In this Issue

Abstract

An article by Stanley Shapiro and colleagues (p.162) at the Johnson and Johnson skin research laboratories provides interesting new insight into the role of melanosome transfer from in the process of pigmentation. The article implicates the protease-activated receptor-2 (PAR-2) in the transfer of melanosomes from melanocytes to keratinocytes, by showing that the PAR-2 activating peptide SLIGRL enhances ingestion of purified melanosomes by keratinocytes, and results in increased pigment deposition after topical application. Conversely, a pharmacologic inhibitor of PAR-2 decreased pigment transfer and diminished skin pigmentation after topical application. Because available skin lightening agents (such as tyrosinase inhibitors and melanocyte cytotoxic agents) act on other stages of the pigmentation process, this discovery opens the way for development of a new class of depigmenting agents based on inhibition of PAR-2. Two articles in this issue provide novel insights into the role of the chemokine receptor CXCR2 in wound healing. One article, by Ann Richmond and colleagues (p.234) of Vanderbilt University and the Nashville Veterans Affairs Hospital, demonstrates large deficits in reepithelialization and neutrophil recruitment and an altered pattern of monocyte recruitment in mice lacking CXCR2. This view is supported by the second article, by Stefan Frank and colleagues (p.245). Their analysis of healing wounds in db/db diabetic mice revealed abnormal persistence of the CXCR2 ligands MIP-1α and MCP-1, concomitant with a persistent and well-organized infiltrate of neutrophils and macrophages at the wound site. While these studies do not directly implicate CXCR2 as a downstream effector of the db/db mutation, they do clearly demonstrate that CXCR2 plays a major role in modulating the influx of PMN and monocyte/macrophages to the wound bed. Keratinocytes from CXCR2–/– mice displayed a delayed wound closure response when grown on plastic dishes, suggesting that this receptor also plays an important role in keratinocyte migration. CXCR2 expression, however, was found to be very limited in epidermal keratinocytes of both normal and db/db mice by Frank and colleagues. Further studies will be required to resolve these discrepancies and to better define the role of CXCR2 signaling in keratinocytes. Tuomo Alanko and Olli Saksela (p.286) of the University of Helsinki report that normal melanocytes are very susceptible to apoptosis induced by TGF-β when grown in three-dimensional collagen matrices. In contrast, nevus cells and melanocytes were markedly resistant to TGF-β induced apoptosis when grown under these conditions. TGF-β was markedly growth inhibitory to both normal melanocytes and nevus cells when they were grown on plastic rather than in collagen; melanoma cells were resistant to the antiproliferative effect of TGF-β. These studies strongly suggest that the process of melanoma tumor progression involves stepwise alteration of TGF-β responsiveness, with the early steps responsible for the formation of nevi cells being critically dependent on appropriate interactions with the extracellular matrix. This model would be consistent with the recent discovery that nevi are clonal (Melanoma Res 8:499–503, 1998), if one assumes that the clonal proliferations of melanocytes appear because they have acquired resistance to TGF-β-induced apoptosis.