title: Commensal anaerobic gut bacteria attenuate inflammation by regulating nuclear-cytoplasmic shuttling of PPAR-gamma and RelA.
abstract: The human gut microflora is important in regulating host inflammatory responses and in maintaining immune homeostasis. The cellular and molecular bases of these actions are unknown. Here we describe a unique anti-inflammatory mechanism, activated by nonpathogenic bacteria, that selectively antagonizes transcription factor NF-kappaB. Bacteroides thetaiotaomicron targets transcriptionally active NF-kappaB subunit RelA, enhancing its nuclear export through a mechanism independent of nuclear export receptor Crm-1. Peroxisome proliferator activated receptor-gamma (PPAR-gamma), in complex with nuclear RelA, also undergoes nucleocytoplasmic redistribution in response to B. thetaiotaomicron. A decrease in PPAR-gamma abolishes both the nuclear export of RelA and the anti-inflammatory activity of B. thetaiotaomicron. This PPAR-gamma-dependent anti-inflammatory mechanism defines new cellular targets for therapeutic drug design and interventions for the treatment of chronic inflammation.
authors.affiliation: Gut Immunology Group, Rowett Research Institute, Greenburn Road, Bucksburn, Aberdeen AB21 9SB, Scotland, UK. D.Kelly@rri.sari.ac.uk
authors.forename: Denise
authors.initials: D
authors.lastname: Kelly
authors.forename: Jamie I
authors.initials: JI
authors.lastname: Campbell
authors.forename: Timothy P
authors.initials: TP
authors.lastname: King
authors.forename: George
authors.initials: G
authors.lastname: Grant
authors.forename: Emmelie A
authors.initials: EA
authors.lastname: Jansson
authors.forename: Alistair G P
authors.initials: AG
authors.lastname: Coutts
authors.forename: Sven
authors.initials: S
authors.lastname: Pettersson
authors.forename: Shaun
authors.initials: S
authors.lastname: Conway
mesh_terms: D000818:Animals; D001439:Bacteroides / Q000276:immunology*; D018938:Caco-2 Cells; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D041981:Gastrointestinal Tract / Q000276:immunology / Q000382:microbiology*; D006367:HeLa Cells; D006801:Humans; D008856:Microscopy, Fluorescence; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000276:immunology*; D034622:RNA Interference / Q000276:immunology; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000276:immunology; D012480:Salmonella Infections / Q000276:immunology* / Q000382:microbiology; D012477:Salmonella enteritidis / Q000276:immunology*; D051996:Transcription Factor RelA; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D051996:Transcription Factor RelA; D014157:Transcription Factors