INTERLEUKIN-1-BETA ACTIVATES PROTEIN-KINASE C-ZETA IN RENAL MESANGIALCELLS - POTENTIAL ROLE IN PROSTAGLANDIN E(2) UP-REGULATION

Protein kinase C (PKC) plays a rob in signal transduction mediated by interleukin-1 beta (IL-1 beta) leading to the increase in prostaglandi n E(2) (PGE(2)) production. In the present study we suggest that there are at least two distinct PKC isotypes involved in the signaling mech anism. Staurosporine potentiated the effect of IL-1 beta on coxII mRNA expression while calphostin C totally inhibited mRNA expression. The down-regulation of PKC by growing mesangial cells in the presence of p horbol 12-myristate 13-acetate for 24 h failed to modify the upregulat ed response in PGE(2) formation by IL-1 beta. Furthermore, incubation of mesangial cells with IL-1 beta causes translocation of PKC zeta fro m cytosol to a presumed membrane compartment, and this translocation p henomenon was not inhibited by incubating the cells with staurosporine but was inhibited with calphostin C. Gel retardation assays also demo nstrated that staurosporine did not inhibit the IL-1 beta-stimulated b inding of nuclear extracts to the NF kappa B motif. In contrast, calph ostin C inhibited binding to the kappa B motif in a dose-dependent man ner. Finally, antisense oligonucleotides to PKC zeta partially inhibit ed the IL-1 beta-induced PGE(2) formation while control sense oligonuc leotides were without effect. Taken together, these data suggest that PKC zeta is involved in the IL-1 beta signaling responses.