Protective potential of IL-6 against trimethyltin-induced neurotoxicity in vivo

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• 作者：Hoang-Yen Phi Tran^a ; ¹ ; ² ; Eun-Joo Shin^a ; ¹ ; Kuniaki Saito^b ; Xuan-Khanh Thi Nguyen^a ; Yoon Hee Chung^c ; ^{yoonhee@cau.ac.kr} ; Ji Hoon Jeong^d ; Jae-Hyung Bach^a ; Dae Hun Park^a ; Kiyofumi Yamada^e ; Toshitaka Nabeshima^f ; Yukio Yoneda^g ; Hyoung-Chun Kim^a ; ^{kimhc@kangwon.ac.kr}
• 关键词：纬-GCL ; 纬-glutamylcysteine ligase ; GSH ; reduced glutathione ; GSSG ; oxidized glutathione ; HO-1 ; heme oxygenase-1 ; TNF-伪 ; tumor necrosis factor-伪 ; IFN-纬 ; interferon-纬 ; IL-6 ; interleukin-6 ; rIL-6 ; recombinant IL-6 protein ; Nrf2 ; NF-E2-related factor 2
• 刊名：Free Radical Biology and Medicine
• 出版年：2012
• 期刊代码：105_08915849
• 类别：med
• 出版时间：1 April, 2012
• 卷：52
• 期：7
• 页码：1159-1174
• 文件大小：2149 K

摘要

We investigated the role of cytokines in trimethyltin (TMT)-induced convulsive neurotoxicity. Evaluation of TNF-伪, interferon-纬, and interleukin (IL)-6 knockout (鈭?鈭? mice showed that the IL-6^{鈭?鈭?/sup> mice had the greatest susceptibility to TMT-induced seizures. In both wild-type and IL-6鈭?鈭?/sup> mice, TMT treatment increased glutathione oxidation, lipid peroxidation, protein oxidation, and levels of reactive oxygen species in the hippocampus. These effects were more pronounced in the IL-6鈭?鈭?/sup> mice than in wild-type controls. In addition, the ability of TMT to induce nuclear translocation of Nrf2 and upregulation of heme oxygenase-1 and 纬-glutamylcysteine ligase was significantly decreased in IL-6鈭?鈭?/sup> mice. Treatment of IL-6鈭?鈭?/sup> mice with recombinant IL-6 protein (rIL-6) restored these effects of TMT. Treatment with rIL-6 also significantly attenuated the TMT-induced inhibition of phosphoinositol 3-kinase (PI3K)/Akt signaling, thereby increasing phosphorylation of Bad (Bcl-xL/Bcl-2-associated death promoter protein), expression of Bcl-xL and Bcl-2, and the interaction between p-Bad and 14-3-3 protein and decreasing Bax expression and caspase-3 cleavage. Furthermore, in IL-6鈭?鈭?/sup> mice, rIL-6 provided significant protection against TMT-induced neuronal degeneration; this effect of rIL-6 was counteracted by the PI3K inhibitor LY294002. These results suggest that activation of Nrf2-dependent glutathione homeostasis and PI3K/Akt signaling is required for the neuroprotective effects of IL-6 against TMT.}