Cl Mo&~u~r and Cellular E~do~r~olo~, 93 (1993) Cl-C6 0 1993 Elsevier Scientific Publishes Ireland, Ltd. 0303-7207/93/$~.~

MOLCEL 03006

At the Cutting Edge

On. the potential role of proopiomelanocortin in skin physiology and pathology

Andrzej Slominski a, Ralf Paus b and Jacob0 Wortsman ’ ’ Department of Microbiology, immunology and Molecular Genetics, Albany Medical College, Albany, New York, USA;

’ Department o~~e~tolo~, Uniue~i~ Hos~.tal R. Virchow, Freie Universit~t Berlin, Berlin, peony; ’ ~~~rnent of ~e~&ine Southern 111~~ U~uers~~~ Spinal lll~~, USA

(Received 24 November 1992; accepted 19 February 1993)

Key words: Pro-opiomelanocortin; Skin; Melanotropin; Adrenocorticotropin; Endorphin; Stress

Summary

Pro-opiomelanocortin (POMC) is the precursor of ACI’H, cu-MSH and P-endorphin, neuropeptides with multiple regulatory functions. Both the pituitary gland and peripheral tissues such as mammalian skin are capable of generating POMC-derived neuropeptides. Mammahan skin is also a target for POMC products; their possible roles in skin physiology and patholo~ are discussed in this ~mmunication.

Background

Pro-opiomelanocortin (POMC) is the precursor of the biologically active molecules adrenocorticotropin (ACTH), endorphins, melanotropins (MSH) and lipotropins (LPI-I) (Smith and Funder, 1988). The gene coding for POMC is transcribed predominantly in the pituitary gland, which releases POMC peptides into the blood. POMC expression has also been detected in the central nervous system (Autelitano et al., 1989); in a variety of peripheral tissues such as gonads, thyroid, pancreas and gastrointestinal tract (DeBold et al., 1988; Clark et al., 1989; Drouin et al., 1989); in cells of the immune system (Oates et al., 1988; Blalock, 1989); and in nonpituitary tumors (DeBold et al., 1988; Clark et al., 1989), including skin cancers (Slominski, 1991; Slominski et al., 1992c).

POMC gene The mammali~ POMC gene contains three exons

and two introns that are spliced out from the primary transcripts to generate a POMC mRNA of about 1.1 kb in the pituitary gland and the hypothalamus (Aute- litano et al., 1989). Shorter and longer POMC tran- scripts have also been found but only in extrapituitary

Correspotie~ce to: A. Slominsky, Dept. of Microbiology, Im- munology and Molecuiar Genetics, Albany Medical College, Albany, NY 12208, USA.

tissues and tumors of nonpituitary origin (DeBold et al., 1988; Clark et al., 1989; Drouin et al., 19891, including melanomas (Slominski, 1991). It has been postulated that POMC mRNA size-heterogeneity may variously represent alternative splicing, variation in the length of the poly +(A) tail, or use of alternative transcription initiation sites (Chang et al., 1989).

POMC processing POMC mRNA is translated into a single primary

product, and the different regulatory neuropeptides are generated by subsequent tissue-specific processing and postranslational modifications that include endo- and exopeptidase cleavage a-amidation and acetylation (Smith and Funder, 1988). Recent interest in posttrans- lational processing has focussed on the role of tissue specific ‘prohormone convertases’ e.g., mPC1, mPC2 in the mouse (Marx, 1991; Seidah et al., 1992). The strik- ing structural and functional similarities with conver- tases of two seemingly unrelated enzymes, yeast pro- tease kex2 and furin, a product of the mammalian protooncogene fes/fps (Marx, 1991; Seidah et al., 19921, had led to the suggestion that prohormone pro- cessing is evolutionarily highly conserved and that it represents a critical step in the controlled generation of distinct regulatory peptides from a single precursor. The factors regulating convertase expression and activ- ity are still undefined, although POMC gene transcrip- tion and release of POMC-derived peptides are clearly under multiho~onal control (CRH, glucocorticoids, dopamine/GABA, Jones and Gillham, 1988; Aute-

litano et al., 1989). This control is lobe-specific in the pituitary, and organ-specific in peripheral tissues.

Secretory POMC peptides Physiologically, the most important POMC-derived

peptides are ACTH, /3-endorphin and the a-, /3- and y-MSH peptides (Ling et al., 1979). The POMC prod- ucts are now recognized as key signal molecules in the bidirectional communication between the immune and neuroendocrine system and in stress responses (Blalock, 1989; McCubbin et al., 1991). Depending on site of production and target tissue, POMC neuropeptides can act as hormones, neurotransmitters, growth factors and/or biological response modifiers. The POMC pep- tides implicated in the regulation of skin function are ACTH and melanotropins (Eberle, 1988; Fitzpatrick et al., 1987). Each of the melanotropins derives from a different region of the POMC molecule: y-MSH from the 16 kDa N-terminal fragment, &MSH from the C-terminal p-LPH, and (w-MSH is the C terminally amidated first 13 amino acids of the intervening ACTI-I sequence. MSH peptides share the common sequence -Tyr-x-Met-x-His-Phe-~g-Trp-, of which the tetrapep- tide His-Phe-Arg-Trp is critical for the malanotropic activity (Hadley, 1988; Hruby et al., 1987). Both ACTH and a- and /3-MSH peptides appears to be involved in the regulation of melanocyte activity (Lerner and McGuire, 1961; Eberle, 1988; Hadley, 1988).

POMC peptides in the skin Recently, immunoreactive fragments of POMC and

POMC mRNA have been detected in keratinocytes cultured in vitro (~ornisiripanit~h and Nordlund, 1989; I&k et al., 1990), and in mammalian skin (Slominski et al., 1992a). Both POMC-derived antigens (Lunec et al., 1990) and POMC gene transcription (Slominski, 1991) have also been detected in melanomas, melanocytic tumors of cutaneous origin. These data form the basis for the inclusion of mam- malian skin among the tissues capable of expressing and translating the POMC gene, raising therefore questions on the functional significance of POMC-de- rived peptides in the context of skin physiology and pathology.

POMC expression in the skin

The concept that the skin may produce POMC peptides originated from the observations of Thody et al. (19831, who identified a-MSH in human and rodent epidermal extracts in these experiments detection of cu-MSH was unrelated to either serum MSH concentra- tion or skin pigmentation (Thody et al., 1983). Expres- sion and translation of the POMC gene was initially reported in murine epidermal cells (Amornisiripanitch and Nordlund, 1989). Subsequently, K&k et al., (1990)

using cultured human keratinocytes, also reported POMC gene expression and production of cr-MSH and ACTH (Kock et al., 1990). In addition, they showed that (r-MSH and ACTH release was stimulated by UV light, IL-1 and IL-4, but not by LPS, GM-CSF, IL-6 or TNF.

Functional correlates of the cutaneous expression of POMC

Developmentally-associated regulation of POMC expression in ma~alian skin has recently been shown in C57BL6 mice (Slominksi et al., 1992a). In this species POMC expression is restricted to the growth phase of the hair cycle (anagen) with P-endorphin readily detec- talbe in the sebaceous gland of anagen follicles (Slominski et al., 1992a). These data suggest that murine skin can not only transcribe and translate the POMC gene, but also process its products, in syn- chrony with the developmental stage of the hair cycle. More recently, we detected ACTH, /3-endorphin, p- MSH and y3-MSH antigens in whole human skin biopsies, using standard ~un~t~hemical tech- niques (Slominski et al., 1992~). Previously Johansson et al, (1991) have found y-MSH antigen(s) by indirect immunofluorescence in neutrophils and nerve endings of human trunk skin. In our studies, POMC antigens in normal human skin were restricted to scalp skin, local- ized in the hair bulb keratinocytes of anagen hair follicles (Slominski et al., 1992~).

Murine and human skin differ in localization and type of POMC-derived antigens while /3-endorphin im- munoreactivity in murine skin is restricted to seba- ceous glands, none of a battery of POMC-derived antigens was detected in sebaceous glands of human skin, though some immunoreactivi~ was found in ker- atinocytes of human-hair follicles (Slominski et al., 1992a,c). POMC-derived antigens which are unde- tectable in normal human trunk skin were, however, often seen in biopsies of pathologic skin specimens including inflammatory lesions, epithelial tumors and tumors of melanocytic origin (Slominski et al., 1992~). These observations complement the previously re- ported detection of POMC mRNA (and POMC anti- gens) in human basal cell carcinoma (K&k et al., 19901, in murine and hamster melanoma cells (Slomin- ski, 1991) and of a-MSH in human melanomas (Lunec et al., 1990). Taken together, these data suggest that local POMC peptides production and secretion may be involved in the modulation of skin function under normal and pathologic conditions.

Production of POMC peptides Though the studies quoted above provide strong

evidence for the production of POMC peptides by mammalian skin, the processing of the precursor pro- tein differs in skin and pituitary. Most important, the

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POMC mRNA detected in the skin (0.9 kb) (Slominski et al., 19921, is shorter than in the pituitary (1.1 kb) (Autelitano et al., 1989). It is unclear whether smaller mRNAs are translated or whether they lack the signal peptide enabling the end products to exit the cell (Clark et al., 1998; Jeannotte et al., 1987). However, the POMC mRNA found in placenta, testis and ovary which is only 0.8 kb, is known to be associated with the presence of secretory POMC peptides (Jeannotte et al., 1987; Petraglia et al., 1987; Li et al., 1991). Further- more, mechanisms for the translocation of peptides and proteins lacking signal sequences have been re- cently described (Kuchler and Thorner, 1992).

It remains to be determined whether tissues which generate smaller POMC transcripts, e.g., skin, testis, ovary and placenta, produce native or variant forms of MSH or ACTH peptides. Also unclear is the relation between POMC expression, in resident skin cells and in cells of immune origin that can also produce and secrete POMC peptides (cf Autelitano et al., 1989; Blalock, 1989); on this question in situ hybridization and immunocytochemistry may provide definitive infor- mation. In other tissues, for example the lung, POMC gene expression was detected in monocyte-macro- phages (Mechanick et al., 1992); while in the gonads it was detected in both monocyte-macrophages and in resident testicular Leydig cells (Li et al., 1991). The skin, being a powerful immune organ, contains abun- dant immune response-associated cells (e.g. ker- atinocytes, Langerhans cells, endothelial cells, mast cells, tissue macrophages and T lymphocytes) in addi- tion to a variety of other cells (keratinocytes, fibro- blasts, sebocytes, eccrine and aprocrine gland cells with their myoepithelial and duct cellular components, melanocytes, lipocytes, pericytes, smooth muscle, Merkel cells and nerve dendrites) (Bos, 1990). All these cell types could theoretically generate POMC peptides, in addition to cells recruited into the skin such as monocytes, granulocytes, mast cells, and the pool of circulating immune cells (Bos, 1990). Thus various cellular compartments may differentially ex- press, secrete and process POMC peptides in response to possibly distinct regulatory mechanisms.

Skin as a target for POMC peptides

The skin is a recognized target for POMC-derived peptides (cf Eberle, 1988; Fitzpatrick et al., 1987; Goldsmith, 1991; Hadley, 1988; Rheins et al., 1989). For example, humans with pathologically increased levels of plasma ACTH (ectopic ACTH production by tumors, Cushing’s syndrome) have hyperpigmentation and skin atrophy, and elevated serum concentrations of a-MSH are associated with enhancement of skin pig- mentation (Eberle, 1988; Fizpatrick et al., 1987; Hadley, 1988; Pears et al., 1992). In humans, administration of

a-MSH or ACIH stimulates melanogenesis and hyper- pigmentation, and may induce skin atrophy (Eberle, 1988; Fitzpatrick et al., 1987; Hadley, 1988). The new superpotent a-MSH derivatives may even stimulate skin tanning (Levine et al., 1991) when injected subcu- taneously. In rodents the application of (u-MSH in vivo can stimulate melanogenesis and/or regulate the type of melanin produced (Hadley, 1988; Hirobe, 1992).

Melanocytes Cell surface receptors for MSH have been detected

and characterized in normal human melanocytes (Donatien et al., 19921, and MSH- and ACTH-recep- tors have been characterized in malignant human and rodent melanocytes (Eberle, 1988; Pawelek, 1985). The cDNAs for the ACTH and MSH receptors have been subsequently cloned, and transcription of the MSH receptor gene detected in normal human melanocytes (Mountjoy et al., 1992). In culture, a-MSH stimulates proliferation of normal human melanocytes (Herlyn et al., 1988) and the differentiation of normal rodent melanocytes (Hirobe, 1992) (Y-, P-MSH and ACTH can stimulate malanogenesis and dendrite formation and either inhibit or stimulate proliferation of rodent ma- lignant melanocytes, depending on genotype and cul- ture conditions (Eberle, 1988; Pawelek, 1985). There is thus good evidence that MSH and ACTH peptides directly regulate complex melanocyte functions in mammals.

J?-MSH, y-MSH The functional relevance of P-MSH in mammalian

skin pigmentation has been questioned, because some authors have considered the peptide to be an artifact of the proteolytic degradation of P-LPH (Scott and Lowry, 1974). However, studies by Bertagna et al. (1986) convincingly demonstrated that P-MSH is a normal product of POMC processing in human nonpi- tuitary tissues, supporting previous suggestions that P-MSH stimulates skin pigmentation in humans (Lerner and McGuire, 1961), and changes the phenotype of rodent melanoma cells in vitro (Eberle, 1988; Pawelek, 1985; Slominski et al., 1989). y-MSH peptides have low intrisic melanotropic activity in murine and hamster malignant melanocytes (Slominski et al., 1992b) and minimal melanogenic activity on frog and lizard melanophores (Eberle, 1988; McCormack et al., 1982; O’Donohue et al., 1981). Though the overall role of y-MSH peptides in the regulation of mammalian pig- mentation may be small, selected y-MSH peptides could modulate pigmentation by modifying the cellular response to other melanotropins. For example, y,-MSH may potentiate the melanogenic activity of P-MSH, while -y3-MSH - acting as a partial agonist at MSH receptors - could largely inhibit the melanogenic activ- ity of /3-MSH (Slominski et al., 1992b).

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Hair fo&li~les Hormone-sensitive skin appendages are another cu-

taneous target for POMC-derived peptides. Specific binding sites for a-MSH have been detected in human hair follicles (Naninga et al., 1990, while immunoreac- tive POMC-derived peptides have been actually ob- served in follicle keratinocytes (Slominski et al., 1992c). The possibility that hair follicles may be a target for POMC peptides is further supported by the anagen dependence of POMC gene expression in murine skin (Slominski et al., 1992a). Recently we observed rapid hair growth induction in the skin of C57BL6 mice after intradermal injection of ACTH, coincidental with mast cell degranulation (Paus et al., unpublished). ACTH and B-endorphin are both known to be mast cell secretagogues in vitro (Goldsmith et al., 1991).

Sebaceous gland The sebaceous glands are known targets for POMC

peptides, inasmuch as ACTH, (r-MSH and p-LPH have sebotropic activity (Thody and Shuster, 1989). Prolonged administration of synthetic ACTH may in- duce acne, h~e~i~entation and h~e~richosis in humans (Fitzpatrick et al., 1987; Hadley, 1988). It is still unclear to what extent this represents a direct effect on sebocyte functions since the common amino acid backbone responsible for the melanotropic activity does not appear to be involved in the regulation of sebaceous gland activity (Thody and Shuster, 1989). Interestingly, murine sebaceous glands express p-en- dorphin immunoreactivity in a hair cycle-dependent manner (Slominski et al., 1992), which raises the possi- bility that sebocytes themselves may generate /3-en- dorphin.

Keratinocytes The direct effects of melanotropins, corticotropins

and endorphins on keratinocyte functions have not been yet fully evaluated. When selected y-MSH pep- tides are added to telogen-mouse skin grown in organ culture, there is an increased proliferation rate of epidermal keratinocytes, with effects which are signifi- cant for y,- yz- and /3-MSH but not for y,-MSH (Slominski et al., 1991a,b). MSH binding also been detected in cultured malignant and normal human keratinocytes ~Birchall et al., 1991; Pawelek, personal communication).

Immunomodulation Melanocytes may also have functions unrelated to

melanogenesis, such as immunomodulation by the stimulation of cytokine production by (Y-, p- and y- MSH and /3-MSH peptides, as reported by Schauer et al. (1992) in cultured human melanocytes. It has been further suggested that immunomodulatory functions reflect mainly rx-MSH activity (Hiltz et al., 1991; Smith

et al., 19921, which may thus play a role in the patho- genesis of cutaneous contact hypersensitivity (Rheins et al., 1989). cu-MSH is a recognized IL-1 antagonist (Daynes et al., 1987) that may inhibit interferon-y (INF-y) synthesis by human peripheral blood mononu- clear cells, and INF-y induced MHC class I transcrip- tion (Schaurer et al., 1992). The amino acid sequence responsible for the anti-inflammatory activity of cu-MSH is contained in the 11-13 residues of the C-terminus (Hilts et al., 1991). Since p-endorphin and ACTH have been reported as potent immunomodulators that may act directly on immun~es (Blalock, 1989, Smith et al., 19921, they may play similar roles in the skin immune system. Thus, both human and rodent skin display multiple potential cellular targets for bioregula- tory actions of POMC-derived peptides. Classification of cutaneous targets will require systematic identifica- tion of receptors using such techniques as in situ recep- tor autoradiography.

Perspectives

The studies s~mar~ed above suggest (1) that POMC is expressed, translated and processed in the mammalian skin; (2) that this process is developmen- tally regulated; (3) that dysregulation of POMC expres- sion, translation and/or processing may accompany or be causally related to skin disease; and (4) that the targets for POMC products may include both resident and migratory skin cell populations.

Skin as a neuroendocrine organ The possibility that the skin is both a source of and

target for ‘pituitary’ hormones, and that the generation of and the response to these neuroend~rine, growth- and immunomodulatory peptides may be regulated in a cell-specific fashion, opens a new area for research: the functional relationship between the endocrine cells of the central nervous system, and the skin, two important ectodermal derivatives. Using the pituitary hormone prolactin as an example we previously proposed that a ‘neuroimmune-dermatological’ axis would operate bidirectionally between the skin and the endocrine glands in combination with the immune system (Paus, 1991). Such interaction may be expressed as stress-de- pendent neurogenic in~amation, a frequently men- tioned factor in common skin diseases like psoriasis and atopic dermatitis (Gupta and Vorhees, 1990), em- phasizing the role of skin itself as a source and target of classical ‘stress hormones’ like ACTH, tu-MSH, and /3-endorphin.

Cutaneous response to stress Given that the skin is directly and permanently

exposed to multiple physical, chemical and biological stimuli, it might be expected to respond immediately by

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recruiting appropriate signals for defense against stres- sors and for re-establishing tissue homeostasis. The multifunctional POMC-derived peptides in the skin seem particularly suited for the complex defense sys- tem against environmental insults. Teleologically, the most important pituitary component of the stress re- sponse is the highly restricted differential expression, translation and processing of the POMC gene (McCub- bin et al., 1991; Wortsman et al., 1985). Thus, in the case of the skin, differential POMC production and processing appears a more targetted mode of stress-re- sponse than reliance on pituitary neuropeptides for the restoration of locally disturbed tissue homeostasis.

Several of the signal molecules released and/or generated in the skin in response to stressful stimuli, like serotonin, epinephrine, bradykinin, IL-2 and IL-l (Bos, 1990; Goldsmith, 1991) are recognized as factors stimulating POMC expression. In addition, high-inten- sity UV light irradiation stimulates the production and secretion of ACTH and MSH by cultured keratinocytes (K&k et al., 19901, while whole body UV-irradiation of human subjects produces a rapid increase of the (Y- MSH concentration in the serum (Ghanem et al., 19891. These data indicate the skin has the capability of mounting a differential, local POMC-related stress re- sponse that could contribute to the overall systemic stress response.

CRH The cutaneous role of corticotropin releasing hor-

mone (CRH), the major regulatory factor for the con- trol of pituitary POMC peptide production and secre- tion, remains to be explored (Orth, 1992; Owens and Nemeroff, 1991). Interestingly, CRH has been detected in most of the extracranial sites where POMC is ex- pressed, including lung intestine, adrenal and placenta (Orth, 1992; Owens and Nemeroff, 1991; Petraglia et al., 1987; Robinson et al., 1988). CRH receptors have been identified in testis, splenic macrophages, lympho- cytes and in the placenta (Petraglia et al., 1987; Orth, 1992; Owens and Nemeroff, 1991). It is therefore possi- ble that cutaneous expression of the CRH gene and of CRH receptors in the skin may also regulate local POMC expression.

Final comments The role of POMC fragments in the regulation of

hair growth and pigmentation, of sebaceous gland function, and in regulation of the immune system must be clarified to better understand skin physiology. It is possible that these processes may be closely interde- pendent (Paus and Czametzki, 1992; Slominski et al., 1992; Slominski and Paus, 19921, and influence by POMC peptides generated in the follicle, the seba- ceous gland or neighboring cellular components. To explore POMC systematically in a dermatological con-

text is a new and exciting investigational challenge which may unveil a previously unsuspected role for locally generated POMC-derived ‘pituitary’ hormones in the modulation of skin biology and pathology.

Acknowledgement

We acknowledge gratefully critical reading of Dr. B. Czarnetzki and Dr. L. King, and valuable comments and editorial help of Dr. J.W. Funder. The work was supported in part by grants from Lawrence M. Gelb Foundation to A.S. and Deutsche Forschungsgemein- schaft to R.P.

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