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IKKα limits macrophage NF-κB activation and contributes to the resolution of inflammation

Nature volume 434, pages 1138–1143 (2005)Cite this article

Abstract

Inflammation and innate immunity involve signalling pathways leading to the production of inflammatory mediators. Usually such responses are self-limiting, but aberrant resolution of inflammation results in chronic diseases1. Much attention has focused on pro-inflammatory signalling but little is known about the mechanisms that resolve inflammation. The IκB kinase (IKK) complex contains two catalytic subunits, IKKα and IKKβ, and controls the activation of NF-κB transcription factors, which play a pivotal role in inflammation2. Ample evidence indicates that IKKβ mediates NF-κB activation in response to pro-inflammatory cytokines and microbial products. IKKα regulates an alternative pathway important for lymphoid organogenesis2, but the role of IKKα in inflammation is unknown. Here we describe a new role for IKKα in the negative regulation of macrophage activation and inflammation. IKKα contributes to suppression of NF-κB activity by accelerating both the turnover of the NF-κB subunits RelA and c-Rel, and their removal from pro-inflammatory gene promoters. Inactivation of IKKα in mice enhances inflammation and bacterial clearance. Hence, the two IKK catalytic subunits have evolved opposing but complimentary roles needed for the intricate control of inflammation and innate immunity.

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Figure 1: IKKα limits the inflammatory response to Gram-positive infection.
Figure 2: IKKα deficiency in haematopoietic cells increases the systemic inflammatory response to LPS.
Figure 3: IKKα suppresses macrophage activation in response to GBS infection in vitro.
Figure 4: IKKα negatively regulates RelA and c-Rel nuclear accumulation and NF-κB target gene expression in LPS-stimulated macrophages.
Figure 5: IKKα mediates C-terminal RelA phosphorylation and promotes its stimulus-induced turnover.

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Acknowledgements

We thank H. Sakurai, H. Kamata, and G. Fresno for plasmid constructs, and J.M. Park and A. Hoffmann for discussions and advice. T.L. is the recipient of a Wellcome Trust International Research Fellowship. V.N. is an Edward J. Mallinckrodt, Jr Scholar. Research was supported by NIH grants to M.K., who is the Frank and Else Schilling American Cancer Society Research Professor.

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Author notes

  1. Toby Lawrence

    Present address: Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College, 1 Aspenlea Road, London, W6 8LH, UK

  2. Toby Lawrence and Magali Bebien: *These authors contributed equally to this work

Authors and Affiliations

  1. Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, California, 92093, USA

    Toby Lawrence, Magali Bebien & Michael Karin

  2. Division of Paediatric Infectious Diseases, School of Medicine, University of California San Diego, 9500 Gilman Drive, California, 92093, USA

    George Y. Liu & Victor Nizet

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Corresponding author

Correspondence to Toby Lawrence.

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Supplementary information

Supplementary Figure S1

IkkαAA/AA mice exposed to aerosolized LPS showed increased recruitment of neutrophils to the lung which correlated with elevated release of IL-12. (JPG 26 kb)

Supplementary Figure S2

IkkαAA/AA mice showed elevated leukocyte recruitment and chemokine release in response to the TLR2 ligand zymosan. (JPG 11 kb)

Supplementary Figure S3

Macrophages elicited from IkkαAA/AA mice are resistant to GBS0-induced apoptosis and this correlated with elevated production of nitric oxide in vitro. (JPG 29 kb)

Supplementary Figure S4

IKKα mediated C-terminal phosphorylation of RelA and c-Rel in LPS stimulated macrophages. (JPG 21 kb)

Supplementary Figure S5

Termination of NF- B activation in LPS-stimulated macrophages is proteasome dependent. In the presence of a proteasome inhibitor RelA and c-Rel accumulated in the nucleus which correlated with increased recruitment of RelA to the IL-12p40 gene promoter. (JPG 17 kb)

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Lawrence, T., Bebien, M., Liu, G. et al. IKKα limits macrophage NF-κB activation and contributes to the resolution of inflammation. Nature 434, 1138–1143 (2005). https://doi.org/10.1038/nature03491

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