytes or immune
cells could have similar effects on sensory nerve endings. In the
visceral organs the cytokine IL-1, IL-6, and TNF signals can be
potentially transmitted through an indirect mechanism via the vagus
nerve to the central nervous system (26, 28, 321). Lastly, upon leaving
the skin, some afferent neural signals may also be relayed from the
spinal cord to other organs without ever reaching the higher centers.
To summarize, the skin can generate rapid (neural) or slow (humoral)
moving signals to induce responses at the general or systemic level or
at the organ-specific level. These responses are designed to counteract
the damaging effect of environmental insults or to adjust the
homeostatic system to the optimal mode that would buffer environmental
noxious agents most efficiently.
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VI. Regulation of Cutaneous Neuroendocrine System |
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TopAbstractI. IntroductionII. Structure of the...III. Skin as a...IV. Skin as a...V. Molecular and Structural...VI. Regulation of Cutaneous...VII. Regulation of Cutaneous...VIII. Final Comments and...References |
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A. Solar radiation
UV light is a form of electromagnetic energy that includes the
wavelength between 100 to 400 nm of the solar spectrum. Although it
includes vacuum UV, UVC, UVB, and UVA, only the 290–400 nm wavelengths
that comprise UVA and UVB reach the surface of the earth, because of
the partial absorption by atmosphere. UVB (290–320 nm) interacts very
efficiently with the skin, inducing sunburn and pigmentation (3, 4, 9).
UVA (320–400 nm) has better penetration through the atmosphere but
lower efficiency in inducing erythema and melanogenesis. It is
classified as UVA1 (320–340 nm) and UVA2 (340–400 nm), and it has
been proposed that the photobiological mechanism of action for UVA1 is
similar to that of UVB; the effects of UVA2 would involve distinctive
oxygen-dependent photochemistry. The cutaneous effects of UV radiation
are dependent on the penetration and absorption of the particular
wavelength. In human skin UVB is absorbed predominantly by stratum
corneum and to a lesser degree by the epidermis. The very small
fraction of UVB that reaches the dermis, however, has significant
biological effects inducing immediate and delayed erythema (3, 4, 9).
Transmission of UVA through epidermis of white skin is high, resulting
in approximately 50% of energy reaching the dermis. UVA has only
1/1,000 of UVB biological activity, but it also contributes to the
cutaneous actions of solar radiation (3, 4, 9). Thus, it has a major
effect in aging of the skin, it has a more limited role in the
induction of skin cancer, and it does not produce burning of the skin.
In general, the biological responses to solar radiation are dependent
on individual susceptibility determined by skin pigmentation, prior
exposure to UV radiation (decreases the threshold for subsequent
responses), region affected, radiation field size, and environmental
conditions (3, 4, 9). There is, nevertheless, a high degree of
precision and predictability of the cutaneous response to UV,
demonstrating that mechanisms have evolved to transform some of the
solar energy into a catalyst activating a recording system (9). Such a
recording role could be served by the local neuroendocrine system,
whose activation is designed to buffer or counteract the damaging
effect of UV.
1. CRH-POMC system. UVB stimulates production of CRH peptide
in normal melanocytes without noticeable changes in CRH mRNA levels,
suggesting posttranscriptional regulation (322). UVR can
stimulate/induce POMC gene expression in the skin in human and rodent
normal and malignant keratinocytes and melanocytes maintained in cell
culture (5, 9, 17, 64, 108, 230, 323). The stimulation of ACTH,
-MSH, ß-LPH, and ß-endorphin production and secretion in
response to UVB is dose dependent in normal and malignant epidermal
cells, and in dermal endothelial cells; POMC mRNA production is
correspondingly increased (17, 64, 108, 323). UVA can also stimulate
POMC gene expression with subsequent MSH and ACTH production in human
keratinocytes and endothelial cells (17, 64, 108). This stimulation of
POMC gene expression and production of POMC peptides are observed after
a 10-h latency period; production becomes significant at 10–24 h (17).
Of interest, humans and horses exposed to sunlight exhibit increases in
the circulating levels of -MSH and ACTH, and experimental whole-body
exposure to UVR in humans increases ß-LPH and ß-endorphin serum
levels (5). In the case of ß-LPH the response is abrogated by
UV-absorbing topical sun blockers, implicating mediation by a
photoreaction (324).
UVB can also up-regulate expression of MC1-R on normal and malignant cultured melanocytes and keratinocytes (5, 17, 323). This UVB up-regulation of MSH receptors expression is associated in melanocytes, with increased responsiveness to MSH in terms of stimulation of melanogenesis, as shown in both cell culture and in vivo conditions (75, 323, 325). These experimental findings are consistent with the effects of exogenous MSH and ACTH in humans, which cause increased skin pigmentation affecting predominantly the sun-exposed areas. Clinically, the similarly increased skin pigmentation of patients with Addison’s disease is most striking in the sun-exposed areas. These experimental and clinical observations led Pawelek and colleagues (9, 75, 325) to propose that the effects of UVB on cutaneous melanogenesis do not represent random (unrelated) events but, instead, a highly coordinated sequence in which expression of MSH receptors and local production of POMC-derived MSH and ACTH peptides are important intermediate steps.
2. Immunoregulatory molecules. UV radiation influences the immune system at both local and systemic levels with the net effect being immunosuppressive (7, 17, 64, 82, 108, 114, 326, 327). The mechanism for this action can be either direct absorption of light energy by cells of skin immune system that include resident and nonresident (circulating cells) or indirect through UV-induced activation of nonimmune cells in epidermis and dermis with release of cytokines and chemical mediators (7, 9, 17, 64, 82, 108, 114, 326, 327, 328, 329, 330, 331, 332, 333). Important in this regard is trans-urocanic acid (UCA) which, after absorption of UVB, or to lesser degree of UVA energy, isomerizes into cis-UCA in the stratum corneum (303, 304). cis-UCA acts as a potent local and systemic immunomodulator and immunosuppressor (7, 303, 304).
Keratinocytes stimulated by UVR can produce and secrete the cytokines
IL-1, IL-6, IL-8, IL-10, IL-12, IL-15, TNF, and macrophage
inhibitory factor (MIF), eicosanoids, basic fibroblast growth factor
(bFGF), IGF-I, transforming growth factor (TGF-), and endothelins
(7, 17, 108, 114, 326, 327, 328, 329, 330, 331, 332, 333). This effect is rapid (within 1–3 h) and
predominantly mediated by UVB, although UVA also stimulates IL-10 and,
to a lesser degree, IL-6 production. UVR also switches the local
cytokines and mediators release profile of nonepithelial components of
epidermis and dermis including lymphocytes, macrophages, mast cells,
endothelial cells, and melanocytes. The cytokines IL-1, IL-6, TNF,
and MIF exert local activity, which does not preclude systemic effects
upon entering the circulation.
3. Neuropeptides, neurotrophins, and neurotransmitters. UVA, but not UVB, irradiation increases the skin levels of met-enkephalin, and multiple whole-body UVA exposure can also increase the plasma level of the peptide (245). For its part, UVB induces release of CGRP, SP, and NKA from cutaneous sensory nerves (38, 108). CGRP appears to have immunosuppressive properties, while SP and NKA enhance cutaneous neuroinflammation (38, 108, 114). UVB also stimulates NO production by keratinocytes, melanocytes, and NO release from sensory nerve endings (9, 108, 314). Also, UVB induces production and release of the neutrophin NGF by epidermal keratinocytes (123, 256).
Schallreuter et al. (334, 335) have shown that UVB enhances tetrahydrobiopterin production and phenylalanine hydroxylase activity, with net increase in the epidermal supply of L-tyrosine. L-Tyrosine is a precursor for both catecholamine biosynthesis and melanogenesis. Stimulation of melanogenesis by UVB is associated with increased production of the biologically active products L-DOPA, dihydroxyindole (DHI), and DHI carboxylic acid (9, 123).
B. Hair cycle
Hair growth and the cyclic activity of the hair follicle are timed
by a "biological clock," which in rodents changes periodically the
physiology and morphology of the entire skin (30, 31). In mice, the
expression of POMC gene and production of the POMC peptides
ß-endorphin, ACTH, and -MSH are synchronized with hair follicle
cycle (5). POMC production is lowest in telogen (resting phase),
increases during anagen (growing phase), and decreases in catagen
(involution phase). These changes correlate closely with the local
expression of the MC1 gene (65). The intracutaneous concentration of
CRH and expression of CRH-R1 exhibit similar changes coupled with the
hair cycle, being highest during anagen and lowest during the catagen
and telogen phases (44). A similar phenomenon has been described for
SP, with maximal levels occurring in early anagen and minimal levels
occurring in catagen skin (116). Thus, the biological clock regulating
the cyclic activity of hair follicles appears to regulate
simultaneously the local production or release of neuropeptides and the
expression of the corresponding receptors.
The hair cycle is associated with striking changes, which are qualitative in distribution and quantitative in expression levels of the neutrophins NT-3 and NGF and their corresponding receptors in the skin of the C57 BL/6 mouse (128, 129, 130, 131, 132). Furthermore, the pattern of sensory and sympathetic innervation of different cutaneous structures including the hair follicle itself, shows significant hair cycle-dependent changes (128, 300, 311). The changes in adrenergic innervation are accompanied by specific patterns of follicular ß2-adrenergic receptor expression. Therefore, the whole cutaneous neural network involved in the regulation of hair growth undergoes cyclic changes (128, 300, 311), which can potentially affect the function of other cutaneous structures, sensory skin responsiveness, and transmission of afferent signals to the spinal cord. Because of the extent and magnitude of the hair cycle-dependent changes, it is likely that these are regulated within the skin itself, under the control of the "biological clock" governing hair cycle.
C. Cytokines
Similar to its effects at the central level, the proinflammatory
IL-1 has significant local stimulatory/inductory effects on POMC gene
expression and production of POMC peptides in normal and malignant
epidermal melanocytes and keratinocytes, dermal endothelial cells, and
circulating immune cells that include macrophages (5, 17, 64, 108, 230). Another cytokine, TNF, stimulates production of POMC mRNA in
normal dermal fibroblasts, while TGF-ß inhibits it in keratinocytes
and normal dermal fibroblasts, but not in keloid fibroblasts (231).
TNF also stimulates production of the POMC products ß-endorphin
and ACTH peptides (336). Many cytokines can up-regulate expression of
the MC-1 gene and of functional cell surface MSH receptors in normal
and malignant melanocytes (5, 17, 64, 323). Those include Il-1,
IL-1ß, endothelin-1 (ET-1), adult T cell leukemia-derived
factor/thioredoxin (ADF/TRX), INF-, INF-ß, INF-,
(Bu)2cAMP, and the hormones -MSH, ß-MSH, and
ACTH. IL-1 can also stimulate MC-1 receptor expression in normal and
malignant human keratinocytes and in human dermal microvascular
endothelial cells (HDMEC) (17, 64, 230). Conversely, TNF inhibits
MC1 expression in melanocytes. Thus, selected cytokines regulate
precisely ("fine-tuning") the level of expression of POMC and
MC1-R. The roles of cytokines in the cutaneous regulation of epidermal
cholinergic system, production of catecholamines, steroid synthesis and
metabolism, and synthesis of neuropeptides CRH, urocortin, and
enkephalins remain to be investigated.
D. Degradation or inactivation of hormones and neurotransmitters
One important mechanism regulating the availability of locally
produced hormones is their degradation in situ. In this
context peptide hormones and neuropeptides can be degradated by neutral
endopeptidases (NEP) and angiotensin converting enzyme (ACE), which are
present in dermal fibroblasts, endothelial cells, and keratinocytes
(34, 38, 108, 337). NEP activity is not static, but can be stimulated
by proinflammatory cytokines, by factors raising intracellular cAMP,
and glucocorticoids (38); in addition, its cutaneous pattern of
expression changes during wound healing (337). Other proteolytic
enzymes such as mast cells-derived tryptase or chymase can degrade
neuropeptides, effectively attenuating their activity (7, 34, 38, 108, 115, 203).
Catecholamines and other biogenic amines can be inactivated directly in the epidermis, by the action of MAO and/or by catechol-methyl transferase (21, 268, 269); the latter enzyme has been already characterized in keratinocytes and melanocytes. Acetylcholine is degraded to acetate and choline by epidermal acetylcholinesterase (20, 259). The skin is, in addition, a well recognized site for the transformation of glucocorticoids and sex hormones to molecular forms with higher or lower hormonal activity, or overtly inactive (4, 11, 160, 297).
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VII. Regulation of Cutaneous Vitamin D Production |
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TopAbstractI. IntroductionII. Structure of the...III. Skin as a...IV. Skin as a...V. Molecular and Structural...VI. Regulation of Cutaneous...VII. Regulation of Cutaneous...VIII. Final Comments and...References |
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). Vitamin D3
enters the circulation bound with high specificity to vitamin D binding
protein (DBP) to exert its systemic actions (338). When newly formed
previtamin D3 and vitamin
D3 continue to be irradiated, they convert into
additional steroids such as lumisterol, pyrocalciferol, and
tachysterol, which are practically devoid of vitamin
D3 activity (14). Although light and temperature
are the only variables involved in the biosynthetic process, they do
not account entirely for the rates of biosynthesis observed in tissues.
Thus, irradiation of 7-DHC dissolved in isotropic organic solvents such
as hexane generates only one tenth of the amount observed in similarly
irradiated skin (14). The explanation for this discrepancy was obtained
in experiments with artificial liposomes, which uncovered the crucial
role played by plasma membrane phospholipids in the kinetics of the
reaction. Thus, through amphipatic interactions, previtamin
D3 remains stabilized in its "cholesterol
like" cZc–conformation, the only one leading to conversion to
vitamin D3. Furthermore, the fastest rate of
previtamin D3 isomerization was seen in
association with phospholipids containing 18 carbon atoms in the
hydrocarbon chain (339).
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B. Precutaneous regulation
1. Environment dependent. This category includes geographic
latitude. Thus, as the earth experiences its seasonal tilting during
fall and winter, sunlight arrives at an angle at the more polar
latitudes crossing the atmosphere almost tangentially during winter,
and lessening transmission of UVB wavelengths. For example, during
winter in Boston, Massachusetts (latitude 42.2
oN) these wavelengths disappear (339), and a
similar situation is observed in the Southern Hemisphere, where vitamin
D3 photosynthesis is extremely low during winter
in Cape Town, South Africa (latitude 35oS), but
almost unchanged throughout the year in Johannesburg
(26oS)(340). Another environmental variable is
the time of day, since vitamin D3 synthesis is
maximal at midday, with only very small amounts being formed before
0800 h or after 1700 h. In fact, in Cape Town, only
negligible amounts of previtamin D3 are formed in
the winter before 0010 h and after 1500 h. In general,
latitude, season of the year, and time of day affect the cutaneous
photosynthetic process in a highly coordinated, mutually dependent
manner (14).
2. Environment independent.
a. Clothing.
Garments provide significant protection against
the damaging effects of solar light that include erythema, accelerated
aging, and development of skin cancer. Experiments on transmission of
UVB light through different fabrics showed significant effects on the
photosynthesis of vitamin D3 (341). Of fabrics with similar
thread density, black wool had the highest light absorption coefficient
followed, respectively, by black polyester, black cotton, white cotton,
white wool, and white polyester. All of the fabrics produced
significant attenuation of the shorter wavelengths (UVB), and studies
in volunteers wearing garments made of the same materials showed
complete obliteration of the normal serum vitamin D3
photosynthetic response to one MED (minimal erythema dose) of UVB
(341). This absence of vitamin D serum response persisted after
whole-body irradiation was increased to the equivalent of 6 MEDs. In
addition, regular street clothing, even that worn during summer, also
produced significant suppression of the vitamin D3 response
to UVB (341).
b. Sunscreens.
These agents prevent skin penetration of solar
radiation. Thus, PABA (para-aminobenzoic acid), the common active
ingredient of sunscreens, has an absorption spectrum that overlaps the
spectrum responsible for the photosynthesis of vitamin
D3 (342). As would be expected, application of
PABA to skin pieces blocked the conversion of 7-DHC to previtamin
D3 that normally follows exposure to simulated
sunlight. Moreover, in healthy volunteers, coverage of the whole body
with sunscreens abolished the serum vitamin D3
response to UVB light delivered in a phototherapy unit (342). Also
patients with photodependent cutaneous disorders such as skin cancer,
who must use sunscreen chronically, have lower serum levels of
25-hydroxyvitamin D as compared with matched controls (343).
Nevertheless, it must be noted that these lower 25-hydroxyvitamin D
levels have not been associated with secondary hyperparathyroidism or
metabolic bone disease (344).
C. Cutaneous regulation
1. Regional (anatomical) activity of solar radiation. The
segmental body contributions to the supply of vitamin
D3 were evaluated in healthy individuals who had
sunscreens applied to selected areas of the body before UVB irradiation
(345). Significant and almost equivalent serum vitamin
D3 increases occurred after selective irradiation
of either trunk, legs, or the entire body. UVB exposure of only the
head and neck or arms produced a lesser rise in vitamin
D3 serum levels, which did not reach statistical
significance (345).
2. Race-related skin pigmentation. Melanin is not a "neutral
density" light filter, but exhibits varying absorption coefficients,
with maximal absorption for the shorter wavelengths of the spectrum
(
300 nm) (346). Thus, melanin has a significant effect on the
synthesis of vitamin D3. As would be expected,
the highest vitamin D3 response to UVB is seen in white
individuals, followed by Orientals (East Asians) and Indians (South
Asians) and is extremely attenuated in blacks (African Americans)
(347). This race effect is also associated with lower prevailing levels
of 25-hydroxyvitamin D, although the serum concentrations of
1,25-dihydroxyvitamin D are similar among race groups. The latter
results from the intrinsic properties of the renal enzyme
l-hydroxylase, which can compensate for wide differences in
availability of 25-hydroxyvitamin D (348). Asian Indian individuals,
who have additional peculiarities in their vitamin D metabolism, are
particularly sensitive to the development of clinical vitamin D
deficiency, rickets and osteomalacia, when living in areas with low
levels of ambient sunlight (349).
The UVB light threshold that produced measurable synthesis of vitamin D3 was 18 mjoules/cm2 in a population of white subjects with similar cutaneous photosensitivity (skin type III of the Fitzpatrick-Pathak classification; 1 MED=30 mjoules/cm2), although every dose tested was associated with blood levels higher than baseline (350). Serum GC is another factor involved in the availability of vitamin D3 that could be race dependent. Thus, anthropologists have identified a large number of variants, each related to different human populations. By isoelectric focusing, the observed GC suballele frequencies appear to correlate with skin pigmentation, but electrophoretically identical variants were also found in populations widely differing genetically and geographically (351). From the functional point of view, there is no evidence for differences in vitamin D binding among those variants. Moreover, the serum concentration of GC is similar across race groups that include blacks, whites, Orientals, and Asian Indians (347).
3. Suntanning. In the setting of suntanning, vitamin D3 formation is affected in a complex manner. As already mentioned, both previtamin D3 and vitamin D3 are photosensitive substrates that, if irradiated continuously, undergo further conversion to inactive metabolites while still in the skin (14). Nevertheless, measurements performed in tanned white subjects showed elevated vitamin D3 serum levels with correspondingly higher serum 25-hydroxyvitamin D concentration (352). Acute exposure to UVB radiation resulted, however, in attenuated serum vitamin D3 response, presumably the result of acquired cutaneous melanization (352).
4. Aging. Elderly individuals have lower serum levels of 25-hydroxyvitamin D as compared with their younger counterparts. This aging effect is due to progressive decrease in epidermal 7–dehydrocholesterol substrate content (353). As would be expected, acute irradiation with UVB in older subjects results in blunted serum vitamin D3 responses (354).
5. Cutaneous disease. The only cutaneous disorders in which vitamin D3 formation has been systematically studied are the epidermal disease, psoriasis (355), and the connective tissue disease, progressive systemic sclerosis (356). The latter, although predominantly a dermal disorder, is often associated with epidermal atrophy. Acute irradiation experiments in these two groups of patients did show similar vitamin D3 responses in patients and controls. Moreover, the responses were unrelated to the extent of cutaneous involvement. These results probably reflect the small fraction of irradiated body surface required to sustain the normal vitamin D3 requirements. A small fraction of vitamin D3 formation does occur in the dermis (<10%), which has a much lower 7-DHC content than the epidermis and is less exposed to the low-penetrance shorter light wavelengths responsible for vitamin D3 formation. As mentioned above, the dermal disease, progressive systemic sclerosis, even when widespread, does not interfere with the vitamin D3 response to UVB (356).
D. Postcutaneous regulation
1. Obesity. Overweight appears to represent the only
postcutaneous factor interfering with vitamin D3
photosynthesis. Obese individuals have lower serum 25-hydroxyvitamin D
levels than lean controls and also have blunted response to UVB. Oral
absorption of vitamin D2 is also decreased in
obesity. In vitro experiments of irradiation of skin pieces
from obese and lean individuals showed similar epidermal 7-DHC content
and in vitro response to UVB. These results are suggestive
of defective translocation of the vitamin into the circulation, or
defective plasma transport (357). Of note, obesity is also associated
with increases in plasma FFA, which can displace vitamin
D3 from plasma vitamin D binding protein (358).
E. General comments
An important consideration on the physiology of vitamin
D3 synthesis is that it represents a mostly
biophysical reaction. Thus, the serum vitamin D3
response to UVB is not altered by the oral administration of
pharmacological doses of vitamin D2 (359) or of
1,25-dihydroxyvitamin D (360). There are nevertheless local regulatory
mechanisms that can influence the process. When exposure to sunlight is
excessive, inactivation of previtamin D3 and vitamin
D3 itself are well known consequences. Moreover,
when high irradiance levels are sustained, melanocyte activity is
enhanced, resulting in tanning and blunted response to acute UVB
exposure. The opposite situation, decreased exposure to UVB with
reduced vitamin D3 production, can be
compensated, at least partly, by enhanced activity of the renal
1-hydroxylase enzyme (348).
Lastly, there has been some controversy regarding the significance of findings in acute vs. chronic studies evaluating the vitamin D response to UVB. Within this context, it must be noted that acute studies are performed under more stringent conditions, i.e., mostly during the winter, to prevent the interference of ambient sunlight, which involves exposure of the whole body to UVB, and require a phototherapy unit that must be continuously calibrated. It is then apparent that biological significance is better evaluated in larger populations. Thus, small acute responses that do not reach statistical significance, such as those observed after selective irradiance of the upper extremities or head and neck, or after subthreshold doses of UVB, may still result in normal vitamin D3 levels, when irradiation is continued through much longer periods. A similar explanation would be operative in black individuals, who show lack of response to acute UVB irradiance, yet also exhibit the normal seasonal variance (UVB dependent) in 25-hydroxyvitamin D serum levels (361).
|
VIII. Final Comments and Future Directions |
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TopAbstractI. IntroductionII. Structure of the...III. Skin as a...IV. Skin as a...V. Molecular and Structural...VI. Regulation of Cutaneous...VII. Regulation of Cutaneous...VIII. Final Comments and...References |
|---|
This field represents, therefore, a fertile ground for future studies
on cutaneous biology, including the application of more advanced
methodology to confirm previous findings; the determination of other
hormonal factors that could be produced by the skin; and the further
definition of existent or yet-to-be-discovered regulatory pathways.
Moreover, the potential clinical implications cannot be overlooked, as
this area opens the possibility for multiple points of interaction on
ongoing pathological processes. Possible pathological target conditions
include not only inflammatory diseases, but benign hyperproliferative
skin disorders, vasculopathic and autoimmune reactions, disorders of
pigmentation and hair cycling, and malignant processes such as melanoma
development and epidermal carcinogenesis. Specifically, locally
produced POMC peptides ACTH and -MSH can affect skin functions by
enhancing melanogenesis, stimulating hair growth and sebaceous gland
functions, and attenuating inflammatory responses. CRH, in addition to
its local vasodilatory and proinflammatory effects, may also inhibit
proliferation of epidermal keratinocytes. Vitamin D is already used in
the therapy of psoriasis, and glucocorticoids are drugs of choice in
the treatment of inflammatory skin disorders. Finally, the
multidirectional communication between skin, endocrine, immune, and
central nervous systems suggests that the skin may be an important
regulator of global homeostasis acting as a sensor for external or
internal disturbances, and as an effector/producer of humoral or neural
signals sent to other coordinating centers. In this context, the
possibility of pathological consequences for dysregulation in this
cutaneous neuroendocrine system poses a powerful challenge that can
only be addressed with a strong, coordinated, and multidisciplinary
approach.
|
Acknowledgments |
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|
Footnotes |
|---|
1 This work was supported by grants from National Science Foundation
(NSF) (IBN-9604364, IBN-9896030, and IBN-9405242), and American Cancer
Society, Illinois Division (no. 99–51) to A.S., and internal funding
from the Department of Pathology, University of Tennessee. 
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References |
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TopAbstractI. IntroductionII. Structure of the...III. Skin as a...IV. Skin as a...V. Molecular and Structural...VI. Regulation of Cutaneous...VII. Regulation of Cutaneous...VIII. Final Comments and...References |
|---|
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