期刊
JOURNAL OF CROHNS & COLITIS
卷 14, 期 6, 页码 831-840出版社
OXFORD UNIV PRESS
DOI: 10.1093/ecco-jcc/jjz176
关键词
Inflammatory bowel disease [IBD]; Crohn's disease [CD]; interleukin 10 [IL-10]; interleukin 6 [IL-6]; extraintestinal manifestation
资金
- National Institute of Health [DK077064, P30DK089502]
- National Natural Science Foundation of China [81270468, 81870391]
Background and Aims: Interleukin 6 [IL-6] or its receptor is currently a candidate for targeted biological therapy of inflammatory bowel disease [IBD]. Thus, a comprehensive understanding of the consequences of blocking IL-6 is imperative. We investigated this by evaluating the effects of IL-6 deletion on the spontaneous colitis of IL-10-deficient mice [IL-10(-/-)]. Methods: IL-6/IL-10 double-deficient mice [IL-6(-/-)/IL-10(-/-)] were generated and analysed for intestinal inflammation, general phenotypes and molecular/biochemical changes in the colonic mucosa compared with wild-type and IL-10(-/-) mice. Results: Unexpectedly, the IL-6(-/-)/IL-10(-/-) mice showed more pronounced gut inflammation and earlier disease onset than IL-10(-/-) mice, both locally [colon and small bowel] and systemically [splenomegaly, ulcerative dermatitis, leukocytosis, neutrophilia and monocytosis]. IL-6(-/-)/IL-10(-/-) mice exhibited elevations of multiple cytokines [IL-1 beta, IL-4, IL-12, TNF alpha] and chemokines [MCP-1 and MIG], but not IFN-gamma [Th1], IL-17A and IL-17G [Th17], or IL-22 [Th22]. FOXP3 and TGF-beta, two key factors for regulatory T [Treg] cell differentiation, were significantly down-regulated in the colonic mucosa, but not in the thymus or mesenteric lymph nodes, of IL-6(-/-)/IL-10(-/-) mice. CTLA-4 was diminished while iNOS was up-regulated in the colonic mucosa of IL-6(-/-)/IL-10(-/-) mice. Conclusion: In IL-10(-/-) mice, complete IL-6 blockade significantly aggravates gut inflammation, at least in part by suppressing Treg/CTLA-4 and promoting the IL-1 beta/Th2 pathway. In addition, the double mutant exhibits signs of severe systemic inflammation. Our data define a new function of IL-6 and suggest that caution should be exercised when targeting IL-6 in IBD patients, particularly those with defects in IL-10 signalling.
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