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(Journal of Leukocyte Biology. 2001;69:815-824.)
© 2001 by Society for Leukocyte Biology

Peroxynitrite mediates cytokine-induced IL-8 gene expression and production by human leukocytes

^* Research Center, Maisonneuve-Rosemont Hospital and
Department of Medicine, University of Montréal, Québec, Canada H1T 2M4

Correspondence: Dr. János G. Filep, Research Center, Maisonneuve-Rosemont Hospital, 5415 boulevard de l’Assomption, Montréal, Québec, Canada H1T 2M4. E-mail: filepj{at}ere.umontreal.ca

Recent studies indicate that nitric oxide (NO) or related compounds may regulate the production of interleukin (IL)-8, a potent proinflammatory chemokine. Here we report that peroxynitrite (ONOO^-) formed by a reaction of NO with superoxide mediates IL-8 gene expression and IL-8 production in IL-1ß- and TNF--stimulated human leukocytes in whole blood. The NO synthase inhibitors aminoguanidine and N^G-nitro-L-arginine methyl ester blocked nuclear accumulation of activator protein-1 (AP-1) and nuclear factor (NF)-B in both polymorphonuclear (PMN) and mononuclear leukocytes and inhibited IL-8 mRNA expression and IL-8 release by 90% in response to IL-1ß and TNF-. Enhanced ONOO^- formation was detected in granulocytes, monocytes, and lymphocytes after challenge with IL-1ß or TNF-. The addition of ONOO^- (0.2–80 µM) to whole blood increased nuclear accumulation of AP-1 and NF-B in PMN and mononuclear leukocytes and augmented IL-8 mRNA expression and IL-8 production in a concentration-dependent fashion. Pyrrolidine dithiocarbamate, an inhibitor of NF-B activation, attenuated 70% of IL-8 release evoked by IL-1ß, TNF-, or ONOO^-. These results indicate that ONOO^- formation may underlie the action of cytokines towards IL-8 gene expression in human leukocytes.

Key Words: neutrophil granulocytes • mononuclear leukocytes • interleukin-1ß • tumor necrosis factor- • inflammation • nitric oxide

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