期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：6
页码：E702-E711
DOI：10.1073/pnas.1322691111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：{beta}-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-{kappa}B inhibitor I{kappa}B. To appreciate tissue-specific roles of {beta}-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{beta} as the culprit of mucositis onset, inducing mucosal barrier breach. Surprisingly, epithelial IL-1{beta} is induced by DNA damage via an NF-{kappa}B-independent mechanism. Tissue damage caused by gut barrier disruption is exacerbated in the absence of NF-{kappa}B, with failure to express the endogenous IL-1{beta} receptor antagonist IL-1Ra upon four-allele loss. Antibody neutralization of IL-1{beta} prevents epithelial tight junction dysfunction and alleviates mucositis in {beta}-TrCP-deficient mice. IL-1{beta} antagonists should thus be considered for prevention and treatment of severe morbidity associated with mucositis.
