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Peroxynitrite Mediates IL-8 Gene Expression and Production in Lipopolysaccharide-Stimulated Human Whole Blood¹

Research Center, Maisonneuve-Rosemont Hospital, and Department of Medicine, University of Montreal, Quebec, Canada

Recent evidence indicates that free oxygen radicals, in particular hydroxyl radicals, may act as intracellular second messengers for the induction of IL-8, a potent chemoattractant and activator of neutrophil granulocytes. Here we report that peroxynitrite (ONOO^-), formed by a reaction of nitric oxide (NO) with superoxide, mediates IL-8 gene expression and IL-8 production in LPS-stimulated human whole blood. The NO synthase inhibitors aminoguanidine and N^G-nitro-L-arginine methyl ester (L-NAME) blocked IL-8 release by 90% in response to LPS (1 µg/ml), but did not affect the production of IL-1ß or TNF-. Both aminoguanidine and L-NAME blocked the induction of IL-8 mRNA by LPS. Authentic ONOO^- (2.5–80 µM) augmented IL-8 mRNA expression and stimulated IL-8 release in a concentration-dependent manner, whereas the NO-releasing compounds, S-nitroso-N-acetyl-DL-penicillamine and sodium nitroprusside failed to induce cytokine production. Combination of the NO-generating chemicals with a superoxide-generating system (xanthine/xanthine oxidase) markedly increased IL-8 release. Enhanced ONOO^- formation was detected in granulocytes, monocytes, lymphocytes, and plasma after challenge with LPS. Furthermore, pyrrolidine dithiocarbamate, an inhibitor of activation of nuclear factor-B, markedly attenuated the induction of IL-8 mRNA expression and IL-8 release by either LPS or ONOO^-. Our study identifies ONOO^- as a novel signaling mechanism for IL-8 gene expression and suggests that inhibition of ONOO^- formation or scavenging ONOO^- may represent a novel therapeutic approach to inhibit IL-8 production that could lead to reduction of neutrophil accumulation and activation.

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