p38 mitogen-activated protein kinase down-regulates nitric oxide and up-regulates prostaglandin E(2) biosynthesis stimulated by interleukin-1 beta

The inflammatory cytokine interleukin 1 beta (IL-1 beta) induces both cyclooxygenase-2 (Cox-2) and the inducible nitric-oxide synthase (iNOS) with increases in the release of prostaglandins (PGs) and nitric oxide (NO) from glomerular mesangial cells. However, the intracellular signaling mechanisms by which IL-1 beta induces iNOS and Cox-a expression is obscure, Our current studies demonstrate that IL-1 beta produces a rapid increase in p38 mitogen-activated protein kinase (MAPK) phosphorylation and activation. Serum starvation and SC68376, a drug which selectively inhibits p38 MAPK in mesangial cells, were used to investigate whether p38 MAPK contributes to the signaling mechanism of IL-1 beta induction of NO and PG; synthesis. Serum starvation and SC68376 selectively inhibited IL-1 beta-induced activation of p38 MAPK. Both SC68376 and serum starvation enhanced NO biosynthesis by increasing iNOS mRNA expression, protein expression, and nitrite production. In contrast, both SC68376 and serum starvation suppressed PO release by inhibiting Cox-a mRNA, protein expression, and PGE, synthesis. These data demonstrate that IL-1 beta phosphorylates and activates p38 MAPK in mesangial cells, The activation of p38 MAPK may provide a crucial signaling mechanism, which mediates the up-regulation of PG synthesis and the down-regulation of NO biosynthesis induced by IL-1 beta.