A novel human truncated IL12rβ1-Fc fusion protein ameliorates experimental autoimmune encephalomyelitis via specific binding of p40 to inhibit Th1 and Th17 cell differentiation.
A novel human truncated IL12rβ1-Fc fusion protein ameliorates experimental autoimmune encephalomyelitis via specific binding of p40 to inhibit Th1 and Th17 cell differentiation.
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一种新型人截短 IL12r beta 1-Fc 融合蛋白通过特异性结合 p40 抑制 Th1 和 Th17 细胞分化，改善实验性自身免疫性脑脊髓炎
DOI：
10.18632/oncotarget.5164
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发表时间：
2015-10-06
期刊：
影响因子：
--
通讯作者：
Yao W
中科院分区：
文献类型：
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作者：
Guo W;Wang C;Wang X;Luo C;Yu D;Wang Y;Chen Y;Lei W;Gao X;Yao W
白细胞介素(IL)-12和IL-23分别驱动辅助性T细胞（Th） 1和Th17细胞的极化，与多发性硬化症（MS）和实验性自身免疫性脑脊髓炎（EAE）的发病机制密切相关。在这项研究中，我们首先构建、表达和纯化了一种新的人类截断IL12rβ1-Fc融合蛋白（tIL12rβ1/Fc），该蛋白结合了人类IL-12和IL-23的多种形式的p40亚基。tIL12rβ1/Fc通过减少Th1-和th17极化的促炎细胞因子的产生，抑制病灶部位的炎症和脱髓鞘，有效改善mog35 - 55诱导的EAE。此外，tIL12rβ1/Fc在体内抑制Th1 （IFN-γ+单独）和IFN-γ+ IL-17+以及经典Th17 （IL-17+单独）细胞的数量。此外，tIL12rβ1/Fc通过抑制STAT通路改善疾病高峰期的EAE，从而导致RORγt （Th17）和T-bet （Th1）表达显著降低。值得注意的是，tIL12rβ1/Fc可以增加CD4+ Foxp3+调节性T细胞的相对数量。这些发现表明tIL12rβ1/Fc是一种新的融合蛋白，可以特异性结合多种形式的p40亚基，发挥有效的抗炎作用，为MS和其他自身免疫性疾病的治疗提供了有价值的途径。
Interleukin (IL)-12 and IL-23 respectively driving polarization of T helper (Th) 1 and Th17 cells has been strongly implicated in the pathogenesis of both multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). In this study, we first constructed, expressed and purified a novel human truncated IL12rβ1-Fc fusion protein (tIL12rβ1/Fc) binding multiple forms of the p40 subunit of human IL-12 and IL-23. tIL12rβ1/Fc was found to effectively ameliorate MOG35–55-induced EAE through reducing the production of Th1- and Th17-polarized pro-inflammatory cytokines and suppressing inflammation and demyelination in the focused parts. Moreover, tIL12rβ1/Fc suppressed Th1 (IFN-γ+ alone) and IFN-γ+ IL-17+ as well as the population of classic Th17 (IL-17+ alone) cells in vivo. Furthermore, tIL12rβ1/Fc ameliorated EAE at the peak of disease via the inhibition of STAT pathway, thereby causing a prominent reduction of RORγt (Th17) and T-bet (Th1) expression. Notably, tIL12rβ1/Fc could increase the relative number of CD4+ Foxp3+ regulatory T cells. These findings indicates that tIL12rβ1/Fc is a novel fusion protein for specific binding multiple forms of p40 subunit to exert potent anti-inflammatory effects and provides a valuable approach for the treatment of MS and other autoimmune diseases.