title: Regulation by C5a of neutrophil activation during sepsis.
abstract: 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.
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Niels C
authors.initials: NC
authors.lastname: Riedemann
authors.forename: Ren-Feng
authors.initials: RF
authors.lastname: Guo
authors.forename: Kurt D
authors.initials: KD
authors.lastname: Bernacki
authors.forename: Jayne S
authors.initials: JS
authors.lastname: Reuben
authors.forename: Ines J
authors.initials: IJ
authors.lastname: Laudes
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Neff
authors.forename: Hongwei
authors.initials: H
authors.lastname: Gao
authors.forename: Cecilia
authors.initials: C
authors.lastname: Speyer
authors.forename: Vidya J
authors.initials: VJ
authors.lastname: Sarma
authors.forename: Firas S
authors.initials: FS
authors.lastname: Zetoune
authors.forename: Peter A
authors.initials: PA
authors.lastname: Ward
mesh_terms: 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
chemical_list: 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