Details

Autor(en) / Beteiligte

• Kanarek, Naama
• Grivennikov, Sergei I
• Leshets, Michael
• Lasry, Audrey
• Alkalay, Irit
• Horwitz, Elad
• Shaul, Yoav D
• Stachler, Matthew
• Voronov, Elena
• Apte, Ron N
• Pagano, Michele
• Pikarsky, Eli
• Karin, Michael
• Ghosh, Sankar
• Ben-Neriah, Yinon

Titel

Critical role for IL-1[Beta] in DNA damage-induced mucositis

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2014-02, Vol.111 (6), p.E702

Ort / Verlag

Washington: National Academy of Sciences

Erscheinungsjahr

2014

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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-kB inhibitor IkB. 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-kB-independent mechanism. Tissue damage caused by gut barrier disruption is exacerbated in the absence of NF-kB, 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. [PUBLICATION ABSTRACT]