HIGHLIGHTS

NATURE REVIEWS | IMMUNOLOGY VOLUME 4 | FEBRUARY 2004 | 81

HIGHLIGHT ADVISORS

CEZMI AKDIS

SWISS INSTITUTE OF ALLERGYAND ASTHMA RESEARCH,SWITZERLAND

BRUCE BEUTLER

SCRIPPS RESEARCH INSTITUTE,USA

PETER CRESSWELL

YALE UNIVERSITY, USA

JAMES DI SANTO

PASTEUR INSTITUTE, FRANCE

GARY KORETZKY

UNIVERSITY OFPENNSYLVANIA, USA

CHARLES MACKAY

GARVAN INSTITUTE OFMEDICAL RESEARCH,AUSTRALIA

CORNELIS J. M. MELIEF

LEIDEN UNIVERSITY MEDICALCENTRE, THE NETHERLANDS

MICHEL NUSSENZWEIG

THE ROCKEFELLER UNIVERSITY,USA

SARAH ROWLAND-JONES

CENTRE FOR TROPICALMEDICINE, OXFORD, UK

ALAN SHER

NATIONAL INSTITUTE OFALLERGY AND INFECTIOUSDISEASE, USA

ANDREAS STRASSER

THE WALTER AND ELIZA HALLINSTITUTE, AUSTRALIA

MEGAN SYKES

HARVARD MEDICAL SCHOOL,USA

ERIC VIVIER

CENTRE D’IMMUNOLOGIE DEMARSEILLE-LUMINY, FRANCE

MATTHIAS VON HERRATH

LA JOLLA INSTITUTE FORALLERGY AND IMMUNOLOGY,USA.

How can we mount an immuneresponse to pathogenic bacteria in thegut yet tolerate the large number ofcommensals that live inside us? Pro-inflammatory responses to pathogenicbacteria by intestinal epithelial cellsinvolve gene transcription activated bytranslocation of nuclear factor-κB(NF-κB) into the nucleus. This studynow shows that anti-inflammatoryresponses to commensals are medi-ated by a reversal of this NF-κB move-ment. This shuttling of transcriptionfactors out of the nucleus occurs by anew pathway involving peroxisomeproliferator activated receptor-γ(PPAR-γ).

Exposure of intestinal epithelial-cellcultures (Caco-2 cells) to the patho-genic bacterium Salmonella enteritidisresulted in the upregulation ofexpression of pro-inflammatorygenes encoding, for example, inter-leukin-8 (IL-8). However, addition of the anaerobic gut commensalBacteroides thetaiotaomicron attenu-ated this response. The reduced levelsof IL-8 resulting from exposure toB. thetaiotaomicron correlated withreduced neutrophil recruitment to theintestinal epithelium and with less his-tological disruption of the ileal mucosain rats infected with both bacteria.

Next, the authors looked at howthese responses to gut bacteria arecontrolled. Exposure of Caco-2 cellsto S. enteritidis led to nuclear importof the NF-κB subunit RelA; additionof B. thetaiotaomicron did not alter theinitial nuclear translocation of RelA,but did result in accelerated cyto-

plasmic redistribution. In other sys-tems, cytoplasmic retention of NF-κBis mediated by the inhibitor of NF-κB(IκB) complex, but there was no dif-ference in IκBα phosphorylation ordegradation in Caco-2 cells exposedto B. thetaiotaomicron. Furthermore,nuclear export of RelA did not involveCRM1 (exportin 1), which is the onlyknown pathway for the movement ofNF-κB complexes out of the nucleus.

However, nuclear accumulationof RelA in response to S. enteritidisdid correlate with nuclear import ofPPAR-γ, which was also redistributedto the cytoplasm after co-culturewith B. thetaiotaomicron. RelA andPPAR-γ were found to associate,explaining their common localiza-tion. In cells in which the level ofPPAR-γwas decreased or its bindingto RelA was prevented, the inhibitoryeffect of B. thetaiotaomicron on

transcription did not occur. Usingfluorescent labelling and RNA inter-ference, the authors confirmed thatPPAR-γ is essential for the nucleo-cytoplasmic redistribution of RelAin response to B. thetaiotaomicron.

As B. thetaiotaomicron is preva-lent in the human gut, the anti-inflammatory pathway described inthis study might make an importantcontribution to immune homeostasisand be a relevant therapeutic targetfor inflammatory conditions ofthe gut. The new nuclear exportmechanism involving PPAR-γcouldalso be a more general method oftranscriptional control.

Kirsty Minton

References and linksORIGINAL RESEARCH PAPER Kelly, D. et al.Commensal anaerobic gut bacteria attenuateinflammation by regulating nuclear-cytoplasmicshuttling of PPAR-γand RelA. Nature Immunol. 5, 104–112 (2004)

PPAR-γ

The ins and outs of gut inflammation

M U C O S A L I M M U N O LO G Y