Suppressive effect of IL-27 on encephalitogenic Th17 cells and the effector phase of experimental autoimmune encephalomyelitis
Suppressive effect of IL-27 on encephalitogenic Th17 cells and the effector phase of experimental autoimmune encephalomyelitis
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DOI：
10.4049/jimmunol.179.5.3268
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发表时间：
2007-09-01
影响因子：
4.4
通讯作者：
Rostami, Abdolmohamad
中科院分区：
文献类型：
--
作者：
Fitzgerald, Denise C.;Ciric, Bogoljub;Rostami, Abdolmohamad
IL-27已被证明在实验性自身免疫性脑脊髓炎(EAE)中发挥抑制作用，在IL-2711缺陷(WSX-1(-/-))小鼠中更严重的疾病证明了这一点。然而，IL-27是否影响EAE的诱导期或效应期尚不清楚。这是一个重要的问题，因为自身免疫性疾病的治疗通常是在自身反应性T细胞被激活之后开始的。在本研究中，我们证明了IL-27亚基及其受体在复发缓解型EAE的效应阶段，包括疾病高峰和复发开始时，在中枢神经系统中的基因表达最高。我们还发现，激活的星形胶质细胞培养物会分泌IL-27p28蛋白，内源性因子干扰素-γ会增强IL-27p28蛋白的表达。为了研究基因表达和疾病活动性之间的相关性的功能意义，我们通过过继转移EAE检测了IL-27在疾病效应阶段的作用。外源性IL-27可明显抑制脑源性淋巴结和脾细胞转导EAE的能力。IL-27显着抑制髓鞘反应性T细胞非极化和IL-23驱动的IL-17的产生，从而抑制过继转移性EAE的脑原性。此外，我们证明了IL-27在体内对活动性EAE有很强的抑制作用。渗透泵。IL-27处理的小鼠减少了中枢神经系统的炎症渗透，值得注意的是，Thl7细胞比例较低。综上所述，这些数据显示了IL-27对启动的、自身反应性T细胞的抑制作用，尤其是Thl7细胞。IL-27在体内能有效抑制EAE的效应相，因此可能对多发性硬化症等自身免疫性疾病有治疗潜力。
IL-27 has been shown to play a suppressive role in experimental autoimmunc encephalomyelitis (EAE) as demonstrated by more severe disease in IL-2711-deficient (WSX-1(-/-)) mice. However, whether IL-27 influences the induction or effector phase of EAE is unknown. This is an important question as therapies for autoimmune diseases are generally started after autoreactive T cells have been primed. In this study, we demonstrate maximal gene expression of IL-27 subunits and its receptor in the CNS at the effector phases of relapsing-remitting EAE including disease peak and onset of relapse. We also show that activated astrocyte cultures secrete IL-27p28 protein which is augmented by the endogenous factor, IFN-gamma. To investigate functional significance of a correlation between gene expression and disease activity, we examined the effect of IL-27 at the effector phase of disease using adoptive transfer EAE. Exogenous IL-27 potently suppressed the ability of encephalitogenic lymph node and spleen cells to transfer EAE. IL-27 significantly inhibited both nonpolarized and IL-23-driven IL-17 production by myelin-reactive T cells thereby suppressing their encephalitogenicity in adoptive transfer EAE. Furthermore, we demonstrate a strong suppressive effect of IL-27 on active EAE in vivo when delivered by s.c. osmotic pump. IL-27-treated mice had reduced CNS inflammatory infiltration and, notably, a lower proportion of Thl7 cells. Together, these data demonstrate the suppressive effect of IL-27 on primed, autoreactive T cells, particularly, cells of the Thl7 lineage. IL-27 can potently suppress the effector phase of EAE in vivo and, thus, may have therapeutic potential in autnimmune diseases such as multiple sclerosis.