title: Critical role of cRel subunit of NF-κB in sepsis survival.
abstract: NF-κB is a critical regulator of gene expression during severe infections. NF-κB comprises homo- and heterodimers of proteins from the Rel family. Among them, p50 and p65 have been clearly implicated in the pathophysiology of sepsis. In contrast, the role of cRel in sepsis is still controversial and has been poorly studied in single-pathogen infections. We aimed to investigate the consequences of cRel deficiency in a cecal ligation and puncture (CLP) model of sepsis. We have approached the underlying mechanisms of host defense by analyzing bacterial clearance, systemic inflammation, and the distribution of spleen dendritic cell subsets. Moreover, by using a genome-wide technology, we have also analyzed the CLP-induced modifications in gene expression profiles both in wild-type (wt) and in rel(-/-) mice. The absence of cRel enhances mortality due to polymicrobial sepsis. Despite normal pathogen clearance, cRel deficiency leads to an altered systemic inflammatory response associated with a sustained loss of the spleen lymphoid dendritic cells. Furthermore, a whole-blood microarray study reveals that the differential outcome between wt and rel(-/-) mice during sepsis is preceded by remarkable changes in the expression of hundreds of genes involved in aspects of host-pathogen interaction, such as host survival and lipid metabolism. In conclusion, cRel is a key NF-κB member required for host antimicrobial defenses and a regulatory transcription subunit that controls the inflammatory and immune responses in severe infection.
authors.affiliation: Département de Biologie Cellulaire des Interactions Hôte-Pathogène, Institut Cochin, Paris, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Courtine
authors.forename: Frédéric
authors.initials: F
authors.lastname: Pène
authors.forename: Nicolas
authors.initials: N
authors.lastname: Cagnard
authors.forename: Julie
authors.initials: J
authors.lastname: Toubiana
authors.forename: Catherine
authors.initials: C
authors.lastname: Fitting
authors.forename: Jessy
authors.initials: J
authors.lastname: Brocheton
authors.forename: Christophe
authors.initials: C
authors.lastname: Rousseau
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; D015153:Blotting, Western; D004195:Disease Models, Animal; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006790:Host-Parasite Interactions / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D020569:Proto-Oncogene Proteins c-rel / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D018805:Sepsis / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D051996:Transcription Factor RelA / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D020569:Proto-Oncogene Proteins c-rel; D051996:Transcription Factor RelA