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 ind...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2014-02, Vol.111 (6), p.E702-E711
Main Authors: Kanarek, Naama, Grivennikov, Sergei I, Leshets, Michael, Lasry, Audrey, Alkalay, Irit, Horwitz, Elad, Shaul, Yoav D, Stachler, Matthew, Voronov, Elena, Apte, Ron N, Pagano, Michele, Pikarsky, Eli, Karin, Michael, Ghosh, Sankar, Ben-Neriah, Yinon
Format: Article
Language:English
Subjects:
Animals
Base Sequence
beta-Transducin Repeat-Containing Proteins - genetics
beta-Transducin Repeat-Containing Proteins - metabolism
Biological Sciences
DNA Damage
DNA Primers
Interleukin-1beta - metabolism
Interleukin-1beta - physiology
Male
Mice
Mice, Knockout
Mitosis
Mucositis - physiopathology
NF-kappa B - antagonists & inhibitors
PNAS Plus
Polymerase Chain Reaction
Tumor Necrosis Factor-alpha - metabolism
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1322691111