Low dose CP-690,550 (tofacitinib), a pan-JAK inhibitor, accelerates the onset of experimental autoimmune encephalomyelitis by potentiating Th17 differentiation
Low dose CP-690,550 (tofacitinib), a pan-JAK inhibitor, accelerates the onset of experimental autoimmune encephalomyelitis by potentiating Th17 differentiation
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DOI：
10.1016/j.bbrc.2011.12.156
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发表时间：
2012-02-10
影响因子：
3.1
通讯作者：
Yoshimura, Akihiko
中科院分区：
文献类型：
--
作者：
Yoshida, Hideyuki;Kimura, Akihiro;Yoshimura, Akihiko
与自身免疫性疾病有关的Th 17细胞需要由IL-6或IL-23激活的STAT 3信号传导来发育。其他Th 1和Th 2细胞因子如IL-2、IFN-γ和IL-4强烈抑制Th 17的发育。最近，最初作为JAK 3抑制剂开发的CP-690，550（托法替尼）已在类风湿性关节炎和胶原诱导的关节炎（CIA）模型的III期临床试验中显示出有效性，但其作用的确切机制，特别是关于Th 17细胞的机制，知之甚少。令我们惊讶的是，低剂量CP-690，550被发现在抑制CIA的浓度下加速实验性自身免疫性脑脊髓炎（EAE）的发作。在免疫后的早期阶段，在15 mg/kg体重CP-690，550处理的小鼠中观察到比未处理的小鼠更多的IL-17产生。在体外，CP-690，550在10-50 nM浓度下抑制Th 1和Th 2的发育，同时促进Th 17的分化。CP-690，550对Th 17的增强可能是由于抑制IL-2信号传导，因为抗IL-2抗体抵消了CP-690，550的Th 17促进作用。CP-690，550在3-30 nM时选择性抑制IFN诱导的STAT 1、IL-4诱导的STAT 6和IL-2诱导的STAT 5，而抑制IL-6诱导的STAT 3磷酸化需要大于100 nM的浓度。在HEK 293 T细胞中，与JAK 3相比，CP-690，550对JAK 1介导的STAT 3磷酸化的抑制效果较差。这些结果表明CP-690，550在JAK和STAT中具有不同的作用，从而影响辅助性T细胞分化和鼠自身免疫性疾病模型。(C)2012 Elsevier Inc. All rights reserved.
Th17 cells, which have been implicated in autoimmune diseases, require STAT3 signaling activated by IL-6 or IL-23 for their development. Other Th1 and Th2 cytokines such as IL-2, IFN-gamma and IL-4 strongly suppress Th17 development. Recently, CP-690,550 (tofacitinib), originally developed as a JAK3 inhibitor, has been shown to be effective in phase III clinical trials of rheumatoid arthritis and collagen-induced arthritis (CIA) models, but the precise mechanism of the effect, especially with respect to Th17 cells, is poorly understood. To our surprise, a low dose CP-690,550 was found to accelerate the onset of experimental autoimmune encephalomyelitis (EAE) at a concentration that suppressed CIA. At an early stage after immunization, more IL-17 production was observed in 15 mg/kg body weight CP-690,550-treated mice than in untreated mice. In vitro, CP-690,550 inhibited both Th1 and Th2 development, while promoting Th17 differentiation at 10-50 nM concentrations. Enhancement of Th17 by CP-690,550 is probably due to suppression of IL-2 signaling, because anti-IL-2 antibodies cancel the Th17-promoting effect of CP-690,550. CP-690,550 selectively inhibited IFN-induced STAT1, IL-4-induced STAT6 and IL-2-induced STAT5 at 3-30 nM, while suppression of IL-6-induced STAT3 phosphorylation required a concentration greater than 100 nM. In HEK293T cells, CP-690,550 less effectively suppressed JAK1-mediated STAT3 phosphorylation compared with JAK3. These results suggest that CP-690,550 has a different effects among JAKs and STATs, thereby affecting helper T cell differentiation, and murine autoimmune disease models. (C) 2012 Elsevier Inc. All rights reserved.