Mechanism of interleukin-27 mediated inhibition of Th17 cells in experimental autoimmune encephalomyelitis.

多发性硬化(MS)是一种中枢神经系统炎症性脱髓鞘疾病，实验性自身免疫性脑脊髓炎(EAE)是其最常用的动物模型。产生IL-17的辅助性T细胞亚群(Th17)可诱导EAE，数据显示在MS和其他自身免疫性疾病中起重要作用。Th17细胞的分化受细胞因子转化生长因子(TGF)-α和IL-6的调节，而IL-23对其稳定是必不可少的。Th17细胞分化和EAE表现可以由抗炎细胞因子IL-27控制，尽管确切的潜在细胞机制尚不清楚。在这里，我们将从实验上探讨这些机制，并研究Th17分化改变是否也决定了周围神经的自身免疫。IL-23受体(IL-23R)与IL-12受体(IL-12R)共享一个共同的亚基，称为IL-12Rä1。初步实验证明，IL-27的抗炎作用需要IL-12特异性受体亚基。我们认为，IL-27通过诱导IL-12R信号来抑制促炎的IL-23R信号，并以一种相互作用的方式调节这两个特定的受体亚单位。我们将使用报告鼠研究IL-12R和IL-23R信号之间的这种平衡，以寻找所有相关细胞因子的受体。我们将研究IL-12R是否通过调节IL-23R的表达来调节Th17细胞的生成，表明这两个信号通路是相互作用的。我们将分析IL-27是否通过调节IL-23R的表达来抑制EAE中的Th17细胞，以及在EAE过程中IL-27是否调节Th17细胞的稳定性。我们将进行转录分析，以进一步确定IL-27的抗炎机制。计划中的项目将进一步阐明IL-27如何调节Th17细胞的功能，这构成了未来治疗自身免疫性疾病的潜在靶点。

Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system and experimental autoimmune encephalomyelitis (EAE) serves as its most commonly used animal model. The interleukin (IL)-17 producing T helper cell subset (Th17) induces EAE and data indicate a central relevance in MS and other autoimmune diseases. The differentiation of Th17 cells is regulated by the cytokines transforming growth factor (TGF)-ý and IL-6, while IL-23 is essential for their stabilization. Th17 cell differentiation and EAE manifestation can be controlled by the anti-inflammatory cytokine IL-27, although the exact underlying cellular mechanisms remain unknown. Here, we will experimentally approach these mechanisms and study whether altered Th17 differentiation also determines autoimmunity in peripheral nerves.The IL-23 receptor (IL-23R) shares a common subunit - termed IL-12Rý1 - with the IL-12 receptor (IL-12R). Preliminary experiments have demonstrated that the IL-12 specific receptor subunit is required for the anti-inflammatory effect of IL-27. We propose that IL-27 inhibits pro-inflammatory IL-23R signaling by inducing IL-12R signaling and regulates both specific receptor subunits in a reciprocal fashion. We will study this proposed balance between IL-12R and IL-23R signaling using reporter mice for the receptors of all cytokines involved. We will study if IL-12R modulates the generation of Th17 cells by regulating expression of the IL-23R indicating interaction of both signaling pathways. We will analyze if IL-27 inhibits Th17 cells in EAE by regulating expression of the IL-23R and if IL-27 modulates the stability of Th17 cells during the course of EAE. We will perform a transcriptional analysis to further identify anti-inflammatory mechanisms of IL-27. The intended project will further clarify how IL-27 modulates Th17 cell function, which constitutes a potential target for the future treatment of autoimmune disorders.