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

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


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.

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

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • DNA Damage*
  • DNA Primers
  • Interleukin-1beta / metabolism
  • Interleukin-1beta / physiology*
  • Male
  • Mice
  • Mice, Knockout
  • Mitosis
  • Mucositis / physiopathology*
  • NF-kappa B / antagonists & inhibitors
  • Polymerase Chain Reaction
  • Tumor Necrosis Factor-alpha / metabolism
  • beta-Transducin Repeat-Containing Proteins / genetics
  • beta-Transducin Repeat-Containing Proteins / metabolism


  • DNA Primers
  • Interleukin-1beta
  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • beta-Transducin Repeat-Containing Proteins