IL-27 Blocks RORc Expression to Inhibit Lineage Commitment of Th17 Cells
IL-27 Blocks RORc Expression to Inhibit Lineage Commitment of Th17 Cells
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DOI：
10.4049/jimmunol.0801162
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发表时间：
2009-05-01
影响因子：
4.4
通讯作者：
Kastelein, Robert A.
中科院分区：
文献类型：
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作者：
Diveu, Caroline;McGeachy, Mandy J.;Kastelein, Robert A.
IL-27是apc在炎症刺激下分泌的，具有促炎th1增强活性，但也具有显著的抗炎功能。我们研究了IL-27调节TGF β + IL-6或il -23依赖性Th17在小鼠和人类系统中的分子机制。IL-27以stat1依赖的方式抑制th17特异性转录因子ROR γ T的表达，从而抑制幼稚T细胞中IL-17A和IL-17F的产生。IL-27在延迟型超敏反应和实验性自身免疫性脑脊髓炎（EAE）中作用的体内意义得到了解决。通过生成IL-27 p28亚基缺失的小鼠，我们发现IL-27通过其对Th17细胞的作用调节延迟型超敏反应和EAE的严重程度。此外，IL-10在中枢神经系统中的上调通常发生在EAE发病后期，并在疾病的消退中发挥作用，但在IL-27p28（-/-）小鼠中明显不存在。这些结果表明，在体内，IL-27作为发展中的IL-17A应答的负调节因子，提示IL-27在自身免疫性疾病中具有潜在的治疗作用。免疫学杂志，2009,32(2):5748-5756。
IL-27 is secreted by APCs in response to inflammatory stimuli and exerts a proinflammatory Th1-enhancing activity but also has significant anti-inflammatory functions. We examined the molecular mechanism by which IL-27 regulates TGF beta plus IL-6- or IL-23-dependent Th17 development in the mouse and human systems. IL-27 inhibited the production of IL-17A and IL-17F in naive T cells by suppressing, in a STAT1-dependent manner, the expression of the Th17-specific transcription factor ROR gamma t. The in vivo significance of the role of IL-27 was addressed in delayed-type hypersensitivity response and experimental autoimmune encephalomyelitis (EAE). By generating mice deficient for the p28 subunit of IL-27, we showed that IL-27 regulated the severity of delayed-type hypersensitivity response and EAE through its effects on Th17 cells. Furthermore, up-regulation of IL-10 in the CNS, which usually occurs late after EAE onset and plays a role in the resolution of the disease, was notably absent in IL-27p28(-/-) mice. These results show that IL-27 acts as a negative regulator of the developing IL-17A response in vivo, suggesting a potential therapeutic role for IL-27 in autoimmune diseases. The Journal of Immunology, 2009, 182: 5748-5756.