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

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.

Stability of Wake-Sleep Cycles Requires Robust Degradation of the PERIOD Protein

“…Since constitutive β-Trcp2 deletion could lead to embryonic lethality, we generated a conditional β-Trcp2 mutant mouse to circumvent this issue using the cre-loxP technology (Figure S4). During the course of our study, Ben-Neriah and colleagues demonstrated that β-Trcp2 is indeed essential for development [50]. While β-Trcp1 knockout (ko) mice do not exhibit any discernible defects other than male sterility [51], our constitutive β-Trcp2 ko mice (like Ben-Neriah's) showed embryonic lethality: no homozygous β-Trcp2 ko offspring were generated from the mating of heterozygote parents ( β-Trcp2 +/knockout first ) (n > 40 pups).…”

Radiation induces proinflammatory dysbiosis: transmission of inflammatory susceptibility by host cytokine induction

“…However, several recent studies support our findings which attribute an important role for IL-1β in the context of radiation. One study demonstrated that IL-1β exacerbated mucositis in a mouse model through tight junction disruption 37. Another study reported that both IL-1α and IL-1β play a role in radiodermatitis, but IL-1β had greater impact on the inflammatory process 38.…”

Effect of Oral Silymarin Administration on Prevention of Radiotherapy Induced Mucositis: A Randomized, Double‐Blinded, Placebo‐Controlled Clinical Trial

“…These factors can trigger the production of proinflammatory cytokines including TNF‐α, IL‐1β, and IL‐6 which can stimulate damage to connective tissue and endothelium and finally cause epithelial cell death and injury. (Sonis, ; Logan et al ., ; Chung et al ., ; Kanareka et al ., ).…”