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utocrine role of endogenous interleukin‐18 on inflammatory cytokine generation by human neutrophils
Author(s) -
Fortin Carl F.,
Ear Thornin,
McDonald Patrick P.
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.08-110213
Subject(s) - innate immune system , microbiology and biotechnology , cytokine , mapk/erk pathway , secretion , p38 mitogen activated protein kinases , lipopolysaccharide , biology , proinflammatory cytokine , signal transduction , acquired immune system , immunology , interleukin , inflammation , immune system , endocrinology
Neutrophils are key players of innate immunity and influence inflammatory and immune reactions through the production of numerous cyto‐kines. Interleukin‐18 (IL‐18) is known to stimulate several neutrophil responses, and recent evidence sug‐gests that neutrophils might represent a source of IL‐18. Here, we show that neutrophils constitutively produce both IL‐18 and its antagonist, IL‐18BP. Cell activation does not affect IL‐18BP release but leads to an increased gene expression and secretion of IL‐18, a process that depends on NF‐κB activation. Moreover, endogenous IL‐18 feeds back on the neutrophils to augment cytokine generation in lipopolysaccharide‐treated cells. Accordingly, exogenous IL‐18 can induce the gene expression and release of several inflamma‐tory cytokines in neutrophils, including its own expression. We finally report that IL‐18 activates the p38 MAPK, MEK/ERK, and PI3K/Akt pathways in neutro‐phils. The IKK cascade is also activated by IL‐18, resulting in IκB‐α degradation, NF‐κB activation, and RelA phosphorylation. Accordingly, these pathways contribute to the generation of inflammatory cytokines in IL‐18‐stimulated neutrophils. By contrast, the phos‐phorylation and DNA‐binding activity of various STAT proteins were not induced by IL‐18. Collectively, our results unveil new interactions between IL‐18 and neutro‐phils and further support a role for these cells in influencing both innate and adaptive immunity.—Fortin, C. F., Ear, T., McDonald, P. P. Autocrine role of endogenous interleukin‐18 on inflammatory cytokine generation by human neutrophils. FASEB J. 23, 194‐203 (2009)