There is growing evidence that keratinocytc (KC) intercellular adhesion molecule-i (ICAM-i) expression is involved in the epidermal trafficking øf T lymphocytes. To further characterize the molecular basis of KC ICAM-i expression, the detailed kinetics of induction by gamma interferon (IFN-γ)) 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-γ, 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-γ-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-γ), 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.