Therapeutic effect of IL-12/23 and their signaling pathway blockade on brain ischemia model
Therapeutic effect of IL-12/23 and their signaling pathway blockade on brain ischemia model
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DOI：
10.1016/j.bbrc.2010.10.058
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发表时间：
2010-11-19
影响因子：
3.1
通讯作者：
Yoshimura, Akihiko
中科院分区：
文献类型：
--
作者：
Konoeda, Fumie;Shichita, Takashi;Yoshimura, Akihiko
最近，T细胞细胞因子如IL-17和IFN-γ已显示在缺血诱导的脑损伤的进展中起重要作用。我们已显示来自浸润的巨噬细胞的IL-23激活γ δ T细胞，从而从这些细胞诱导IL-17。然而，在小鼠中IL-23基因的缺失显示出比γ δ T细胞缺失更显著的对脑缺血再灌注（I/R）模型的保护作用，这表明IL-23除了在IL-17诱导中的作用外，在脑损伤中还起一些其它关键作用。为了开发基于这些发现的治疗方法，我们检测了JAK激酶抑制剂CP-690550和抗IL-12/23单克隆抗体对I/R模型的作用，CP-690550有效抑制IL-12/23，抗p40抗体阻断IL-12和IL-23，有效地抑制I/R损伤并改善神经功能缺损的恢复。抗p40抗体治疗减少了产生IL-17的细胞的数量。因此，IL-17抑制剂和抗p40抗体，这两种药物都已经在试验中用于治疗几种人类炎症性疾病，似乎是改善中风的有前途的治疗药物（C）2010 Elsevier Inc版权所有
Recently, T cell cytokines such as IL-17 and IFN-gamma have been shown to play important roles in the progression of brain injury induced by ischemia We have shown that IL-23 from infiltrated macrophages activates gamma delta T cells, thereby inducing IL-17 from these cells However, deletion of the IL-23 gene in mice showed a more dramatic protective effect against brain ischemia reperfusion (I/R) model than gamma delta T cell depletion did, suggesting that IL-23 plays some other pivotal role in brain injury in addition to its role in IL-17 induction To develop therapeutic methods based on these findings, we examined the effect of the JAK kinase inhibitor CP-690550 and an anti-IL12/23 monoclonal antibody on an I/R model CP-690550 efficiently inhibited IL-17 production from memory T cells in vitro and partly suppressed infarct volume increase after I/R Anti-p40 antibody, which blocks both IL-12 and IL-23, efficiently suppressed I/R injury and improved recovery of neurological deficits The number of IL-17-producing cells was decreased by anti-p40 antibody treatment Thus the JAR inhibitor and anti-p40 antibody, both of which have already been under trial for the treatment of several human inflammatory diseases, appear to be promising therapeutic agents for the amelioration of stroke (C) 2010 Elsevier Inc All rights reserved