Selective Inhibition of CCR7- Effector Memory T Cell Activation by a Novel Peptide Targeting Kv1.3 Channel in a Rat Experimental Autoimmune Encephalomyelitis Model
Selective Inhibition of CCR7- Effector Memory T Cell Activation by a Novel Peptide Targeting Kv1.3 Channel in a Rat Experimental Autoimmune Encephalomyelitis Model
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在大鼠实验性自身免疫性脑脊髓炎模型中，靶向 kv1.3 通道的新型肽选择性抑制 CCR7 效应记忆 T 细胞活化
DOI：
10.1074/jbc.m112.379594
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发表时间：
2012-08-24
影响因子：
4.8
通讯作者：
Li, Wen-Xin
中科院分区：
文献类型：
--
作者：
Li, Zhi;Liu, Wan-Hong;Li, Wen-Xin
效应记忆T细胞中的电压门控Kv1.3 K+通道作为多发性硬化症的新治疗靶点。在我们以前的研究中，新的肽ADWX-1被设计和合成为特异性Kv1.3阻断剂。然而，目前尚不清楚ADWX-1是否以及如何使实验性自身免疫性脑脊髓炎（多发性硬化症的模型）恶化。在这项研究中，ADWX-1的施用通过选择性抑制CD 4（+）CCR 7（-）表型效应记忆T细胞活化而显著改善大鼠实验性自身免疫性脑脊髓炎模型。相反，Kv1.3特异性肽对CD 4（+）CCR 7（+）细胞几乎没有影响，从而限制了副作用。此外，我们确定ADWX-1通过上游蛋白激酶C-θ（PKC θ）参与调节CD 4（+）CCR 7（-）细胞IL-2通路中的NF-κ B B信号传导。激活的CD 4（+）CCR 7（-）细胞中Kv1.3 mRNA和蛋白的表达升高被ADWX-1抑制;然而，未观察到CD 4（+）CCR 7（+）细胞中Kv1.3 mRNA和蛋白的明显改变。此外，ADWX-1对Kv1.3通道基因表达模式的选择性调节提供了对CD 4（+）CCR 7（-）表型的进一步和持续的抑制，这取决于Kv1.3的活性来调节其激活信号。此外，ADWX-1通过CCR 7（-）表型介导分化的Th 17细胞的活化。ADWX-1的疗效得到多种功能的支持，这些功能基于通过两种不同途径的Kv1.3（高）CD 4（+）CCR 7（-）T细胞选择性，包括经典的通道活性相关IL-2途径和新的Kv1.3通道基因表达途径。
The voltage-gated Kv1.3 K+ channel in effector memory T cells serves as a new therapeutic target for multiple sclerosis. In our previous studies, the novel peptide ADWX-1 was designed and synthesized as a specific Kv1.3 blocker. However, it is unclear if and how ADWX-1 alleviates experimental autoimmune encephalomyelitis, a model for multiple sclerosis. In this study, the administration of ADWX-1 significantly ameliorated the rat experimental autoimmune encephalomyelitis model by selectively inhibiting CD4(+)CCR7(-) phenotype effector memory T cell activation. In contrast, the Kv1.3-specific peptide had little effect on CD4(+)CCR7(+) cells, thereby limiting side effects. Furthermore, we determined that ADWX-1 is involved in the regulation of NF-kappa B signaling through upstream protein kinase C-theta (PKC theta) in the IL-2 pathway of CD4(+)CCR7(-) cells. The elevated expression of Kv1.3 mRNA and protein in activated CD4(+)CCR7(-) cells was reduced by ADWX-1 engagement; however, an apparent alteration in CD4(+)CCR7(+) cells was not observed. Moreover, the selective regulation of the Kv1.3 channel gene expression pattern by ADWX-1 provided a further and sustained inhibition of the CD4(+)CCR7(-) phenotype, which depends on the activity of Kv1.3 to modulate its activation signal. In addition, ADWX-1 mediated the activation of differentiated Th17 cells through the CCR7(-) phenotype. The efficacy of ADWX-1 is supported by multiple functions, which are based on a Kv1.3(high) CD4(+)CCR7(-) T cell selectivity through two different pathways, including the classic channel activity-associated IL-2 pathway and the new Kv1.3 channel gene expression pathway.