There is growing evidence that keratinocyte (KC) intercellular adhesion molecule-I (ICAM-I) expression is involved in the epidermal trafficking of T lymphocytes. To further characterize the molecular basis of KC ICAM-I expression, the detailed kinetics of induction by gamma interferon (IFN-gamma), as well as the phorbol ester, 12-O tetradecanoylphorbol-13-acetate (TPA), were studied. This study reports that KCs express both the class II major histocompatibility antigen (HLA-DR) and ICAM-I in response to IFN-gamma, although the response is distinctive for each molecule. Also, TPA induces ICAM-I, but not HLA-DR expression, whilst the protein kinase inhibitor, H7, blocks the TPA, but not the IFN-gamma-mediated response. The results provide a molecular basis whereby non-cytokine-mediated stimuli (e.g. TPA) alter KC signal transduction events involving protein kinase-C (PK-C) and thereby generate such immunologically relevant events as ICAM-I expression. Thus, KCs may be targets for both T-cell derived cytokines (e.g. IFN-gamma), and non-cytokine TPA-like molecules which stimulate PK-C. Induction of ICAM-I by either mechanism would be capable of instigating intraepidermal T-cell trafficking.