Journal
GUT
Volume 63, Issue 4, Pages 598-609Publisher
BMJ PUBLISHING GROUP
DOI: 10.1136/gutjnl-2012-303329
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Funding
- Cancer and Inflammation (INFLA-CARE)
- Israel Ministry of Science (MOS)
- Deutsches Krebsforschungscentrum (DKFZ), Heidelberg, Germany
- Israel Science Foundation - Israel Academy of Sciences and Humanities
- Israel Cancer Association
- Israel Ministry of Health Chief Scientist's Office
- Cancer and Inflammation
- Israel Science Foundation
- National Institutes of Health [AI-15614, AR-45584, CA-04 6934]
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Objective The differential role of the IL-1 agonists, IL-1 alpha, which is mainly cell-associated versus IL-1 beta, which is mostly secreted, was studied in colon inflammation. Design Dextran sodium sulfate (DSS) colitis was induced in mice globally deficient in either IL-1 alpha or IL-1 beta, and in wild-type mice, or in mice with conditional deletion of IL-1 alpha in intestinal epithelial cells (IECs). Bone marrow transplantation experiments were performed to assess the role of IL-1 alpha or IL-1 beta of myeloid versus colon non-hematopoietic cells in inflammation and repair in acute colitis. Results IL-1 alpha released from damaged IECs acts as an alarmin by initiating and propagating colon inflammation, as IL-1 alpha deficient mice exhibited mild disease symptoms with improved recovery. IL-1 beta is involved in repair of IECs and reconstitution of the epithelial barrier during the resolution of colitis; its deficiency correlates with disease exacerbation. Neutralisation of IL-1 alpha in control mice during acute colitis led to alleviation of clinical and histological manifestations, whereas treatment with rIL-1Ra or anti-IL-1 beta antibodies was not effective. Repair after colitis correlated with accumulation of CD8 and regulatory T cells in damaged crypts. Conclusions The role of IL-1 alpha and IL-1 beta differs in DSS-induced colitis in that IL-1 alpha, mainly of colon epithelial cells is inflammatory, whereas IL-1 beta, mainly of myeloid cell origin, promotes healing and repair. Given the dissimilar functions of each IL-1 agonistic molecule, an IL-1 receptor blockade would not be as therapeutically effective as specific neutralising of IL-1 alpha, which leaves IL-1 beta function intact.
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