Cross-talk between cyclooxygenase and nitric oxide pathways: Prostaglandin E₂ negatively modulates induction of nitric oxide synthase by interleukin 1

The inflammatory cytokine interleukin 1β (IL-1β) 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 not been fully clarified. Thus we determined the effect of COX inhibition and exogenous PGs on NO production and NOS induction in rat mesangial cells. A COX inhibitior, indomethacin, enhanced IL-1β-induced steady-state level of the inducible NOS (iNOS) mRNA and nitrite production. The effect of indomethacin was dose dependently reversed by the replacement of endogenous PGE₂ with exogenous PGE₂, which is the predominant product of the COX pathway in rat mesangial cells. In contrast to PGE₂, a stable analog of PGI₂, carba prostacyclin, enhanced IL-1β-induced iNOS mRNA levels and nitrite production. Forskolin, an activator of the adenylate cyclase, mimicked the effect of carba prostacyclin but not PGE₂. These data suggest that (i) endogenous PGE₂ downregulates iNOS induction, (ii) this inhibitory effect of PGE₂ on iNOS induction is not mediated by activation of adenylate cyclase, and (iii) exogenous PGI₂ stimulates COX induction possibly by activation of adenylate cyclase.