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Commensal anaerobic gut bacteria attenuate inflammation by regulating nuclear-cytoplasmic shuttling of PPAR-γ 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-κB. Bacteroides thetaiotaomicron targets transcriptionally active NF-κB subunit RelA, enhancing its nuclear export through a mechanism independent of nuclear export receptor Crm-1. Peroxisome proliferator activated receptor-γ (PPAR-γ), in complex with nuclear RelA, also undergoes nucleocytoplasmic redistribution in response to B. thetaiotaomicron. A decrease in PPAR-γ abolishes both the nuclear export of RelA and the anti-inflammatory activity of B. thetaiotaomicron. This PPAR-γ-dependent anti-inflammatory mechanism defines new cellular targets for therapeutic drug design and interventions for the treatment of chronic inflammation.

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Figure 1: B. thetaiotaomicron specifically attenuates inflammatory responses in Caco-2 cells and in vivo.
Figure 2: B. thetaiotaomicron attenuates inflammation by enhancing nuclear export of NF-κB RelA protein in Caco-2 cells.
Figure 3: The nuclear export of RelA induced by B. thetaioatoamicron is independent of the Crm-1 pathway.
Figure 4: B. thetaiotaomicron induces cellular shuttling of PPAR-γ in Caco-2 cells.
Figure 5: PPAR-γ, but not the dominant negative PPAR-γ, interacts with active RelA and facilitates its nuclear export.
Figure 6: RNA interference of PPAR-γ.
Figure 7: PPAR-γ RNAi abolishes the nuclear export of RelA and the transcriptional inhibition of IL-8 in Caco-2 cells treated with S. enteritidis and B. thetaiotaomicron.

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Acknowledgements

We thank E.T. Logan, K.E Garden, D.J. Fraser-Pitt, D.L. Wilson and J.C. Martin for technical support. We also thank V.K. Chatterjee (Addenbrooke's Hospital, Cambridge, UK) and J.A. Schmid (University of Vienna, Austria) for providing the PPAR-γ and YFP-RelA clones for this work. Supported by SEERAD (Scottish Executive for Environmental and Rural Affairs Department).

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Kelly, D., Campbell, J., King, T. et al. Commensal anaerobic gut bacteria attenuate inflammation by regulating nuclear-cytoplasmic shuttling of PPAR-γ and RelA. Nat Immunol 5, 104–112 (2004). https://doi.org/10.1038/ni1018

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