title: IKKalpha limits macrophage NF-kappaB activation and contributes to the resolution of inflammation.
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 diseases. 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 inflammation. 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 organogenesis, 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.
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, California 92093, USA. t.lawrence@imperial.ac.uk
authors.forename: Toby
authors.initials: T
authors.lastname: Lawrence
authors.forename: Magali
authors.initials: M
authors.lastname: Bebien
authors.forename: George Y
authors.initials: GY
authors.lastname: Liu
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005347:Fibroblasts; D005786:Gene Expression Regulation; D051550:I-kappa B Kinase; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology; D007249:Inflammation / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D008262:Macrophage Activation; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020569:Proto-Oncogene Proteins c-rel / Q000378:metabolism; D012772:Shock, Septic / Q000139:chemically induced / Q000276:immunology / Q000382:microbiology; D013292:Streptococcus agalactiae / Q000276:immunology / Q000502:physiology; D016019:Survival Analysis; D051996:Transcription Factor RelA
chemical_list: D008070:Lipopolysaccharides; D016328:NF-kappa B; D020569:Proto-Oncogene Proteins c-rel; D051996:Transcription Factor RelA; D017346:Protein Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse