IL-6 signaling regulates small intestinal crypt homeostasis

Jeffery, Victoria, Goldson, Andrew J., Dainty, Jack R. ORCID: https://orcid.org/0000-0002-0056-1233, Chieppa, Marcello and Sobolewski, Anastasia (2017) IL-6 signaling regulates small intestinal crypt homeostasis. Journal of Immunology, 199 (1). pp. 304-311. ISSN 0022-1767

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Abstract

Gut homeostasis is a tightly regulated process requiring finely tuned complex interactions between different cell types, growth factors, or cytokines and their receptors. Previous work has implicated a role for IL-6 and mucosal immune cells in intestinal regeneration following injury and in promoting inflammation and cancer. We hypothesized that IL-6 signaling could also modulate crypt homeostasis. Using mouse in vitro crypt organoid and in vivo models, this study first demonstrated that exogenous IL-6 promoted crypt organoid proliferation and increased stem cell numbers through pSTAT3 activation in Paneth cells. Immunolabeling studies showed that the IL-6 receptor was restricted to the basal membrane of Paneth cells both in vitro and in vivo and that the crypt epithelium also expressed IL-6. Either a blocking Ab to the IL-6 receptor or a neutralizing Ab to IL-6 significantly reduced in vitro basal crypt organoid proliferation and budding, and in vivo significantly reduced the number of nuclei and the number of Lgr5EGFP-positive stem cells per crypt compared with IgG-treated mice, with the number of Paneth cells per crypt also significantly reduced. Functional studies demonstrated that IL-6-induced in vitro crypt organoid proliferation and crypt budding was abrogated by the Wnt inhibitor IWP2. This work demonstrates that autocrine IL-6 signaling in the gut epithelium regulates crypt homeostasis through the Paneth cells and the Wnt signaling pathway.

Item Type:	Article
Additional Information:	Copyright © 2017 by The American Association of Immunologists, Inc.
Uncontrolled Keywords:	sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
Faculty \ School:	Faculty of Science > School of Biological Sciences Faculty of Medicine and Health Sciences > Norwich Medical School Faculty of Science > School of Pharmacy
UEA Research Groups:	Faculty of Science > Research Groups > Molecular and Tissue Pharmacology
Depositing User:	Pure Connector
Date Deposited:	25 Jul 2017 05:09
Last Modified:	24 Oct 2023 00:55
URI:	https://ueaeprints.uea.ac.uk/id/eprint/64242
DOI:	10.4049/jimmunol.1600960

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