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

beta-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-kappaB inhibitor IkappaB. To appreciate tissue-specific roles of beta-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-1beta as the culprit of mucositis onset, inducing mucosal barrier breach. Surprisingly, epithelial IL-1beta is induced by DNA damage via an NF-kappaB-independent mechanism. Tissue damage caused by gut barrier disruption is exacerbated in the absence of NF-kappaB, with failure to express the endogenous IL-1beta receptor antagonist IL-1Ra upon four-allele loss. Antibody neutralization of IL-1beta prevents epithelial tight junction dysfunction and alleviates mucositis in beta-TrCP-deficient mice. IL-1beta antagonists should thus be considered for prevention and treatment of severe morbidity associated with mucositis.