RORγ-Expressing Th17 Cells Induce Murine Chronic Intestinal Inflammation via Redundant Effects of IL-17A and IL-17F
RORγ-Expressing Th17 Cells Induce Murine Chronic Intestinal Inflammation via Redundant Effects of IL-17A and IL-17F
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DOI：
10.1053/j.gastro.2008.10.018
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发表时间：
2009-01-01
期刊：
影响因子：
29.4
通讯作者：
Neurath, Markus F.
中科院分区：
文献类型：
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作者：
Leppkes, Moritz;Becker, Christoph;Neurath, Markus F.
背景和目标：产生IL-17的CD 4（+）Thelper细胞（Th 17）促进大脑中的慢性自身免疫性炎症，并且Th 17衍生的细胞因子水平在结肠炎患者中增加，表明在发病机制中的作用。我们分析了Th 17细胞和调节Th 17分化的转录因子视黄酸受体相关器官受体（ROR）γ在慢性肠道炎症中的作用。研究方法：使用结肠炎的过继转移模型，我们比较了野生型、白细胞介素-17A（IL-17 A）-、IL-17 F-、IL-22-和ROR γ缺陷型CD 4（+）CD 25（-）T细胞在RAG 1缺失小鼠中的致结肠炎潜力。结果如下：IL-17 A-、IL-17 F-或IL-22-缺陷型T淋巴细胞连续转移到RAG 1缺失小鼠中引起的严重结肠炎与野生型细胞引起的结肠炎难以区分。相比之下，ROR γ-null T细胞的转移未能增加粘膜IL-17细胞因子水平，并且不诱导结肠炎。用IL-17 A治疗能够在转移ROR γ-null T细胞后恢复结肠炎，表明Th 17细胞在发病机制中的关键作用。用中和性抗IL-17 A抗体治疗接受IL-17 F-无效（但非野生型）T细胞的RAG 1小鼠显著抑制疾病，表明IL-17 A和IL-17 F的冗余生物学效应。结论，我们已经确定了ROR γ表达Th 17细胞在慢性肠道炎症中的关键作用。ROR γ控制IL-17 A和IL-17 F的产生，这些细胞因子在肠道炎症中具有冗余但高致病性的作用。靶向ROR γ的试剂或抗IL-17 A和抗IL-17 F的组合可能被开发为慢性结肠炎的治疗剂。
Background and Aims: IL-17-producing CD4(+) Thelper cells (Th17) contribute to chronic autoimmune inflammation in the brain, and levels of Th17-derived cytokines increase in patients with colitis, suggesting a role in pathogenesis. We analyzed the roles of Th17 cells and the transcription factor retinoic acid receptor-related organ receptor (ROR)gamma, which regulates Th17 differentiation, in chronic intestinal inflammation. Methods: Using an adoptive transfer model of colitis, we compared the colitogenic potential of wildtype, interleukin-17A (IL-17A)-, IL-17F-, IL-22-, and ROR gamma-deficient CD4(+)CD25(-) T cells in RAG1-null mice. Results: Adoptive transfer of IL-17A-, IL-17F-, or IL-22-deficient T lymphocytes into RAG1-null mice caused severe colitis that was indistinguishable from that caused by wild-type cells. In contrast, transfer of ROR gamma-null T cells failed to increase mucosal IL-17 cytokine levels and did not induce colitis. Treatment with IL-17A was able to restore colitis after transfer of ROR gamma-null T cells, indicating a crucial role for Th17 cells in pathogenesis. Treatment of RAG1 mice that received IL-17F-null (but not wild-type) T cells with a neutralizing anti-IL-17A antibody significantly suppressed disease, indicating redundant biological effects of IL-17A and IL-17F. Conclusions., We have identified a crucial role of ROR gamma-expressing Th17 cells in chronic intestinal inflammation. ROR gamma controls IL-17A and IL-17F production, and these cytokines have a redundant but highly pathogenic role in gut inflammation. Reagents that target ROR gamma or a combination of anti-IL-17A and anti-IL-17F might be developed as therapeutics for chronic colitis.