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Regulatory role of C5a in LPS‐induced IL‐6 production by neutrophils during sepsis
Author(s) -
Riedemann Niels C.,
Guo RenFeng,
Hollmann Travis J.,
Gao Hongwei,
Neff Thomas A.,
Reuben Jayne S.,
Speyer Cecilia L.,
Sarma J. Vidya,
Wetsel Rick A.,
Zetoune Firas S.,
Ward Peter A.
Publication year - 2004
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.03-0708fje
Subject(s) - p38 mitogen activated protein kinases , sepsis , mapk/erk pathway , phosphorylation , lipopolysaccharide , c5a receptor , kinase , proinflammatory cytokine , immunology , signal transduction , protein kinase a , stimulation , microbiology and biotechnology , medicine , chemistry , inflammation , biology , complement system , immune system
Experimental sepsis in rodents occurring after cecal ligation/puncture (CLP) is associated with excessive complement activation and a systemic inflammatory response. The proinflammatory mediator IL‐6 has recently been shown to be an important inducer of the C5a receptor (C5aR) during sepsis. We now provide evidence that serum IL‐6 production during sepsis in rats was reduced in neutrophil‐depleted animals and that absence of C5aR in mice as well as antibody‐ blockade of C5a in rats significantly reduced serum levels of IL‐6 during sepsis. Lipopolysaccharide (LPS)‐induced production in vitro of IL‐6 by neutrophils was significantly enhanced in the co‐presence of C5a, likely due to transcriptional up‐regulation of IL‐6. Production of IL‐6 in neutrophils by LPS was NF‐κB dependent (but not on the presence of p50) and dependent on phosphorylation of p38‐mitogen activated protein kinase (MAPK) as well as p44/p42 MAPK (ERK1/2) but not on phosphorylation of c‐Jun N‐terminal kinases (JNK1/2). C5a stimulation of neutrophils elicited a rapid phosphorylation of ERK1/2 and p38 MAPK. Accordingly, we suggest that induction of IL‐6 after CLP is neutrophil and C5a/C5aR dependent, likely due to the ability of C5a to cause activation of ERK1/2 and p38 MAPK signaling pathways.