Inflammatory bowel diseases (IBD) are chronic conditions that result from uncontrolled intestinal inflammation. Pathogenic Th17 cells, characterized by production of IL‐17A in the absence of IL‐10, are thought to contribute to this inflammation, but in humans, antibody‐mediated blockade of IL‐17A is an ineffective IBD therapy whereas IL‐23 blockade is effective. Here, we investigated the effects of pharmacological inhibition of RORC2, the Th17 cell lineage‐defining transcription factor, on in vivo‐differentiated human Th17 cells and Th17‐like Tregs (Th17‐Tregs). BMS‐336, a small molecule RORC2 inverse agonist, inhibited expression of RORC2‐regulated genes in peripheral Th17 cells (CD4⁺CD25^–CD127⁺CXCR3^–CCR4⁺CCR6⁺) in a dose–dependent manner, with similar inhibitory effects on laminar propria mononuclear cells from IBD and non‐IBD subjects. Exposure of peripheral Th17‐Tregs (CD4⁺CD25^hiCD127^loCXCR3^–CCR4⁺CCR6⁺) to BMS‐336 also inhibited IL‐17A production and prevented inflammatory cytokine‐induced destabilization, as evidenced by preserved FOXP3 expression and epigenetic status of the Treg‐specific demethylation region. In parallel, RORC2 inhibition increased the production of IL‐10 in Th17‐Tregs, resulting in enhanced suppression of inflammatory cytokines from myeloid cells. Thus, via its ability to simultaneously inhibit Th17 cells and enhance the stability and function of Th17‐Tregs, pharmacological inhibition of RORC2 is a promising approach to suppress inflammation and promote immune regulation in IBD.

中文翻译：

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RORC2的药理抑制作用可增强人Th17-Treg的稳定性和功能。

炎症性肠病（IBD）是由不受控制的肠道炎症导致的慢性疾病。病原性Th17细胞的特征是在没有IL-10的情况下会产生IL-17A，但这种炎症被认为是造成这种炎症的原因，但在人类中，抗体介导的IL-17A阻断是无效的IBD治疗，而IL-23阻断是有效。在这里，我们研究了在体内分化的人Th17细胞和类似Th17的Tregs（Th17-Tregs）的药理学抑制作用，即Th17细胞谱系的转录因子RORC2。BMS-336，一种小分子RORC2反向激动剂，抑制了外周Th17细胞（CD4 ⁺ CD25 ^– CD127 ⁺ CXCR3 ^– CCR4 ⁺CCR6 ⁺）呈剂量依赖性，对IBD和非IBD受试者的层状固有层单核细胞具有相似的抑制作用。外周Th17-Tregs（CD4 ⁺ CD25 ^hi CD127 ^lo CXCR3 ^– CCR4 ⁺ CCR6 ⁺）BMS-336还可以抑制IL-17A的产生并预防炎性细胞因子引起的不稳定，这可以通过保留的FOXP3表达和Treg特异性去甲基化区域的表观遗传状态来证明。同时，RORC2抑制作用增加了Th17-Tregs中IL-10的产生，从而增强了对来自髓样细胞的炎性细胞因子的抑制。因此，通过其同时抑制Th17细胞并增强Th17-Tregs的稳定性和功能的能力，药理抑制RORC2是抑制炎症和促进IBD免疫调节的有前途的方法。