Non-redundant properties of IL-1 alpha and IL-1 beta during acute colon inflammation in mice

M Bersudsky, L Luski, D Fishman, RM White, N Ziv-Sokolovskaya, S Dotan, P Rider, I Kaplanov, Tagest Aychek, CA Dinarello, RN Apte, E Voronov, Rosalyn M. White, Tegest Aychek

Research output: Contribution to journalArticlepeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)598-609
Number of pages12
JournalGut
Volume63
Issue number4
DOIs
StatePublished - Apr 2014

All Science Journal Classification (ASJC) codes

  • Gastroenterology

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