The protease-activated receptor 2 regulates pigmentation via keratinocyte-melanocyte interactions

Close association exists between melanocytes, the pigment melanin-producing cells in the body, and their neighboring keratinocytes. Keratinocytes are the pigment recipients and skin pigmentation is the result of this interact ion. While the chemical basis of melanin production (melanogenesis) is well documented, the molecular mechanism of melanosome transfer needs to be elu cidated. We are now providing first evidence that the protease-activated re ceptor 2 (PAR-2) expressed on keratinocytes, but not on melanocytes, is inv olved in melanosome transfer and therefore may regulate pigmentation, Activ ation of PAR-2 with trypsin or with the peptide agonist SLIGRL induced pigm entation in both two- and three-dimensional cocultures of keratinocytes and melanocytes, but not in cocultures that were spatially separated, indicati ng the need for intimate cell-cell contact, Topical application of SLIGRL o n human skin transplanted on SCID mice resulted in a visible skin darkening . Histological examination revealed increased deposits of melanin in the ke ratinocytes, Inhibition of PAR-2 activation by RWJ-50353, a serine protease inhibitor, resulted in depigmentation and changes in expression of melanog enic-specific genes, Keratinocyte-melanocyte contact was essential for this depigmenting effect, Topical application of this inhibitor induced lighten ing of the dark skin Yucatan swine, which was confirmed by histochemical an alysis. The results presented here suggest a novel mechanism for the regula tion of pigmentation, mediated by the activation or inhibition of the kerat inocyte receptor PAR-2. (C) 2000 Academic Press.