Critical role for IL-1ß in DNA damage-induced mucositis.
Proc Natl Acad Sci U S A
; 111(6): E702-11, 2014 Feb 11.
Article
in En
| MEDLINE
| ID: mdl-24469832
ABSTRACT
ß-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 ß-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-1ß as the culprit of mucositis onset, inducing mucosal barrier breach. Surprisingly, epithelial IL-1ß 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-1ß receptor antagonist IL-1Ra upon four-allele loss. Antibody neutralization of IL-1ß prevents epithelial tight junction dysfunction and alleviates mucositis in ß-TrCP-deficient mice. IL-1ß antagonists should thus be considered for prevention and treatment of severe morbidity associated with mucositis.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
DNA Damage
/
Mucositis
/
Interleukin-1beta
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Proc Natl Acad Sci U S A
Year:
2014
Type:
Article
Affiliation country:
Israel