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Proc Natl Acad Sci U S A. 2014 Feb 11;111(6):E702-11. doi: 10.1073/pnas.1322691111. Epub 2014 Jan 27.

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

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Lautenberg Centre for Immunology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University Hadassah Medical School, Jerusalem 91120, Israel.


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 therapies and represents a major obstacle to successful chemoradiation therapy. We identified epithelial-derived IL-1β as the culprit of mucositis onset, inducing mucosal barrier breach. Surprisingly, epithelial IL-1β is induced by DNA damage via an NF-κB-independent mechanism. Tissue damage caused by gut barrier disruption is exacerbated in the absence of NF-κB, with failure to express the endogenous IL-1β receptor antagonist IL-1Ra upon four-allele loss. Antibody neutralization of IL-1β prevents epithelial tight junction dysfunction and alleviates mucositis in β-TrCP-deficient mice. IL-1β antagonists should thus be considered for prevention and treatment of severe morbidity associated with mucositis.


anakinra; anti–IL-1 preventive therapy; cytotoxic side effects; graft-vs.-host disease; gut immunity

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