Commensal anaerobic gut bacteria attenuate inflammation by regulating nuclear-cytoplasmic shuttling of PPAR-γ and RelA

• Published in: Nature immunology Vol. 5; no. 1; pp. 104 - 112
• Main Authors: Kelly, Denise, Campbell, Jamie I, King, Timothy P, Grant, George, Jansson, Emmelie A, Coutts, Alistair G P, Pettersson, Sven, Conway, Shaun
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.01.2004
• Subjects: Animals; Bacteroides - immunology; Bacteroides thetaiotaomicron; Caco-2 Cells; Crm-1 protein; Cytokines - immunology; Cytokines - metabolism; Electrophoretic Mobility Shift Assay; Gastrointestinal Tract - immunology; Gastrointestinal Tract - microbiology; HeLa Cells; Humans; Medicin och hälsovetenskap; Microscopy, Fluorescence; NF-B protein; NF-kappa B - antagonists & inhibitors; NF-kappa B - immunology; peroxisome proliferator-activated receptor-g; PPAR-g protein; Rats; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - immunology; RelA protein; RNA Interference - immunology; Salmonella enteritidis - immunology; Salmonella Infections - immunology; Salmonella Infections - microbiology; Transcription Factor RelA; Transcription Factors - genetics; Transcription Factors - immunology
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/ni1018

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.