PROOPIOMELANOCORTIN-DERIVED PEPTIDES ARE SYNTHESIZED AND RELEASED BY HUMAN KERATINOCYTES

Proopiomelanocortin (POMC), the precursor for melanotropic, corticotro pic, and opioid peptides such as alpha-melanocyte-stimulating hormone (alpha MSH), ACTH, and other related peptides, was originally identifi ed as a product of the pituitary gland. However, recent evidence shows that POMC products can also be produced by nonpituitary tissues. Beca use keratinocytes, the major constituent of the epidermis exhibit the capacity to release a variety of proinflammatory and immunomodulatory mediators, the present study was performed to investigate whether huma n keratinocytes are able to produce POMC-derived peptides. Supernatant s of human normal keratinocytes and an epidermal carcinoma cell line ( A431) contained significant levels of immunoreactive alpha MSH and ACT H. Upon immuneprecipitation and size-exclusion chromatography, keratin ocyte-derived alpha MSH exhibited a molecular mass of similar to 1 kD and was biologically active as demonstrated in a tyrosinase bioassay. Northern blot analysis revealed the expression of POMC-specific transc ripts (1.3 kb) in both normal keratinocytes and A431 cells. The produc tion of alpha MSH and ACTH could be significantly upregulated both at the protein and mRNA level upon treatment with phorbol myristate aceta te, ultraviolet light, or interleukin 1. These data provide first evid ence that human keratinocytes produce POMC-derived peptides such as al pha MSH and ACTH. Because POMC-derived peptides recently have been rec ognized as potent immunomodulatory mediators, their presence in the ep idermis may have a major impact on the skin immune system.