Publication Date:
2010-08-27
Description:
The activation of pro-inflammatory gene programs by nuclear factor-kappaB (NF-kappaB) is primarily regulated through cytoplasmic sequestration of NF-kappaB by the inhibitor of kappaB (IkappaB) family of proteins. IkappaBbeta, a major isoform of IkappaB, can sequester NF-kappaB in the cytoplasm, although its biological role remains unclear. Although cells lacking IkappaBbeta have been reported, in vivo studies have been limited and suggested redundancy between IkappaBalpha and IkappaBbeta. Like IkappaBalpha, IkappaBbeta 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 nucleus. The crystal structure of IkappaBbeta bound to p65 suggested this complex might bind DNA. In vitro, hypophosphorylated IkappaBbeta can bind DNA with p65 and c-Rel, and the DNA-bound NF-kappaB:IkappaBbeta complexes are resistant to IkappaBalpha, suggesting hypophosphorylated, nuclear IkappaBbeta may prolong the expression of certain genes. Here we report that in vivo IkappaBbeta serves both to inhibit and facilitate the inflammatory response. IkappaBbeta degradation releases NF-kappaB dimers which upregulate pro-inflammatory target genes such as tumour necrosis factor-alpha (TNF-alpha). Surprisingly, absence of IkappaBbeta results in a dramatic reduction of TNF-alpha in response to LPS even though activation of NF-kappaB is normal. The inhibition of TNF-alpha messenger RNA (mRNA) expression correlates with the absence of nuclear, hypophosphorylated-IkappaBbeta bound to p65:c-Rel heterodimers at a specific kappaB site on the TNF-alpha promoter. Therefore IkappaBbeta acts through p65:c-Rel dimers to maintain prolonged expression of TNF-alpha. As a result, IkappaBbeta(-/-) mice are resistant to LPS-induced septic shock and collagen-induced arthritis. Blocking IkappaBbeta might be a promising new strategy for selectively inhibiting the chronic phase of TNF-alpha production during the inflammatory response.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2946371/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2946371/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rao, Ping -- Hayden, Mathew S -- Long, Meixiao -- Scott, Martin L -- West, A Philip -- Zhang, Dekai -- Oeckinghaus, Andrea -- Lynch, Candace -- Hoffmann, Alexander -- Baltimore, David -- Ghosh, Sankar -- R01 AI083453/AI/NIAID NIH HHS/ -- R01 GM071573/GM/NIGMS NIH HHS/ -- R01 GM071573-06/GM/NIGMS NIH HHS/ -- R37 AI033443/AI/NIAID NIH HHS/ -- R37 AI033443-19/AI/NIAID NIH HHS/ -- R37-AI03343/AI/NIAID NIH HHS/ -- England -- Nature. 2010 Aug 26;466(7310):1115-9. doi: 10.1038/nature09283.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunobiology and Department of Molecular Biophysics & Biochemistry, Yale University School of Medicine, New Haven, Connecticut 06520, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20740013" target="_blank"〉PubMed〈/a〉
Keywords:
Adjuvants, Immunologic/pharmacology
;
Animals
;
Arthritis, Experimental/*metabolism
;
Cell Line
;
Cytokines/blood
;
Female
;
*Gene Expression Regulation/drug effects
;
I-kappa B Proteins/*genetics/*metabolism
;
Lipopolysaccharides/pharmacology
;
Male
;
Mice
;
Mice, Inbred DBA
;
Mice, Knockout
;
Tumor Necrosis Factor-alpha/blood/*metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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