Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
Biochem Biophys Res Commun. 2010 Nov 19;402(3):500-6. doi: 10.1016/j.bbrc.2010.10.058. Epub 2010 Oct 20.
Recently, T cell cytokines such as IL-17 and IFN-γ 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 γδT 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 γδT 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 JAK 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.
最近，细胞因子如白细胞介素-17（IL-17）和干扰素-γ（IFN-γ）已被证明在缺血引起的脑损伤进展中发挥重要作用。我们已经表明，浸润巨噬细胞产生的白细胞介素-23（IL-23）激活γδT 细胞，从而诱导这些细胞产生白细胞介素-17。然而，与γδT 细胞耗竭相比，敲除小鼠的 IL-23 基因对脑缺血再灌注（I/R）模型显示出更显著的保护作用，这表明 IL-23 在诱导 IL-17 之外还在脑损伤中发挥其他关键作用。为了基于这些发现开发治疗方法，我们研究了 JAK 激酶抑制剂 CP-690550 和抗 IL-12/23 单克隆抗体对 I/R 模型的影响。CP-690550 可有效抑制体外记忆 T 细胞产生白细胞介素-17，并部分抑制 I/R 后梗死体积的增加。抗 p40 抗体可同时阻断 IL-12 和 IL-23，可有效抑制 I/R 损伤并改善神经功能缺损的恢复。抗 p40 抗体治疗可减少产生白细胞介素-17 的细胞数量。因此，JAK 抑制剂和抗 p40 抗体都已在几种人类炎症性疾病的治疗中进行了临床试验，它们似乎是改善中风的有前途的治疗剂。
