Commensal anaerobic gut bacteria attenuate inflammation by regulating nuclear-cytoplasmic shuttling of PPAR-gamma and RelA.
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.
Kelly
Denise
D
Gut Immunology Group, Rowett Research Institute, Greenburn Road, Bucksburn, Aberdeen AB21 9SB, Scotland, UK. D.Kelly@rri.sari.ac.uk
Campbell
Jamie I
JI
King
Timothy P
TP
Grant
George
G
Jansson
Emmelie A
EA
Coutts
Alistair G P
AG
Pettersson
Sven
S
Conway
Shaun
S
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
D016207:Cytokines; D016328:NF-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D051996:Transcription Factor RelA; D014157:Transcription Factors