IP-10 mRNA expression in cultured keratinocytes is suppressed by inhibition of protein kinase-C and tyrosine kinase and elevation of cAMP

IFN-gamma-inducible protein-10 (IP-10) is a chemokine, which plays an important role in mediating inflammation by attracting activated T cells, and it has been demonstrated in inflammatory skin diseases and cutaneous T cell lymphomas, Keratinocytes can abundantly produce IP-10 mRNA after IFN-gamma treatment. In this study we explored possibilities to downregulate IP-10 expression using human cultured keratinocytes as a model system. Decreased IP-10 mRNA levels were found using specific inhibitors of protein kinase (PK)-C (H-7 and Calphostin C), Moreover, depletion of PK-C by pretreatment of the cells with phorbol myristate (PMA) also down-regulated IP-10 mRNA expression. Tn addition, elevated cAMP levels were shown to inhibit IP-10 mRNA expression as could be concluded from experiments with forskolin and W-7, substances which, directly or indirectly, raise the intracellular cAMP level. With Genistein, an inhibitor of tyrosine kinase, the IFN-gamma-induced IP-10 mRNA expression was also found to be diminished. These data suggest that inhibitors of the IP-10 mRNA expression in cultured keratinocytes may be potentially of clinical relevance to suppress inflammatory processes in the skin. (C) 1999 Academic Press.