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

被引:126
作者
Jarry, Anne [1 ,2 ]
Bossard, Celine [1 ,2 ,3 ]
Bou-Hanna, Chantal [1 ,2 ]
Masson, Damien [1 ,2 ,3 ]
Espaze, Eric [2 ,3 ]
Denis, Marc G. [1 ,2 ,3 ]
Laboisse, Christian L. [1 ,2 ,3 ]
机构
[1] INSERM, U539, Fac Med, F-44035 Nantes 1, France
[2] Univ Nantes, Fac Med, Nantes, France
[3] CHU Nantes, F-44035 Nantes 01, France
关键词
D O I
10.1172/JCI32140
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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-gamma, TNF-alpha, and IL-17. Interestingly, TGF-beta blockade also strongly induced IFN-gamma production. In addition, the high levels of IFN-gamma 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-gamma 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-gamma secretion. These findings demonstrate that IL-10 ablation leads to an endogenous IFN-gamma-mediated inflammatory response via LPS from commensal bacteria in the human colonic mucosa. We also found that both IL-10 and TGF-beta play crucial roles in maintaining human colonic mucosa homeostasis.
引用
收藏
页码:1132 / 1142
页数:11
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