Critical role for IL-1β in DNA damage-induced mucositis
Year: 2014
Type: article
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 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.
Institutions: Hebrew University of Jerusalem, Hadassah Medical Center, University of California San Diego, Broad Institute, Whitehead Institute for Biomedical Research, Koch Institute for Integrative Cancer Research At MIT, Massachusetts Institute of Technology, Brigham and Women's Hospital, Ben-Gurion University of the Negev, Howard Hughes Medical Institute, New York University, Columbia University Irving Medical Center, Columbia University
Language: English
Topic: NF-κB Signaling Pathways
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2019094911