Cisplatin ototoxicity involves cytokines and STAT6 signaling network
Cisplatin ototoxicity involves cytokines and STAT6 signaling network
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DOI：
10.1038/cr.2011.27
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发表时间：
2011-06-01
期刊：
影响因子：
44.1
通讯作者：
Park, Raekil
中科院分区：
文献类型：
--
作者：
Kim, Hyung-Jin;Oh, Gi-Su;Park, Raekil
我们在此研究了STAT信号级联在促炎细胞因子产生和顺铂耳毒性中的作用。在Balb/c（野生型，WT）和STAT 4（-/-）小鼠中观察到顺铂注射引起的显著听力损伤，但在STAT 6（-/-）小鼠中未观察到。此外，WT和STAT 4（-/-）小鼠的血清和耳蜗中促炎细胞因子（包括TNF-α、IL-1 β和IL-6）的蛋白质和mRNA的表达水平显著增加，而STAT 6（-/-）小鼠则没有。器官型培养结果显示，顺铂处理后STAT 6（-/-）小鼠Corti器中静纤毛束和感觉毛细胞层阵列的形状完整，而WT和STAT 4（-/-）小鼠处理后静纤毛束和感觉毛细胞层阵列高度扭曲和排列紊乱。顺铂诱导HEI-OC 1听觉细胞中STAT 6的磷酸化，并且通过STAT 6特异性siRNA敲低STAT 6显著保护HEI-OC 1听觉细胞免于顺铂诱导的细胞死亡并抑制促炎细胞因子的产生。我们进一步证明了顺铂诱导的IL-4和IL-13通过与IL-4受体α和IL-13 R α 1结合来调节STAT 6的磷酸化。这些发现表明，STAT 6信号在顺铂介导的促炎细胞因子产生和耳毒性中起着关键作用。
We herein investigated the role of the STAT signaling cascade in the production of pro-inflammatory cytokines and cisplatin ototoxicity. A significant hearing impairment caused by cisplatin injection was observed in Balb/c (wild type, WT) and STAT4(-/-), but not in STAT6(-/-) mice. Moreover, the expression levels of the protein and mRNA of pro-inflammatory cytokines, including TNF-alpha, IL-1 beta, and IL-6, were markedly increased in the serum and cochlea of WT and STAT4(-/-), but not STAT6(-/-) mice. Organotypic culture revealed that the shape of stereocilia bundles and arrays of sensory hair cell layers in the organ of Corti from STAT6(-/-) mice were intact after treatment with cisplatin, whereas those from WT and STAT4(-/-) mice were highly distorted and disarrayed after the treatment. Cisplatin induced the phosphorylation of STAT6 in HEI-OC1 auditory cells, and the knockdown of STAT6 by STAT6-specific siRNA significantly protected HEI-OC1 auditory cells from cisplatin-induced cell death and inhibited pro-inflammatory cytokine production. We further demonstrated that IL-4 and IL-13 induced by cisplatin modulated the phosphorylation of STAT6 by binding with IL-4 receptor alpha and IL-13R alpha 1. These findings suggest that STAT6 signaling plays a pivotal role in cisplatin-mediated pro-inflammatory cytokine production and ototoxicity.