Non-redundant properties of IL-1α and IL-1β during acute colon inflammation in mice

Marina Bersudsky, Lotem Luski, Daniel Fishman, Rosalyn M. White, Nadya Ziv-Sokolovskaya, Shahar Dotan, Peleg Rider, Irena Kaplanov, Tegest Aychek, Charles A. Dinarello, Ron N. Apte, Elena Voronov

Research output: Contribution to journalArticlepeer-review

151 Scopus citations

Abstract

Objective: The differential role of the IL-1 agonists, IL-1α, which is mainly cell-associated versus IL-1β, which is mostly secreted, was studied in colon inflammation. Design: Dextran sodium sulfate (DSS) colitis was induced in mice globally deficient in either IL-1α or IL-1β, and in wild-type mice, or in mice with conditional deletion of IL-1α in intestinal epithelial cells (IECs). Bone marrow transplantation experiments were performed to assess the role of IL-1α or IL-1β of myeloid versus colon non-hematopoietic cells in inflammation and repair in acute colitis. Results: IL-1α released from damaged IECs acts as an alarmin by initiating and propagating colon inflammation, as IL-1α deficient mice exhibited mild disease symptoms with improved recovery. IL-1β 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-1α in control mice during acute colitis led to alleviation of clinical and histological manifestations, whereas treatment with rIL-1Ra or anti-IL-1β antibodies was not effective. Repair after colitis correlated with accumulation of CD8 and regulatory T cells in damaged crypts. Conclusions: The role of IL-1α and IL-1β differs in DSS-induced colitis in that IL-1α, mainly of colon epithelial cells is inflammatory, whereas IL-1β, 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-1α, which leaves IL-1β function intact.

Original languageEnglish
Pages (from-to)598-609
Number of pages12
JournalGut
Volume63
Issue number4
DOIs
StatePublished - 1 Jan 2014

ASJC Scopus subject areas

  • Gastroenterology

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