Critical role for IL-1β in DNA damageinduced mucositis

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

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

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 fourallele 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.

Original languageEnglish
Pages (from-to)E702-E711
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number6
DOIs
StatePublished - 11 Feb 2014

Keywords

  • Anakinra
  • Anti-IL-1 preventive therapy
  • Cytotoxic side effects
  • Graft-vs.-host disease
  • Gut immunity

ASJC Scopus subject areas

  • General

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