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J. Exp. Med. 205 (6): 1269-1276

Copyright © 2008 by the Rockefeller University Press.

BRIEF DEFINITIVE REPORT

An antiinflammatory role for IKKβ through the inhibition of "classical" macrophage activation

Carol Ho Yan Fong1,2, Magali Bebien1,2, Arnaud Didierlaurent1, Ruth Nebauer1,2, Tracy Hussell1, David Broide3, Michael Karin4, , and Toby Lawrence1,2

1 Kennedy Institute of Rheumatology, Faculty of Medicine, Imperial College London, W6 8LH, UK
2 Centre for Cancer and Inflammation, Institute of Cancer and CR-UK Clinical Centre, Bart's and The London School of Medicine and Dentistry, London EC1M 6BQ, UK
3 Department of Medicine and 4 Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA 92103

CORRESPONDENCE Toby Lawrence: t.lawrence{at}qmul.ac.uk

Abstract: The nuclear factor {kappa}B (NF-{kappa}B) pathway plays a central role in inflammation and immunity. In response to proinflammatory cytokines and pathogen-associated molecular patterns, NF-{kappa}B activation is controlled by I{kappa}B kinase (IKK)β. Using Cre/lox-mediated gene targeting of IKKβ, we have uncovered a tissue-specific role for IKKβ during infection with group B streptococcus. Although deletion of IKKβ in airway epithelial cells had the predicted effect of inhibiting inflammation and reducing innate immunity, deletion of IKKβ in the myeloid lineage unexpectedly conferred resistance to infection that was associated with increased expression of interleukin (IL)-12, inducible nitric oxide synthase (NOS2), and major histocompatibility complex (MHC) class II by macrophages. We also describe a previously unknown role for IKKβ in the inhibition of signal transducer and activator of transcription (Stat)1 signaling in macrophages, which is critical for IL-12, NOS2, and MHC class II expression. These studies suggest that IKKβ inhibits the "classically" activated or M1 macrophage phenotype during infection through negative cross talk with the Stat1 pathway. This may represent a mechanism to prevent the over-exuberant activation of macrophages during infection and contribute to the resolution of inflammation. This establishes a new role for IKKβ in the regulation of macrophage activation with important implications in chronic inflammatory disease, infection, and cancer.

C.H.Y. Fong and M. Bebien contributed equally to this work.

© 2008 Fong et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jgp.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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