Regulation by C5a of neutrophil activation during sepsis.
In sepsis, there is evidence that excessive C5a generation leads to compromised innate immune functions, being associated with poor outcome. We now report that in vitro exposure of neutrophils to C5a causes increased levels of IkappaBalpha, decreased NF-kappaB-dependent gene transcription of TNFalpha, and decreased lipopolysaccharide (LPS)-induced TNFalpha production. Similar findings were obtained with neutrophils from cecal ligation/puncture (CLP)-induced septic rats. Such changes were reversed by antibody-induced in vivo blockade of C5a. In contrast, in vitro exposure of alveolar macrophages to C5a and LPS resulted in enhanced production of TNFalpha and no increase in IkappaBalpha. These data suggest that CLP-induced sepsis causes a C5a-dependent dysfunction of neutrophils, which is characterized by altered signaling associated with NF-kappaB activation.
Riedemann
Niels C
NC
Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Guo
Ren-Feng
RF
Bernacki
Kurt D
KD
Reuben
Jayne S
JS
Laudes
Ines J
IJ
Neff
Thomas A
TA
Gao
Hongwei
H
Speyer
Cecilia
C
Sarma
Vidya J
VJ
Zetoune
Firas S
FS
Ward
Peter A
PA
D000818:Animals; D015936:Complement C5a / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D020672:I-kappa B Proteins / Q000378:metabolism; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000494:pharmacology; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D018805:Sepsis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; C000606206:Nfkbia protein, rat; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D015936:Complement C5a