title: Combined loss of cRel/p50 subunits of NF-κB leads to impaired innate host response in sepsis.
abstract: NF-κB, which comprises homo- and hetero-dimers of the five members of the Rel family, plays a crucial role in immunity to infection. The cRel and p50 subunits have been implicated in the development and function of the immune cells, but their in vivo importance remains poorly explored in sepsis. We aimed to study the impact of the combined loss of these two subunits on the innate response to infection in a cecal ligation and puncture model of sepsis. We have explored the possible defects in host defense, including pathogen clearance, bacterial phagocytosis and cytokine plasma release. We also performed gene profiling of cRel(-/-)p50(-/-) and wild-type LPS-stimulated peritoneal macrophages. Deficiency of cRel and p50 led to enhanced mortality to sepsis that was associated with defective macrophages phagocytosis, decreased bacterial clearance and moderate cytokine response. Transcription profile analysis revealed a common inflammatory response but a significant down-regulated transcription of genes encoding for pathogen recognition receptors and antimicrobial molecules, supporting the in vivo findings in mice. In conclusion, the cRel and p50 subunits of NF-κB play an important combined role in the innate response and are crucial for survival and pathogen clearance in polymicrobial sepsis.
authors.affiliation: CNRS, UMR 8104, INSERM, U1016, Institut Cochin, Paris, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Courtine
authors.forename: Nicolas
authors.initials: N
authors.lastname: Cagnard
authors.forename: Julie
authors.initials: J
authors.lastname: Mazzolini
authors.forename: Marion
authors.initials: M
authors.lastname: Antona
authors.forename: Frédéric
authors.initials: F
authors.lastname: Pène
authors.forename: Catherine
authors.initials: C
authors.lastname: Fitting
authors.forename: Sébastien
authors.initials: S
authors.lastname: Jacques
authors.forename: Christophe
authors.initials: C
authors.lastname: Rousseau
authors.forename: Florence
authors.initials: F
authors.lastname: Niedergang
authors.forename: Steve
authors.initials: S
authors.lastname: Gerondakis
authors.forename: Jean-Daniel
authors.initials: JD
authors.lastname: Chiche
authors.forename: Fatah
authors.initials: F
authors.lastname: Ouaaz
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Mira
mesh_terms: D000818:Animals; D002432:Cecum; D002478:Cells, Cultured; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D008026:Ligation; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D050505:Mutant Proteins / Q000235:genetics; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000378:metabolism*; D020572:Oncogene Proteins v-rel / Q000235:genetics / Q000378:metabolism*; D011677:Punctures; D018805:Sepsis / Q000235:genetics / Q000276:immunology*
chemical_list: D008070:Lipopolysaccharides; D050505:Mutant Proteins; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D020572:Oncogene Proteins v-rel