The Anti–Inflammatory Drug Sodium Salicylate Inhibits Nitric Oxide Formation Induced by Interleukin–1β At A Translational Step, But Not At A Transcriptional Step, in Hepatocytes

Abstract

ABSTRACT Recent evidence suggests that nitric oxide (NO) mediates cellular injury under the pathological conditions such as endotoxemia in the liver of rats. Regulation of NO production is crucial for improving the hepatic dysfunction. We have previously reported that, in cultured rat hepatocytes, a single cytokine interleukin–1β (IL–1β) stimulated a release of nitrite, an oxidation product of NO, into culture medium dose– and time–dependently. The objective of this study was to investigate an ability of the anti–inflammatory drug NaSA to affect the production of NO in hepatocytes. IL–1β 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–κB (NF–κB), that is an important nuclear factor protein in iNOS gene transcription in response to inflammatory mediators, also appeared in the nuclear fraction of hepatocytes 1 hour after addition of IL–1β. Sodium salicylate markedly inhibited the NO formation induced by IL–1β, but did not affect NF–κB activation and iNOS mRNA induction. Western 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 response to IL–1β at the posttranscriptional step.