Recombinant human PDCD5 (rhPDCD5) protein is protective in a mouse model of multiple sclerosis.
Recombinant human PDCD5 (rhPDCD5) protein is protective in a mouse model of multiple sclerosis.
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重组人 PDCD5 (rhPDCD5) 蛋白对多发性硬化症小鼠模型具有保护作用。
DOI：
10.1186/s12974-015-0338-0
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发表时间：
2015-06-12
影响因子：
9.3
通讯作者：
Deng W
中科院分区：
文献类型：
--
作者：
Xiao J;Liu W;Chen Y;Deng W
在多发性硬化症（MS）及其广泛应用的动物模型——实验性自身免疫性脑脊髓炎（EAE）中，自身反应性T细胞对中枢神经系统（CNS）组织损伤和疾病进展起着重要作用。促进自身反应性T细胞凋亡，可能有助于清除引发炎症的细胞，延缓疾病进展，并降低复发频率和严重程度。程序性细胞死亡蛋白5（PDCD5）是一种已知能在各种刺激下加速细胞凋亡的蛋白质。然而，重组人PDCD5（rhPDCD5）对致脑炎性T细胞介导的炎症有何影响，目前尚不清楚。
我们研究了腹腔注射rhPDCD5（10毫克/千克）对EAE的预防（在EAE诱导后第0天开始）和治疗（在EAE发病第8天开始）效果，两种治疗方案均每隔一天给药，直至第25天。采用重复测量双因素方差分析进行统计分析。
结果显示，rhPDCD5的抗炎作用源于Th1/Th17细胞频率降低，同时促炎细胞因子（包括IFN-γ和IL-17A）减少，这种现象在EAE小鼠的rhPDCD5预防和治疗方案中均有体现。此外，rhPDCD5可诱导髓鞘反应性CD4 + T细胞凋亡，同时上调Bax蛋白、下调Bcl - 2蛋白，并激活半胱天冬酶3。
我们的数据表明，rhPDCD5通过抑制Th1/Th17细胞分化并诱导主要致病性T细胞凋亡，改善了自身免疫性中枢神经系统疾病。本研究为解释rhPDCD5对神经炎症的作用提供了一种新机制。该研究成果具有转化医学意义，证明了rhPDCD5在多发性硬化症模型中具有预防和治疗特性。
In multiple sclerosis (MS) and its widely used animal model, experimental autoimmune encephalomyelitis (EAE), autoreactive T cells contribute importantly to central nervous system (CNS) tissue damage and disease progression. Promoting apoptosis of autoreactive T cells may help eliminate cells responsible for inflammation and may delay disease progression and decrease the frequency and severity of relapse. Programmed cell death 5 (PDCD5) is a protein known to accelerate apoptosis in response to various stimuli. However, the effects of recombinant human PDCD5 (rhPDCD5) on encephalitogenic T cell-mediated inflammation remain unknown. We examined the effects of intraperitoneal injection of rhPDCD5 (10 mg/kg) on EAE both prophylactically (started on day 0 post-EAE induction) and therapeutically (started on the onset of EAE disease at day 8), with both of the treatment paradigms being given every other day until day 25. Repeated measures two-way analysis of variance was used for statistical analysis. We showed that the anti-inflammatory effects of rhPDCD5 were due to a decrease in Th1/Th17 cell frequency, accompanied by a reduction of proinflammatory cytokines, including IFN-γ and IL-17A, and were observed in both prophylactic and therapeutic regimens of rhPDCD5 treatment in EAE mice. Moreover, rhPDCD5-induced apoptosis of myelin-reactive CD4+ T cells, along with the upregulation of Bax and downregulation of Bcl-2, and with activated caspase 3. Our data demonstrate that rhPDCD5 ameliorates the autoimmune CNS disease by inhibiting Th1/Th17 differentiation and inducing apoptosis of predominantly pathogenic T cells. This study provides a novel mechanism to explain the effects of rhPDCD5 on neural inflammation. The work represents a translational demonstration that rhPDCD5 has prophylactic and therapeutic properties in a model of multiple sclerosis.
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