THE ANTIINFLAMMATORY DRUG SODIUM-SALICYLATE INHIBITS NITRIC-OXIDE FORMATION INDUCED BY INTERLEUKIN-1-BETA AT A TRANSLATIONAL STEP, BUT NOT AT A TRANSCRIPTIONAL STEP, IN HEPATOCYTES

Recent evidence suggests that nitric oxide (NO) mediates cellular inju ry under the pathological conditions such as endotoxemia in the liver of rats. Regulation of NO production is crucial for improving the hepa tic dysfunction. We have previously reported that, in cultured rat hep atocytes, a single cytokine interleukin-1 beta (IL-1 beta) stimulated a release of nitrite, an oxidation product of NO, into culture medium dose- and time-dependently. The objective of this study was to investi gate an ability of the anti-inflammatory drug NaSA to affect the produ ction of NO in hepatocytes. IL-1 beta increased levels of inducible NO synthase (iNOS) messenger RNA (mRNA) with a maximal effect at 8 hours in primary cultures of rat hepatocytes. Nuclear factor-kappa B (NF-ka ppa B), that is an important nuclear factor protein in iNOS gene trans cription in response to inflammatory mediators, also appeared in the n uclear fraction of hepatocytes 1 hour after addition of IL-1 beta. Sod ium salicylate markedly inhibited the NO formation induced by IL-1 bet a, but did not affect NF-kappa B activation and iNOS mRNA induction. W estern blot analysis revealed that sodium salicylate (NaSA) blocked a step of iNOS protein synthesis. These findings indicate that NaSA may reduce hepatic injury by preventing the induction of NO formation in r esponse to IL-1 beta at the posttranscriptional step.