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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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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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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DOI: https://doi.org/10.1038/nature03491
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