Critical role for IL-1β in DNA damage-induced mucositis.
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.
Lautenberg Centre for Immunology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University Hadassah Medical School, Jerusalem 91120, Israel.
Naama
N
Kanarek
Sergei I
SI
Grivennikov
Michael
M
Leshets
Audrey
A
Lasry
Irit
I
Alkalay
Elad
E
Horwitz
Yoav D
YD
Shaul
Matthew
M
Stachler
Elena
E
Voronov
Ron N
RN
Apte
Michele
M
Pagano
Eli
E
Pikarsky
Michael
M
Karin
Sankar
S
Ghosh
Yinon
Y
Ben-Neriah
D000818:Animals; D001483:Base Sequence; D004249:DNA Damage; D017931:DNA Primers; D053583:Interleukin-1beta / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis; D052016:Mucositis / Q000503:physiopathology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D016133:Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D044844:beta-Transducin Repeat-Containing Proteins / Q000235:genetics / Q000378:metabolism
D017931:DNA Primers; D053583:Interleukin-1beta; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D044844:beta-Transducin Repeat-Containing Proteins
anakinra; anti–IL-1 preventive therapy; cytotoxic side effects; graft-vs.-host disease; gut immunity