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IκBβ acts to inhibit and activate gene expression during the inflammatory response

Rao, Ping and Hayden, Matthew S. and Long, Meixiao and Scott, Martin L. and West, A. Philip and Zhang, Dekai and Oeckinghaus, Andrea and Lynch, Candace and Hoffmann, Alexander and Baltimore, David and Ghosh, Sankar (2010) IκBβ acts to inhibit and activate gene expression during the inflammatory response. Nature, 466 (7310). pp. 1115-1119. ISSN 0028-0836. PMCID PMC2946371.

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The activation of pro-inflammatory gene programs by nuclear factor-κB (NF-κB) is primarily regulated through cytoplasmic sequestration of NF-κB by the inhibitor of κB (IκB) family of proteins1. IκBβ, a major isoform of IκB, can sequester NF-κB in the cytoplasm2, although its biological role remains unclear. Although cells lacking IκBβ have been reported3, 4, in vivo studies have been limited and suggested redundancy between IκBα and IκBβ5. Like IκBα, IκBβ is also inducibly degraded; however, upon stimulation by lipopolysaccharide (LPS), it is degraded slowly and re-synthesized as a hypophosphorylated form that can be detected in the nucleus6, 7, 8, 9, 10, 11. The crystal structure of IκBβ bound to p65 suggested this complex might bind DNA12. In vitro, hypophosphorylated IκBβ can bind DNA with p65 and c-Rel, and the DNA-bound NF-κB:IκBβ complexes are resistant to IκBα, suggesting hypophosphorylated, nuclear IκBβ may prolong the expression of certain genes9, 10, 11. Here we report that in vivo IκBβ serves both to inhibit and facilitate the inflammatory response. IκBβ degradation releases NF-κB dimers which upregulate pro-inflammatory target genes such as tumour necrosis factor-α (TNF-α). Surprisingly, absence of IκBβ results in a dramatic reduction of TNF-α in response to LPS even though activation of NF-κB is normal. The inhibition of TNF-α messenger RNA (mRNA) expression correlates with the absence of nuclear, hypophosphorylated-IκBβ bound to p65:c-Rel heterodimers at a specific κB site on the TNF-α promoter. Therefore IκBβ acts through p65:c-Rel dimers to maintain prolonged expression of TNF-α. As a result, IκBβ^(−/−) mice are resistant to LPS-induced septic shock and collagen-induced arthritis. Blocking IκBβ might be a promising new strategy for selectively inhibiting the chronic phase of TNF-α production during the inflammatory response.

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Baltimore, David0000-0001-8723-8190
Additional Information:© 2010 Nature Publishing Group. Received 05 August 2009; Accepted 11 June 2010. We thank A. Lin at the Yale W.M. Keck Biostatistics Resource for analysis of microarray data. S.G. was supported by grants from the National Institutes of Health (R37-AI03343). Author Contributions P.R. characterized the mice and performed most of the experiments, M.S.H. performed the immunoprecipitation experiments and helped in writing the paper, M.L. performed collagen-induced arthritis experiments, D.Z. and A.P.W. performed generation of BMDM cells, A.O. performed some experiments, M.L.S. and D.B. generated the knockout mice, C.L. and A.H. performed the RNAse protection assays, and S.G. conceived the study and wrote the paper. Author Information The microarray data are deposited in National Center for Biotechnology Information Gene Expression Omnibus under accession number GSE22223. The authors declare no competing financial interests.
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Subject Keywords:Immunology; Molecular biology; Physiology; Genetics; Genomics
PubMed Central ID:PMC2946371
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ID Code:19813
Deposited By: Jason Perez
Deposited On:15 Sep 2010 21:20
Last Modified:09 Nov 2017 00:25

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