Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

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

Copyright © 2008 by the Rockefeller University Press.


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}

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 After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at

The Alveolar Microenvironment of Patients Infected with Human Immunodeficiency Virus Does Not Modify Alveolar Macrophage Interactions with Streptococcus pneumoniae.
S. B. Gordon, R. T. Jagoe, E. R. Jarman, J. C. North, A. Pridmore, J. Musaya, N. French, E. E. Zijlstra, M. E. Molyneux, and R. C. Read (2013)
Clin. Vaccine Immunol. 20, 882-891
   Abstract »    Full Text »    PDF »
Genome-Wide Mapping of Cystitis Due to Streptococcus agalactiae and Escherichia coli in Mice Identifies a Unique Bladder Transcriptome That Signifies Pathogen-Specific Antimicrobial Defense against Urinary Tract Infection.
C. K. Tan, A. J. Carey, X. Cui, R. I. Webb, D. Ipe, M. Crowley, A. W. Cripps, W. H. Benjamin Jr., K. B. Ulett, M. A. Schembri, et al. (2012)
Infect. Immun. 80, 3145-3160
   Abstract »    Full Text »    PDF »
Loss of the Oxygen Sensor PHD3 Enhances the Innate Immune Response to Abdominal Sepsis.
J. Kiss, M. Mollenhauer, S. R. Walmsley, J. Kirchberg, P. Radhakrishnan, T. Niemietz, J. Dudda, G. Steinert, M. K. B. Whyte, P. Carmeliet, et al. (2012)
J. Immunol. 189, 1955-1965
   Abstract »    Full Text »    PDF »
Inhibiting NF-{kappa}B in the developing lung disrupts angiogenesis and alveolarization.
C. Iosef, T.-P. Alastalo, Y. Hou, C. Chen, E. S. Adams, S.-C. Lyu, D. N. Cornfield, and C. M. Alvira (2012)
Am J Physiol Lung Cell Mol Physiol 302, L1023-L1036
   Abstract »    Full Text »    PDF »
Opposing effects of bortezomib-induced nuclear factor-{kappa}B inhibition on chemical lung carcinogenesis.
S. P. Karabela, I. Psallidas, T. P. Sherrill, C. A. Kairi, R. Zaynagetdinov, D.-S. Cheng, S. Vassiliou, F. McMahon, L. A. Gleaves, W. Han, et al. (2012)
Carcinogenesis 33, 859-867
   Abstract »    Full Text »    PDF »
Cell-Selective Inhibition of NF-{kappa}B Signaling Improves Therapeutic Index in a Melanoma Chemotherapy Model.
T. Enzler, Y. Sano, M.-K. Choo, H. B. Cottam, M. Karin, H. Tsao, and J. M. Park (2011)
Cancer Discovery 1, 496-507
   Abstract »    Full Text »    PDF »
NF-{kappa}B1 Inhibits TLR-Induced IFN-{beta} Production in Macrophages through TPL-2-Dependent ERK Activation.
H.-T. Yang, Y. Wang, X. Zhao, E. Demissie, S. Papoutsopoulou, A. Mambole, A. O'Garra, M. F. Tomczak, S. E. Erdman, J. G. Fox, et al. (2011)
J. Immunol. 186, 1989-1996
   Abstract »    Full Text »    PDF »
Priming innate immune responses to infection by cyclooxygenase inhibition kills antibiotic-susceptible and -resistant bacteria.
M. J. Stables, J. Newson, S. S. Ayoub, J. Brown, C. J. Hyams, and D. W. Gilroy (2010)
Blood 116, 2950-2959
   Abstract »    Full Text »    PDF »
Lipopolysaccharide-activated Alveolar Macrophages Having Cytotoxicity toward Lung Tumor Cells through Cell-to-Cell Binding-dependent Mechanism.
Anticancer Res 30, 3159-3165
   Abstract »    Full Text »    PDF »
Different Tumor Microenvironments Contain Functionally Distinct Subsets of Macrophages Derived from Ly6C(high) Monocytes.
K. Movahedi, D. Laoui, C. Gysemans, M. Baeten, G. Stange, J. Van den Bossche, M. Mack, D. Pipeleers, P. In't Veld, P. De Baetselier, et al. (2010)
Cancer Res. 70, 5728-5739
   Abstract »    Full Text »    PDF »
Nuclear Factor-{kappa}B and Tumor-Associated Macrophages.
A. Mancino and T. Lawrence (2010)
Clin. Cancer Res. 16, 784-789
   Abstract »    Full Text »    PDF »
The Nuclear Factor NF-{kappa}B Pathway in Inflammation.
T. Lawrence (2009)
Cold Spring Harb Perspect Biol 1, a001651
   Abstract »    Full Text »    PDF »
Interferons Direct an Effective Innate Response to Legionella pneumophila Infection.
C. R. Plumlee, C. Lee, A. A. Beg, T. Decker, H. A. Shuman, and C. Schindler (2009)
J. Biol. Chem. 284, 30058-30066
   Abstract »    Full Text »    PDF »
Regulation of macrophage function in tumors: the multifaceted role of NF-{kappa}B.
T. Hagemann, S. K. Biswas, T. Lawrence, A. Sica, and C. E. Lewis (2009)
Blood 113, 3139-3146
   Abstract »    Full Text »    PDF »
Science Signaling Podcast: 15 July 2008.
J. F. Foley and A. M. VanHook (2008)
Science Signaling 1, pc6
   Abstract »    Full Text »
IKK{beta}/NF-{kappa}B and the miscreant macrophage.
A. M. Timmer and V. Nizet (2008)
J. Exp. Med. 205, 1255-1259
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882