Proopiomelanocortin (POMC) is a protein synthesized predominately in the pituitary gland but also in a variety of other tissues, including the skin. Through enzyme-mediated cleavage that varies among cell types, POMC can give rise to at least eight distinct peptides whose biologic roles are incompletely delineated. Although blood-borne pituitary-derived bioactivity for the skin was first recognized 80 years ago and the responsible neuropeptides isolated 20-40 years ago, our understanding of POMC-derived peptides in skin is still rapidly evolving. In particular, recent work in cultured human and murine skin-derived cells has demonstrated POMC gene expression as well as modulation of POMC and many of its derived peptides in response to physiologic signals including ultraviolet irradiation and cytokines. Immunoreactivity for these peptides has also been detected in normal skin and hair follicles, strongly suggesting cutaneous synthesis in vivo. Candidate autocrine or paracrine functions include enhanced melanogenesis, immunomodulation, and effects on cell cycle regulation and differentiated function in both the epidermis and its appendages. This article reviews recent data concerning POMC gene expression and regulation, protein processing, signal transduction, and biologic functions relevant to cutaneous biology.

Proopiomelanocortin (POMC) is the precursor for adrenocorticotropic hormone, melanocyte-stimulating hormones, beta-lipotropic hormone (beta LPH), and beta endorphin. These peptides can function as neurotransmitters, modulate immune responses, and affect melanogenesis. We investigated POMC expression and protein processing in normal human keratinocytes. On Northern blot analysis, the baseline expression of the 1.2-kb POMC transcript was upregulated by ultraviolet radiation (UVR) or by stimulation with interleukin-1 alpha (IL-1 alpha) or phorbol 12-tetradecanoate 13-acetate (TPA). On Western blot analysis, POMC, beta LPH, and beta-endorphin were detected in cell extracts under baseline conditions. beta LPH level increased substantially after UVR, IL-1 alpha, or TPA. Within 36 h after TPA stimulation, beta-endorphin became undetectable in cell extracts, coinciding with an increase of beta-endorphin-immunoreactive protein in the culture medium. Our data establish that keratinocytes synthesize POMC protein as well as its derivatives beta LPH and beta-endorphin, and that this process is modulated by TPA, IL-1A, and UVR. beta LPH and beta-endorphin of keratinocyte origin may thus be involved in melanogenesis and/or immunomodulation in the skin after sun exposure, and their release into the circulation may also have systemic effects.

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On the basis of these results, the skin does not appear to contribute significantly to the levels of circulating betaE or ACTH. These data offer no support for the hypothesis that exposure to UVR leads to an increased concentration of circulating betaE, which could contribute to the feeling of well-being that often accompanies sun-bathing.

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