Avoiding Too Much of a Good Thing

Abstract

The transcription factor nuclear factor κB (NF-κB) plays a critical role in mediating inflammatory responses to bacterial pathogens and proinflammatory cytokines. Proinflammatory stimuli lead to activation of IKK [inhibitor of NF-κB α (IκBα) kinase], a complex that contains two catalytic subunits--IKKα and IKKβ. Whereas IKKβ phosphorylates IκBα, enabling NF-κB activation, the role that IKKα plays in the inflammatory response has been less clear. Lawrence et al. discovered that mice expressing inactivatable IKKα ( Ikkα AA/AA mice) not only showed reduced bacterial titers when challenged with group B Streptococcus (GBS) but, paradoxically, had reduced survival. When injected with Escherichia coli lipopolysaccharide (LPS), Ikkα AA/AA mice exhibited increased expression of NF-κB target genes and enhanced susceptibility to septic shock. Experiments in which the hematopoietic system of wild-type mice was reconstituted with bone marrow from Ikkα AA/AA mice revealed that this exaggerated inflammatory response depended on cells of the hematopoietic system. Macrophages from Ikkα AA/AA mice were resistant to GBS-induced apoptosis and displayed enhanced in vitro bactericidal activity and increased expression of proinflammatory and antiapoptotic genes after exposure to LPS. Although NF-κB DNA binding activity and nuclear translocation of the NF-κB subunits RelA and c-Rel were initially comparable in Ikkα AA/AA and wild-type mice, increased nuclear content of RelA and c-Rel persisted in Ikkα AA/AA mice, as did their association with a target gene promoter. Moreover, phosphorylation of RelA was reduced in macrophages from Ikkα AA/AA mice, and the half-life of RelA and c-Rel was prolonged. Thus, the authors propose that, in contrast to IKKβ, the role of IKKα is to terminate the inflammatory response. T. Lawrence, M. Bebien, G. Y. Liu, V. Nizet, M. Karin, IKKα limits macrophage NF-κB activation and contributes to the resolution of inflammation. Nature 434 , 1138-1143 (2005). [PubMed]