Letters to Nature

Nature 434, 1138-1143 (28 April 2005) | doi:10.1038/nature03491; Received 15 October 2004; Accepted 17 February 2005

IKKalpha limits macrophage NF-kappaB activation and contributes to the resolution of inflammation

Toby Lawrence1,3,4, Magali Bebien1,3, George Y. Liu2, Victor Nizet2 & Michael Karin1

  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 Lawrence1,3,4 Correspondence and requests for materials should be addressed to T.L. (Email: t.lawrence@imperial.ac.uk).

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