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Correspondence to: Anthony J. Thody, Dept. of Biomedical Sciences, University of Bradford, Bradford BD7 1DP, UK. E-mail: a.j.thody@bradford.ac.uk
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Summary |
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Melanocytes are cells of neural crest origin. In the human epidermis, they form a close association with keratinocytes via their dendrites. Melanocytes are well known for their role in skin pigmentation, and their ability to produce and distribute melanin has been studied extensively. One of the factors that regulates melanocytes and skin pigmentation is the locally produced melanocortin peptide -MSH. The effects of
-MSH on melanogenesis are mediated via the MC-1R and tyrosinase, the rate-limiting enzyme in the melanogenesis pathway. Binding of
-MSH to its receptor increases tyrosinase activity and eumelanin production, which accounts for the skin-darkening effect of
-MSH. Other
-MSH-related melanocortin peptides, such as ACTH117 and desacetylated
-MSH, are also agonists at the MC-1R and could regulate melanocyte function. Recent evidence shows that melanocytes have other functions in the skin in addition to their ability to produce melanin. They are able to secrete a wide range of signal molecules, including cytokines, POMC peptides, catecholamines, and NO in response to UV irradiation and other stimuli. Potential targets of these secretory products are keratinocytes, lymphocytes, fibroblasts, mast cells, and endothelial cells, all of which express receptors for these signal molecules. Melanocytes may therefore act as important local regulators of a range of skin cells. It has been shown that
-MSH regulates NO production from melanocytes, and it is possible that the melanocortins regulate the release of other signalling molecules from melanocytes. Therefore, the melanocortin signaling system is one of the important regulators of skin homeostasis. (J Histochem Cytochem 50:125133, 2002)
Key Words: skin pigmentation, pro-opiomelanocortin peptides, melanocortin receptor 1, nitric oxide
Melanocytes are key components of the skin's pigmentary system through their ability to produce melanin. These cells are found at many locations throughout the body. In the skin they are associated with the hair follicle and in some mammals, including humans, are also found in the basal layer of the interfollicular epidermis. Mature melanocytes form long dendritic processes that ramify among the neighboring keratinocytes. In this way, each melanocyte makes contact with around 3040 keratinocytes and this constitutes the epidermalmelanin unit. This association enables the melanocyte to transfer melanin into the keratinocytes, where it determines skin color and helps in protecting against the damaging effects of ultraviolet radiation (UVR). The mechanisms involved in the production of melanin and how they are regulated in the tanning response are still far from clear. During recent years interest has focused on the role of the melanocortin signaling system, and there is evidence that the melanocortin-1 receptor (MC1-R) is a key control point for both constitutive and facultative skin pigmentation. It has been known for 40 years that melanocortin peptides, such as -MSH and ACTH, increase skin darkening in humans (
-MSH affects several aspects of melanocyte behavior. Although certain of these actions could be important for pigmentation, the possibility exists that
-MSH has actions in the melanocyte that are unrelated to pigmentation.
There is increasing evidence that melanocytes are not simply melanin-producing cells but may have a number of functions. Melanocytes are capable of secreting a wide range of signaling molecules and it has been suggested that they could function as regulatory cells in maintaining epidermal homeostasis (-MSH might be an integral part of such a function. This article reviews the role of the epidermal melanocyte in human skin pigmentation, its control by the melanocortin signaling system, and explains how, by studying this control system, we are beginning to appreciate more about the functions of this particular cell.
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Melanocytes and Skin Pigmentation |
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Melanocytes are derived from the neural crest. During development, presumptive melanocytes (melanoblasts) migrate to various sites including the skin, where they proliferate and then differentiate into melanin-producing cells.
Under normal conditions it is not the numbers of melanocytes in the skin that determine the degree of pigmentation but their levels of activity. Although there are regional variations in the density of epidermal melanocytes, their numbers are consistent even in different skin types and ethnic groups. Therefore, constitutive or basal skin pigmentation is considered to depend on the level of melanogenic activity and the transfer of melanin into the neighboring keratinocytes. The type of melanin is also likely to be important, and it is recognized that human melanocytes produce both the brownblack eumelanin and reddishyellow phaeomelanin (
The synthesis of melanin takes place in the melanosome. This is a specialized intracellular membrane-coated organelle that originates from the endoplasmic reticulum. During its development the melanosome acquires tyrosinase and the tyrosinase-related proteins 1 and 2 (TRP1, TRP2). Tyrosinase is the rate-limiting enzyme for melanogenesis and catalyzes the conversion of L-tyrosine to dopaquinone, which is required for the synthesis of both eumelanin and phaeomelanin. It may also catalyze later steps specific to the eumelanin pathway and this could explain why eumelanogenesis is especially dependent on tyrosinase. Less is known about the control of phaeomelanin synthesis, although it appears to be less dependent on tyrosinase and can proceed even when the levels of tyrosinase activity are virtually undetectable (
Once melanin is produced the melanosomes are transferred into the neighboring keratinocytes. The size of these organelles and their numbers are important in determining pigmentation. The melanosomes in black skin are larger than their counterparts in white skin and are packaged as single units rather than in groups. This has the effect of retarding their degradation in the keratinocytes and contributes to a higher level of skin pigmentation. At present, little is known about the mechanisms and regulation of melanosome transfer. It appears that association of melanosomes with microtubules and actin filaments via motor proteins, such as kinesin, dynein, and myosin V, is important for melanosome movement along the dendrites and for subsequent transfer to keratinocytes (
An increase in skin pigmentation over the basal constitutive level is referred to as facultative pigmentation. A major stimulus of facultative pigmentation in humans is UVR. UVR-induced skin pigmentation or tanning, as it is commonly known, involves several processes. There is an increase in the numbers of active epidermal melanocytes, but whether this is a result of increased proliferation, enhanced recruitment, or both events is not entirely clear. The expression of tyrosinase and other related melanosomal proteins are also increased in response to UVR and, as a result, melanogenesis is stimulated. Although phaeomelanogenesis and eumelanogenesis are increased in response to UVR, it is the concentrations of eumelanin that correlate better with the degree of tan. Therefore, eumelanin is believed to make the greater contribution in the tanning response (
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Melanocortins Function as Mediators in the Pigmentary Response |
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-MSH is produced, together with several other peptides, by the proteolytic cleavage of the large precursor protein pro-opiomelanocortin (POMC). The main site of
-MSH production is the pars intermedia of the pituitary gland. However, because of its poorly developed pars intermedia, the human pituitary secretes only small amounts of
-MSH except under pathological conditions (
-MSH and other melanocortin peptides are produced at extrapituitary sites, including the skin (
-MSH (
-MSH could act as a paracrine and an autocrine factor in the regulation of melanocytes and skin pigmentation. In addition to its effects on melanocortin peptide secretion, UVR upregulates the expression of the
-MSH receptor on mouse melanoma cells (
-MSH to human melanocytes (
-MSH in the skin but also the responsiveness of the melanocytes to this peptide. It therefore appears likely that
-MSH and possibly other melanocortins function as mediators of the pigmentary response in the skin.
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How Does ![]() |
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Melanocortin peptides exert their effects through melanocortin receptors (MC-Rs). These are seven transmembrane domain G-protein-coupled receptors, and to date five subtypes have been cloned. The MC-1R, which was the first subtype to be sequenced and characterized (-MSH activates adenylate cyclase which, in turn, causes an increase in intracellular cAMP. This is the classical pathway by which
-MSH is believed to mediate its melanogenic effects on melanocytes. Increases in cAMP result, via protein kinase A (PKA), in the activation of tyrosinase, the rate-limiting enzyme in the melanin pathway. Evidence suggests that
-MSH increases the expression, de novo synthesis, and activation of tyrosinase (
-MSH to its receptor must not be excluded. For example, there is evidence that protein kinase C is involved in mediating the melanogenic actions of
-MSH (
-MSH is able to regulate tyrosinase activity independently of the MC1-R.
-MSH binds (6R)-L-erythro 5,6,7,8 tetrahydrobiopterin (6-BH4) and the latter has been shown to regulate the availability of L-tyrosine and the activity of tyrosinase in melanocytes (
-MSH is particularly abundant in human melanocytes (
-MSH exceed those of 6-BH4, then the peptide itself could function as a substrate for tyrosinase by virtue of its tyrosine residue in position 2. The availability of 6-BH4 in the melanocyte may therefore be important for melanogenesis and in determining responsiveness to
-MSH.
Rather than producing large increases in melanin, -MSH regulates the pattern of melanogenesis by preferentially stimulating the synthesis of eumelanin at the expense of phaeomelanin (
Stimulation of melanogenesis is not the only effect of -MSH on human melanocytes. For example, there is evidence that
-MSH stimulates melanocyte dendricity (
-MSH may be vital for the pigmentary response. It is not clear how
-MSH acts to stimulate melanocyte dendricity, but this process may be dependent on activation of several intracellular signaling pathways. It appears likely that cAMP is important, and there is evidence that, by acting on the GTP-binding proteins Rac and Rho, cAMP increases actin disorganization and promotes melanocyte dendricity (
-MSH affects melanocytes, and possibly pigmentation, is by protecting these cells from the damaging effects of oxygen radicals, such as the superoxide anion (
-MSH could also protect melanocytes through its ability to complex with 6-BH4. As discussed above, the latter controls melanogenesis but its oxidized product, 6-biopterin, is cytotoxic to melanocytes (
-MSH could control the redox status of the pterin and in this way affect both melanogenesis and melanocyte survival.
The acetylated form of -MSH has been the most well studied of the pigmentary melanocortins and is considered to be an important regulator of the pigmentary response in lower vertebrates and many mammals. However, the predominant form of
-MSH in human skin, as in the hypothalamus, is desacetyl
-MSH (
-MSH (
-MSH acts as a partial agonist at the human MC1-R and thus, by opposing the actions of acetylated
-MSH, could influence melanogenic responses (
-MSH acts in a similar way to oppose the actions of
-MSH on the melanophores of the Anolis lizard (
ACTH peptides, e.g., ACTH139 and ACTH117, are also found in human skin and in greater abundance than -MSH (
-MSH, is particularly active in this respect (
-MSH, which produces a typical sigmoidal doseresponse curve, ACTH peptides produce a biphasic doseresponse melanogenic curve in human melanocytes (
-MSH peptides. Therefore, whereas
-MSH activates the cAMP pathway, ACTH117 may stimulate MC-1R coupling to both the cAMP- and IP3-dependent pathways (
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Is the MC-1R a Control Point in the Regulation of Pigmentation? |
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As mentioned above, activation of the MC-1R could be pivotal for UVR-induced melanogenesis. However, at present little is known about the transcriptional regulation of MC-1R expression beyond the effects of UVB and peptides, such as endothelin-1, that are released in the skin in response to UVR (see review by -MSH and ACTH (
-MSH. Melanocytes from red-haired persons were totally unresponsive, failing to show melanogenic and dendritic responses to
-MSH and/or ACTH when in culture (
Many MC-1R mutants have been identified in humans and mammals and were shown to be associated with pigmentation phenotypes (-MSH (
There are some doubts as to whether the MC-1R is the only control point for the red-hair phenotype. There have been reports of homozygous and compound heterozygous mutations of the MC-1R in individuals that do not have red hair (-MSH also failed to respond to cAMP with increases in melanin content, suggesting that the unresponsiveness was due to factors downstream of the MC-1R (
MC-1R alleles, including the Val60Leu variant, have also been identified in an Asian group (-MSH. This is consistent with the view that Asians may express non-functional MC-1R alleles (
The above observations on Asian and African populations suggest that, in dark skin types, the inherited high level of melanogenesis is not necessarily dependent on the functionality of the MC-1R receptor. Recent evidence suggests that there are control points downstream of the melanocortin signaling system that could be important in the regulation of tyrosinase and hence melanogenesis. One such control point is the active transport of L-phenylalanine into melanocytes and its conversion to L-tyrosine by phenylalanine hydroxylase (
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As well as producing melanin, melanocytes are able to secrete a wide range of signal molecules in response to UVR and other stimuli. One such substance is nitric oxide (NO) (
Human melanocytes produce NO in response to UVR and bacterial lipopolysaccharide (LPS) (-MSH could modulate these effects of UVR and LPS. It was found that
-MSH alone could increase NO production but, when present together with LPS, it inhibited the stimulatory effect of the latter. How
-MSH acts to affect the production of NO in melanocytes is not clear. NO is produced via the enzymatic action of nitric oxide synthase (NOS), of which both constitutive (cNOS) and inducible (iNOS) isoforms exist. In melanocytes iNOS expression was seen in control unstimulated cells, and this suggests that, contrary to the situation in most cell types, low levels of iNOS are constitutively expressed in melanocytes (
-MSH modulates the activity of iNOS and hence NO production from melanocytes. It has been recently shown that
-MSH is indeed able to inhibit NF
B in melanocytes, a transcription factor directly involved in the activation of the iNOS gene transcription (
-MSH may also act via this NOS isoform.
One should not exclude the possibility that -MSH could regulate NO production through a mechanism independent of the MC-1R. As discussed above, there is evidence that
-MSH can act intracellularly to regulate melanogenesis through interactions with 6-BH4 (
-MSH complexes with this pterin, then this would affect the activity of iNOS and hence NO production.
It is not clear why melanocytes and melanoma cells produce NO.
An alternative possibility is that the NO produced by melanocytes serves as a second messenger in regulating their differentiation, analogous to the situation in neuronal cells. In the latter, the induction of NOS by nerve growth factor causes growth arrest and differentiation (-MSH has similar effects in melanocytes (
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What is the True Role of the Melanocyte? |
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There is no doubt that melanocytes are able to produce and distribute melanin via their dendrites to surrounding keratinocytes, and hence function as key components of the pigmentary system. However, melanocytes are also able to produce a wide range of signal molecules, such as cytokines (
Nevertheless, it appears that melanocytes are not simply melanin-producing cells and may have some other physiological significance. It has been proposed that melanocytes act as local "stress sensors" in the epidermis ( (
-MSH could also reflect some role in the modulation of the immune system. There is considerable evidence that
-MSH has potent anti-inflammatory and immunomodulatory properties through its ability to antagonize the actions of proinflammatory cytokines (
It is perhaps significant that several of the substances produced by melanocytes have inflammatory properties. This therefore raises questions as to whether melanocytes might contribute to inflammatory dermatoses and UVR-induced erythema. Because the latter tends to be inversely related to tanning ability, one could speculate that the secretion of inflammatory mediators and the production of melanin by melanocytes are reciprocally related. -MSH may well have a role in coordinating these responses. Therefore, on the one hand,
-MSH might stimulate melanin production by the melanocyte and, on the other hand, it might act to modulate the production of NO and other inflammatory mediators.
In conclusion it may be some time before we fully appreciate the precise significance of the melanocyte. Nevertheless, it is clear that the melanocyte is more than a melanin-producing cell. The melanocyte is likely to have a number of extra-pigmentary functions and, whatever these functions, it is reasonable to suppose that, like melanin production, they are regulated by the melanocortin signaling system.
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Acknowledgments |
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The financial support of Stiefel International is gratefully acknowledged.
Received for publication March 20, 2001; accepted August 2, 2001.
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