IL-12p35 Inhibits Neuroinflammation and Ameliorates Autoimmune Encephalomyelitis
IL-12p35 Inhibits Neuroinflammation and Ameliorates Autoimmune Encephalomyelitis
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DOI：
10.3389/fimmu.2017.81258
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发表时间：
2017-10-05
影响因子：
7.3
通讯作者：
Egwuagu, Charles E.
中科院分区：
文献类型：
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作者：
Choi, Jin Kyeong;Dambuza, Ivy M.;Egwuagu, Charles E.
多发性硬化症(MS)是一种炎症性脱髓鞘疾病，由渗透到大脑和脊髓的免疫细胞产生的细胞因子在其中发挥核心作用。IL-12p35是IL-12或IL-35细胞因子的α亚基，可能是抑制神经炎性反应和改善实验性自身免疫性脑脊髓炎(EAE)病理改变的有效生物因子。我们进一步证明，IL-12p35通过抑制致病Th17和Th1细胞的扩张和炎性细胞向脑和脊髓的转移而对神经病起到保护作用。此外，在体外，脑源性细胞暴露于IL-12p35抑制了它们通过过继转移诱导EAE的能力。重要的是，IL-12p35介导的Treg和Breg细胞的扩增及其对EAE的改善与抑制细胞因子诱导的STAT1/STAT3通路的激活有关。此外，IL-12p35通过抑制细胞周期调节蛋白的表达而抑制淋巴细胞增殖。综上所述，这些结果表明，IL-12p35可以作为治疗中枢神经系统自身免疫性疾病的一种新的生物学手段，并有望在体外产生大量的Tregs和Bregs用于免疫治疗。
Multiple sclerosis (MS) is an inflammatory demyelinating disease in which cytokines produced by immune cells that infiltrate the brain and spinal cord play a central role. We show here that the IL-12p35, the alpha subunit of IL-12 or IL-35 cytokine, might be an effective biologic for suppressing neuroinflammatory responses and ameliorating the pathology of experimental autoimmune encephalomyelitis (EAE), the mouse model of human MS. We further show that IL-12p35 conferred protection from neuropathy by inhibiting the expansion of pathogenic Th17 and Th1 cells and inhibiting trafficking of inflammatory cells into the brain and spinal cord. In addition, in vitro exposure of encephalitogenic cells to IL-12p35 suppressed their capacity to induce EAE by adoptive transfer. Importantly, the IL-12p35-mediated expansion of Treg and Breg cells and its amelioration of EAE correlated with inhibition of cytokine-induced activation of STAT1/STAT3 pathways. Moreover, IL-12p35 inhibited lymphocyte proliferation by suppressing the expressions of cell-cycle regulatory proteins. Taken together, these results suggest that IL-12p35 can be exploited as a novel biologic for treating central nervous system autoimmune diseases and offers the promise of ex vivo production of large amounts of Tregs and Bregs for immunotherapy.