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Mucosal IL-10 and TGF-β play crucial roles in preventing LPS-driven, IFN-γ–mediated epithelial damage in human colon explants

Abstract : IL-10 is an immunomodulatory cytokine that plays an obligate role in preventing spontaneous enterocolitis in mice. However, little is known about IL-10 function in the human intestinal mucosa. We showed here that IL-10 was constitutively expressed and secreted by the human normal colonic mucosa, including epithelial cells. Depletion of IL-10 in mucosal explants induced both downregulation of the IL-10-inducible, immunosuppressive gene BCL3 and upregulation of IFN-γ, TNF-α, and IL-17. Interestingly, TGF-β blockade also strongly induced IFN-γ production. In addition, the high levels of IFN-γ produced upon IL-10 depletion were responsible for surface epithelium damage and crypt loss, mainly by apoptosis. Polymyxin B, used as a scavenger of endogenous LPS, abolished both IFN-γ production and epithelial barrier disruption. Finally, adding a commensal bacteria strain to mucosa explant cultures depleted of both IL-10 and LPS reproduced the ability of endogenous LPS to induce IFN-γ secretion. These findings demonstrate that IL-10 ablation leads to an endogenous IFN-γ-mediated inflammatory response via LPS from commensal bacteria in the human colonic mucosa. We also found that both IL-10 and TGF-β play crucial roles in maintaining human colonic mucosa homeostasis. Nonstandard abbreviations used: rh-, recombinant human; TGF-βRII, TGF-β type II receptor.
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Contributor : Anne Jarry Connect in order to contact the contributor
Submitted on : Monday, July 19, 2021 - 2:17:04 PM
Last modification on : Wednesday, April 27, 2022 - 3:47:27 AM
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Anne Jarry, Céline Bossard, Chantal Bou-Hanna, Damien Masson, Eric Espaze, et al.. Mucosal IL-10 and TGF-β play crucial roles in preventing LPS-driven, IFN-γ–mediated epithelial damage in human colon explants. Journal of Clinical Investigation, American Society for Clinical Investigation, 2008, 118 (3), pp.1132-42. ⟨10.1172/jci32140⟩. ⟨inserm-03290641⟩



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