p38 Mitogen-activated protein kinase down-regulates nitric oxide and up- regulates prostaglandin E₂ biosynthesis stimulated by interleukin-1β

The inflammatory cytokine interleukin 1β (IL-1β) 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-1β induces iNOS and Cox-2 expression is obscure. Our current studies demonstrate that IL-1β 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-1β induction of NO and PG synthesis. Serum starvation and SC68376 selectively inhibited IL-1β-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 PG release by inhibiting Cox-2 mRNA, protein expression, and PGE₂ synthesis. These data demonstrate that IL-1β 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-1β.