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Peroxynitrite mediates cytokine‐induced IL‐8 gene expression and production by human leukocytes
Author(s) -
Zouki Christine,
József Levente,
Ouellet Sophie,
Paquette Yves,
Filep János G.
Publication year - 2001
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.69.5.815
Subject(s) - pyrrolidine dithiocarbamate , peroxynitrite , nitric oxide , biology , cytokine , superoxide , microbiology and biotechnology , tumor necrosis factor alpha , peripheral blood mononuclear cell , nitric oxide synthase , gene expression , interleukin , immunology , inflammation , biochemistry , nf κb , in vitro , endocrinology , enzyme , gene
Recent studies indicate that nitric oxide (NO) or related compounds mayregulate the production of interleukin (IL)‐8, a potent proinflammatorychemokine. Here we report that peroxynitrite (ONOO − )formed by a reaction of NO with superoxide mediates IL‐8 geneexpression and IL‐8 production in IL‐1β‐ and TNF‐α‐stimulated humanleukocytes in whole blood. The NO synthase inhibitors aminoguanidineand N G ‐nitro‐ l ‐arginine methylester blocked nuclear accumulation of activator protein‐1 (AP‐1) andnuclear factor (NF)‐κB in both polymorphonuclear (PMN) andmononuclear leukocytes and inhibited IL‐8 mRNA expression and IL‐8release by ∼90% in response to IL‐1β and TNF‐α. EnhancedONOO − formation was detected in granulocytes, monocytes, and lymphocytes after challenge with IL‐1β or TNF‐α. The additionof ONOO − (0.2–80 μM) to whole blood increased nuclearaccumulation of AP‐1 and NF‐κB in PMN and mononuclear leukocytes andaugmented IL‐8 mRNA expression and IL‐8 production in aconcentration‐dependent fashion. Pyrrolidine dithiocarbamate, aninhibitor of NF‐κB activation, attenuated ∼70% of IL‐8 releaseevoked by IL‐1β, TNF‐α, or ONOO − . These resultsindicate that ONOO − formation may underlie the action ofcytokines towards IL‐8 gene expression in human leukocytes.