Modulation of cytokine-induced expression of secretory phospholipase A(2)-type IIA by protein kinase C in rat renal mesangial cells

Renal mesangial cells express the 14 kDa secretory phospholipase A(2)-type IIA (sPLA(2)-IIA) in response to interleukin-1 beta (IL-1 beta). In order t o understand the regulation of cytokine induced sPLA(2)-IIA induction in mo re detail, we investigated whether phorbol ester-activated protein kinase C (PKC) has an influence on the IL-1 beta-induced expression of sPLA(2)-IIA. We found that treatment of mesangial cells with the biologically active ph orbol 12-myristate 13-acetate (PMA) and phorbol 12,13-dibutyrate inhibited IL-1 beta induction of sPLA(2)-IIA mRNA, protein, and activity, whereas the inactive compound 4 alpha-phorbol 12,13-didecanoate was without effect. An 8-hr pretreatment with PMA, which led to down-regulation of PKC-alpha and -delta isoenzymes, still inhibited sPLA(2)-IIA induction. Only after down-r egulation of PKC-epsilon isoenzyme by 24-hr preincubation with PMA were we able to reconstitute the IL-1 beta-induced sPLA(2)-IIA expression. Thrombin as a physiological activator of PKC in mesangial cells exerted similar eff ects as PMA and inhibited sPLA(2)-IIA expression. The selective PKC inhibit or calphostin C potentiated IL-1 beta induction of sPLA(2)-IIA mRNA levers and partially reconstituted the thrombin-induced inhibition of sPLA(2)-IIA mRNA and activity. These data show that IL-1 beta induction of sPLA(2)-IIA can be modulated by PKC and that the epsilon-isoenzyme of the PKC family is the most likely candidate mediating the suppression of cytokine-induced sP LA2-IIA expression in mesangial cells. BIOCHEM PHARMACOL 58;11:1751-1758, 1 999. (C) 1999 Elsevier Science Inc.