NITRIC-OXIDE AMPLIFIES INTERLEUKIN 1-INDUCED CYCLOOXYGENASE-2 EXPRESSION IN RAT MESANGIAL CELLS

Interleukin 1 and nitric oxide (NO) from infiltrating macrophages and activated mesangial cells may act in concert to sustain and promote gl omerular damage. To evaluate if such synergy occurs, we evaluated the effect if IL-1 beta and NO on the formation of prostaglandin (PG) E(2) and cyclooxygenase (COX) expression. The NO donors, sodium nitropruss ide and S-nitroso-N-acetylpenicillamine, alone did not increase basal PGE(2) formation. However, these compounds amplified IL-1 beta-induced PGE(2) production. Similarly, sodium nitroprusside and S-nitroso-N-ac etylpenicillamine by themselves did not induce mRNA and protein for CO X-2, the inducible isoform of COX; however, they both potentiated IL-1 beta-induced mRNA and protein expression of COX-2. The stimulatory ef fect of NO is likely to he mediated by cGMP since (a) an inhibitor of the soluble guanylate cyclase, methylene blue, reversed the stimulator y effect of NO donors on COX-2 mRNA expression; (b) the membrane-perme able cGMP analogue, 8-Br-cGMP, mimicked the stimulatory effect of NO d onors on COX-2-mRNA expression; and (c) atrid natriuretic peptide, whi ch increases cellular cGMP by activating the membrane-bound guanylate cyclase, also amplified; IL-1 beta-induced COX-2 mRNA expression. Thes e data indicate a novel interaction between NO and COX pathways.