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Differential Inhibitory Actions by Glucocorticoid and Aspirin on Cytokine-Induced Nitric Oxide Production in Vascular Smooth Muscle Cells¹

Division of Endocrinology and Metabolism, the Second Department of Internal Medicine, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8519, Japan

Address all correspondence and requests for reprints to: Dr. Yukio Hirata, Division of Endocrinology and Metabolism, Second Department of Internal Medicine, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.

Glucocorticoids and nonsteroidal antiinflammatory drugs (NSAIDs) are widely used for the treatment of inflammatory and immune diseases. Nitric oxide (NO) has a diversity of physiological functions, but its excess production has been implicated in the inflammatory process. The present study was designed to elucidate the mechanisms by which glucocorticoids and NSAIDs affect inducible nitric oxide synthase (iNOS) expression in cultured rat vascular smooth muscle cells (VSMCs). Both interleukin (IL)-1ß and tumor necrosis factor (TNF)- potently stimulated nitrite/nitrate (NOx) production with a concomitant expression of iNOS mRNA and protein as demonstrated by Northern and Western blot analysis, respectively. Both IL-1ß and TNF- activated nuclear factor (NF)-B as demonstrated by electrophoretic mobility shift assay. Dexamethasone, salicylate and aspirin, but not indomethacin, dose dependently inhibited cytokine-stimulated NOx production and iNOS protein expression. Dexamethasone decreased cytokine-induced NF-B activation and iNOS mRNA expression, but neither salicylate nor aspirin affected NF-B activation or iNOS mRNA expression. IL-1ß caused a rapid increase in phosphorylated IB- levels and subsequent transient decrease in IB- levels, an inhibitor of NF-B, as revealed by Western blot analysis using specific antibodies for phosphorylated and nonphosphorylated IB-. These effects were blocked by pretreatment with dexamethasone. Aspirin dose dependently inhibited iNOS enzymatic activity, whereas salicylate and dexamethasone had limited effect. The present study demonstrates that 1) inhibitory effect of dexamethasone on cytokine-induced iNOS expression and NO production in rat VSMCs, although potentially acting at multiple levels, is partly mediated by inhibition of NF-B activation resulting from decreased phosphorylation and degradation of IB-, 2) both salicylate and aspirin inhibit cytokine-stimulated NO production at translational and/or posttranslational levels without affecting NF-B- mediated iNOS gene expression, and 3) aspirin directly inhibits iNOS enzyme activity. These data suggest the differential inhibitory mechanisms of iNOS-mediated NO synthesis by glucocorticoids and NSAIDs in the vasculature.

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