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 IB kinase (IKK) complex contains two catalytic subunits, IKK and IKK, and controls the activation of NF-B transcription factors, which play a pivotal role in inflammation². Ample evidence indicates that IKK mediates NF-B activation in response to pro-inflammatory cytokines and microbial products. IKK regulates an alternative pathway important for lymphoid organogenesis², but the role of IKK in inflammation is unknown. Here we describe a new role for IKK in the negative regulation of macrophage activation and inflammation. IKK contributes to suppression of NF-B activity by accelerating both the turnover of the NF-B subunits RelA and c-Rel, and their removal from pro-inflammatory gene promoters. Inactivation of IKK 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.

1. Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, and
2. Division of Paediatric Infectious Diseases, School of Medicine, University of California San Diego, 9500 Gilman Drive, California 92093, USA
3. *These authors contributed equally to this work
4. †Present address: Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College, 1 Aspenlea Road, London W6 8LH, UK

Correspondence to: Toby Lawrence^1,3,4 Correspondence and requests for materials should be addressed to T.L. (Email: t.lawrence@imperial.ac.uk).

Received 15 October 2004; Accepted 17 February 2005

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