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Volume 271, Number 49, Issue of December 6, 1996 pp. 31585-31592
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Salicylate Is a Transcriptional Inhibitor of the Inducible Nitric Oxide Synthase in Cultured Cardiac Fibroblasts

(Received for publication, May 17, 1996, and in revised form, September 10, 1996)

R. Saeid Farivar and Peter Brecher ^§

From the Departments of ^§ Biochemistry and  Pathology, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02118

We have previously reported that salicylate inhibits the inducible NO synthase (NOS 2) in cytokine-induced cardiac fibroblasts (Farivar, R. S., Chobanian, A. V., and Brecher, P. (1996) Circ. Res. 78, 759-768). To define further the mechanism of inhibition of NOS 2 by salicylate, we investigated NOS 2 mRNA induction by cytokines and determined the kinetics of inhibition by salicylate as compared to dexamethasone. Interferon- plus tumor necrosis factor- induced NOS 2 mRNA synergistically in a time- and dose-dependent manner. Both dexamethasone and salicylate equally inhibited the induction of NOS 2 mRNA in a time- and dose-dependent fashion, both before and after cytokine induction. Salicylate also inhibited interferon- plus interleukin-1-induced NOS 2 mRNA. After 24 h of cytokine stimulation, salicylate stopped the induction of NOS 2 mRNA, whereas dexamethasone delayed the accumulation of transcript. In half-life experiments of NOS 2 mRNA, we found that dexamethasone reduced the half-life of NOS 2 mRNA from 7 to 4 h, whereas salicylate had no effect on mRNA stability. Tumor necrosis factor- and interferon- induced NF-B (p50/p65) and STAT-1, respectively, as assessed by gel shift assays. Salicylate did not inhibit the cytokine induction of NF-B or STAT-1. This study suggests that the anti-inflammatory mechanism of salicylate involves inhibition of NOS 2 transcription and shows that the effect is independent of NF-B activation.

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