Regulatory role of C5a in LPS-induced IL-6 production by neutrophils during sepsis.
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-kappaB 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.
Riedemann
Niels C
NC
Department of Pathology, University of Michigan Medical School, 1301 Catherine Road, Ann Arbor, Michigan 48109-0602, USA.
Guo
Ren-Feng
RF
Hollmann
Travis J
TJ
Gao
Hongwei
H
Neff
Thomas A
TA
Reuben
Jayne S
JS
Speyer
Cecilia L
CL
Sarma
J Vidya
JV
Wetsel
Rick A
RA
Zetoune
Firas S
FS
Ward
Peter A
PA
D000818:Animals; D015936:Complement C5a / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D015850:Interleukin-6 / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D044087:Receptor, Anaphylatoxin C5a / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018805:Sepsis / Q000097:blood / Q000276:immunology
D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D044087:Receptor, Anaphylatoxin C5a; D015936:Complement C5a; D020928:Mitogen-Activated Protein Kinases