Cisplatin cytotoxicity of Auditory cells requires secretions of proinflammatory Cytokines via activation of ERK and NF-κB
Cisplatin cytotoxicity of Auditory cells requires secretions of proinflammatory Cytokines via activation of ERK and NF-κB
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DOI：
10.1007/s10162-007-0084-9
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发表时间：
2007-09-01
影响因子：
2.4
通讯作者：
Park, Raekil
中科院分区：
文献类型：
--
作者：
So, Hongseob;Kim, Hyungjin;Park, Raekil
顺铂是一种广泛使用的化疗药物，其耳毒性涉及多种机制，包括氧化还原状态的扰动、脂质过氧化的增加和DNA加合物的形成。在这项研究中，我们证明顺铂通过激活HEI-OCI细胞中的ERK和NF-kappa B，增加了促炎细胞因子的早期即时释放和新生合成，包括tnf - α、IL-1 β和IL-6， HEI-OCI细胞是表达毛细胞标志物的条件长生化耳蜗细胞。促炎细胞因子的中和和ERK的药理学抑制均可显著减轻顺铂和促炎细胞因子引起的HEI-OCI听觉细胞的死亡。我们还观察到，注射顺铂的大鼠血清和耳蜗中促炎细胞因子的蛋白和mRNA水平显著升高，而腹腔注射TNF-a抑制剂依那西普可以抑制这种水平。免疫组化研究显示，注射顺铂大鼠耳蜗中TNF-a的表达主要位于螺旋韧带、螺旋缘和Corti器官。NF-kappa B蛋白的表达与末端脱氧核苷酸转移酶介导的dUTP镍端标记阳性信号重叠，在耳蜗的特定区域，包括Corti器官、螺旋韧带和血管纹中表达非常强烈。这些结果表明，促炎细胞因子，特别是tnf - α，在顺铂引起的感觉毛细胞损伤的病理生理中起核心作用。
The ototoxicity of cisplatin, a widely used chemotherapeutic agent, involves a number of mechanisms, including perturbation of redox status, increase in lipid peroxidation, and formation of DNA adducts. In this study, we demonstrate that cisplatin increased the early immediate release and de novo synthesis of proinflammatory cytokines, including TNF-alpha, IL-1 beta, and IL-6, through the activation of ERK and NF-kappa B in HEI-OCI cells, which are conditionally immortalized cochlear cells that express hair cell markers. Both neutralization of proinflammatory cytokines and pharmacologic inhibition of ERK significantly attenuated the death of HEI-OCI auditory cells caused by cisplatin and proinflammatory cytokines. We also observed a significant increase in the protein and mRNA levels of proinflammatory cytokines in both serum and cochleae of cisplatin-injected rats, which was suppressed by intraperitoneal injection of etanercept, an inhibitor of TNF-a. Immunohistochemical studies revealed that TNF-a expression was mainly located in the spiral ligament, spiral limbus, and the organ of Corti in the cochleae of cisplatin-injected rats. NF-kappa B protein expression, which overlapped with terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling-positive signal, was very strong in specific regions of the cochleae, including the organ of Corti, spiral ligament, and stria vascularis. These results indicate that proinflammatory cytokines, especially TNF-alpha, play a central role in the pathophysiology of sensory hair cell damage caused by cisplatin.