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Critical role for IL-1? in DNA damage-induced mucositis.


ABSTRACT: ?-TrCP, the substrate recognition subunit of SCF-type ubiquitin ligases, is ubiquitously expressed from two distinct paralogs, targeting for degradation many regulatory proteins, among which is the NF-?B inhibitor I?B. To appreciate tissue-specific roles of ?-TrCP, we studied the consequences of inducible ablation of three or all four alleles of the E3 in the mouse gut. The ablation resulted in mucositis, a destructive gut mucosal inflammation, which is a common complication of different cancer therapies and represents a major obstacle to successful chemoradiation therapy. We identified epithelial-derived IL-1? as the culprit of mucositis onset, inducing mucosal barrier breach. Surprisingly, epithelial IL-1? is induced by DNA damage via an NF-?B-independent mechanism. Tissue damage caused by gut barrier disruption is exacerbated in the absence of NF-?B, with failure to express the endogenous IL-1? receptor antagonist IL-1Ra upon four-allele loss. Antibody neutralization of IL-1? prevents epithelial tight junction dysfunction and alleviates mucositis in ?-TrCP-deficient mice. IL-1? antagonists should thus be considered for prevention and treatment of severe morbidity associated with mucositis.

SUBMITTER: Kanarek N 

PROVIDER: S-EPMC3926043 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Critical role for IL-1β in DNA damage-induced mucositis.

Kanarek Naama N   Grivennikov Sergei I SI   Leshets Michael M   Lasry Audrey A   Alkalay Irit I   Horwitz Elad E   Shaul Yoav D YD   Stachler Matthew M   Voronov Elena E   Apte Ron N RN   Pagano Michele M   Pikarsky Eli E   Karin Michael M   Ghosh Sankar S   Ben-Neriah Yinon Y  

Proceedings of the National Academy of Sciences of the United States of America 20140127 6


β-TrCP, the substrate recognition subunit of SCF-type ubiquitin ligases, is ubiquitously expressed from two distinct paralogs, targeting for degradation many regulatory proteins, among which is the NF-κB inhibitor IκB. To appreciate tissue-specific roles of β-TrCP, we studied the consequences of inducible ablation of three or all four alleles of the E3 in the mouse gut. The ablation resulted in mucositis, a destructive gut mucosal inflammation, which is a common complication of different cancer  ...[more]

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