* 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 NG-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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