Abstract:
:IFN-γ is known as a pro-inflammatory cytokine, but can also block inflammation in certain chronic diseases although the underlying mechanisms are poorly understood. We found that IFN-γ rapidly induced Noxa expression and that extent of inflammation by repeated house dust mite exposure was enhanced in noxa-/- compared with noxa+/+ mice. Noxa expression blocked transforming necrosis factor alpha (TNF-α)-induced nuclear translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and the production of pro-inflammatory cytokines. Noxa did not affect TNF-α-induced IκBα phosphorylation but the degradation of 48-chain-ubiquitylated IκBα. The Cys25 of Noxa was cross-linked with Cys137 of phospho-HSP27 and both proteins were required for blocking the degradation of ubiquitylated IκBα. Because phospho-HSP27 is present in airway epithelial cells and not in fibroblasts or thymocytes, we generated transgenic mice that inducibly expressed Noxa in airway epithelia. These mice showed protection from allergen-induced inflammation and mucous cell metaplasia by blocking nuclear translocation of NF-κB. Further, we identified a Noxa-derived peptide that prolonged degradation of 48-chain-ubiquitylated IκBα, blocked nuclear translocation of NF-κB, and reduced allergen-induced inflammation in mice. These results suggest that the anti-inflammatory role of the Noxa protein may be restricted to airway epithelial cells and the use of Noxa for therapy of chronic lung diseases may be associated with reduced side effects.
journal_name
Mucosal Immunoljournal_title
Mucosal immunologyauthors
Zhang C,Jones JT,Chand HS,Wathelet MG,Evans CM,Dickey B,Xiang J,Mebratu YA,Tesfaigzi Ydoi
10.1038/mi.2017.117subject
Has Abstractpub_date
2018-05-01 00:00:00pages
741-751issue
3eissn
1933-0219issn
1935-3456pii
mi2017117journal_volume
11pub_type
杂志文章abstract::Intestinal fibrosis leading to strictures remains a significant clinical problem in inflammatory bowel diseases (IBD). The role of bacterial components in activating intestinal mesenchymal cells and driving fibrogenesis is largely unexplored. Tamoxifen-inducible α-SMA promoter Cre mice crossed with floxed MyD88 mice w...
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journal_title:Mucosal immunology
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journal_title:Mucosal immunology
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journal_title:Mucosal immunology
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journal_title:Mucosal immunology
pub_type: 评论,杂志文章
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更新日期:2019-03-01 00:00:00
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journal_title:Mucosal immunology
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journal_title:Mucosal immunology
pub_type: 杂志文章,多中心研究
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更新日期:2008-03-01 00:00:00
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journal_title:Mucosal immunology
pub_type: 杂志文章
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journal_title:Mucosal immunology
pub_type: 杂志文章
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journal_title:Mucosal immunology
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