The CD146 (or MUC18/MEL-CAM) antigen is a cell adhesion molecule of the immunoglobulin superfamily. Besides in melanoma, expression of CD146 antigen has been demonstrated in breast epithelia and hair follicles. We studied its expression by human keratinocytes in culture as well as in neoplastic and inflammatory skin diseases. Staining of primary cultured keratinocytes revealed expression of CD146 on the cell membrane, preferentially on cell-cell contact sites. Western blot analysis of keratinocytes detected a band of approximately 113 kDa, corresponding to the CD146 protein. In contrast to primary keratinocytes, neither CD146 protein nor mRNA expression was found in the keratinocyte-derived cell lines A431 and HaCaT. Treatment of keratinocytes with the proinflammatory cytokines interleukin-1 and interleukin-6, tumor necrosis factor-alpha, and interferon-gamma, resulted in no change of CD146 expression and incubation with phorbol 12-myristate 13-acetate led to a reduction of CD146 on keratinocytes. By contrast, when culturing keratinocytes in medium devoid of growth supplements, a distinct upregulation was observed as compared with culture in fully supplemented medium. In normal human epidermis expression of the CD146 antigen was not detectable. It was strongly upregulated, however, on suprabasal keratinocytes in psoriasis, in lichen planus, in the epidermis overlying skin neoplasms, and in viral warts. In squamous cell carcinomas and basal cell carcinomas only a minority of tumor cells expressed CD146. Our findings suggest that the CD146 antigen represents an activation marker of keratinocytes and may be involved in cutaneous inflammatory tissue reaction.