Involvement of p38 mitogen-activated protein kinase in lipopolysaccharide-induced iNOS and COX-2 expression in J774 macrophages

Both the nitrite and prostaglandin E-2 (PGE(2)) release caused by lipopolys accharide (LPS) in J774 macrophages are inhibited by SE 203580, a specific p38 mitogen-activated protein kinase (MAPK) inhibitor, in a concentration-d ependent manner. The 50% inhibitory concentration (IC50) for nitrite and PG E(2) responses was 1 mu M and 0.5 mu M, respectively. Inhibition was marked following simultaneous treatment with SE 203580 and LPS, and was much redu ced when SE 203580 was added 6 hr after LPS treatment. In parallel, LPS ind uction of inducible NO synthase (iNOS) and cyclo-oxygenase-2 (COX-2) protei ns and their steady-state levels of mRNA were reduced by SB 203580. LPS act ivation of nuclear factor-kappa B (NF-kappa B), activator protein-1 (AP-1) and p38 MAPK was also inhibited by SB 203580. These results suggest a cruci al role of p38 MAPK in regulation of the transcriptional level of endotoxin LPS-induced iNOS and COX-2 protein expression.