Activation of Lipopolysaccharide-TLR4 Signaling Accelerates the Ototoxic Potential of Cisplatin in Mice
Activation of Lipopolysaccharide-TLR4 Signaling Accelerates the Ototoxic Potential of Cisplatin in Mice
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DOI：
10.4049/jimmunol.1002183
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发表时间：
2011-01-15
影响因子：
4.4
通讯作者：
So, Hong-Seob
中科院分区：
文献类型：
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作者：
Oh, Gi-Su;Kim, Hyung-Jin;So, Hong-Seob
在患者的抗癌化疗期间免疫监视的功能障碍常常导致宿主防御系统的虚弱和随后的微生物感染的增加。然而，顺铂治疗患者中与微生物挑战相关的器官特异性功能恶化尚未阐明。在这项研究中，我们研究了顺铂诱导的小鼠耳蜗组织TLR 4表达及其与LPS的结合，以及这种相互作用对听力功能的影响。顺铂增加耳蜗组织、Corti器官外植体和HEI-OC 1细胞中TLR 4的转录和翻译表达。此外，顺铂增加了TLR 4与其微生物配体LPS之间的相互作用，从而通过NF-κ B活化上调促炎细胞因子如TNF-α、IL-1 β和IL-6的产生。在C57 BL/6小鼠中，与对照组、顺铂单药组或LPS单药组相比，顺铂和LPS联合注射引起严重的听力障碍，而这种听力障碍在TLR 4突变和敲除小鼠中均被完全抑制。这些结果表明，由于接受包括三至六个周期的单独顺铂或顺铂与其他化疗剂组合的治疗的癌症患者的宿主防御系统减弱，听力功能可以容易地被TLR表达增加和微生物感染损害。此外，即使患者可能没有经历累积顺铂浓度的耳毒性水平，也可能发生这种损害。免疫学杂志，2011，186：1140-1150。
Dysfunction in immune surveillance during anticancer chemotherapy of patients often causes weakness of the host defense system and a subsequent increase in microbial infections. However, the deterioration of organ-specific function related to microbial challenges in cisplatin-treated patients has not yet been elucidated. In this study, we investigated cisplatin-induced TLR4 expression and its binding to LPS in mouse cochlear tissues and the effect of this interaction on hearing function. Cisplatin increased the transcriptional and translational expression of TLR4 in the cochlear tissues, organ of Corti explants, and HEI-OC1 cells. Furthermore, cisplatin increased the interaction between TLR4 and its microbial ligand LPS, thereby upregulating the production of proinflammatory cytokines, such as TNF-alpha, IL-1 beta, and IL-6, via NF-kappa B activation. In C57BL/6 mice, the combined injection of cisplatin and LPS caused severe hearing impairment compared with that in the control, cisplatin-alone, or LPS-alone groups, whereas this hearing dysfunction was completely suppressed in both TLR4 mutant and knockout mice. These results suggest that hearing function can be easily damaged by increased TLR expression and microbial infections due to the weakened host defense systems of cancer patients receiving therapy comprising three to six cycles of cisplatin alone or cisplatin combined with other chemotherapeutic agents. Moreover, such damage can occur even though patients may not experience ototoxic levels of cumulative cisplatin concentration. The Journal of Immunology, 2011, 186: 1140-1150.