CROSS-TALK BETWEEN CYCLOOXYGENASE AND NITRIC-OXIDE PATHWAYS - PROSTAGLANDIN E(2) NEGATIVELY MODULATES INDUCTION OF NITRIC-OXIDE SYNTHASE BYINTERLEUKIN-1

The inflammatory cytokine interleukin 1 beta (IL-1 beta) induces both cyclooxygenase (COX) and nitric oxide synthase (NOS) with increases in the release of prostaglandin (PG) and nitric oxide (NO) by mesangial cells. Recently, activation of the COX enzyme by NO has been described . However, the effects of COX products (PGs) on the NO pathway have no t been fully clarified. Thus we determined the effect of COX inhibitio n and exogenous PGs on NO production and NOS induction in rat mesangia l cells. A COX inhibitor, indomethacin, enhanced IL-1 beta-induced ste ady-state level of the inducible NOS (iNOS) mRNA and nitrite productio n. The effect of indomethacin was dose dependently reversed by the rep lacement of endogenous PGE(2) with exogenous PGE(2), which is the pred ominant product of the COX pathway in rat mesangial cells. In contrast to PGE(2), a stable analog of PGI(2), carba prostacyclin, enhanced IL -1 beta-induced iNOS mRNA levels and nitrite production. Forskolin, an activator of the adenylate cyclase, mimicked the effect of carba pros tacyclin but not PGE(2). These data suggest that (i) endogenous PGE(2) downregulates iNOS induction, (ii) this inhibitory effect of PGE(2) o n iNOS induction is not mediated by activation of adenylate cyclase, a nd (iii) exogenous PGI(2) stimulates COX induction possibly by activat ion of adenylate cyclase.