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

Hoang Yen Phi Tran, Eun Joo Shin, Kuniaki Saito, Xuan Khanh Thi Nguyen, Yoon Hee Chung, Ji Hoon Jeong, Jae Hyung Bach, Dae Hun Park, Kiyofumi Yamada, Toshitaka Nabeshima, Yukio Yoneda, Hyoung Chun Kim

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Abstract

We investigated the role of cytokines in trimethyltin (TMT)-induced convulsive neurotoxicity. Evaluation of TNF-α, interferon-γ, and interleukin (IL)-6 knockout (-/-) mice showed that the IL-6 -/- mice had the greatest susceptibility to TMT-induced seizures. In both wild-type and IL-6 -/- 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 -/- 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 γ-glutamylcysteine ligase was significantly decreased in IL-6 -/- mice. Treatment of IL-6 -/- 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 -/- 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.

Original languageEnglish
Pages (from-to)1159-1174
Number of pages16
JournalFree Radical Biology and Medicine
Volume52
Issue number7
DOIs
Publication statusPublished - 01-04-2012

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology (medical)

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    Tran, H. Y. P., Shin, E. J., Saito, K., Nguyen, X. K. T., Chung, Y. H., Jeong, J. H., Bach, J. H., Park, D. H., Yamada, K., Nabeshima, T., Yoneda, Y., & Kim, H. C. (2012). Protective potential of IL-6 against trimethyltin-induced neurotoxicity in vivo. Free Radical Biology and Medicine, 52(7), 1159-1174. https://doi.org/10.1016/j.freeradbiomed.2011.12.008