TY - JOUR
T1 - Protective potential of IL-6 against trimethyltin-induced neurotoxicity in vivo
AU - Tran, Hoang Yen Phi
AU - Shin, Eun Joo
AU - Saito, Kuniaki
AU - Nguyen, Xuan Khanh Thi
AU - Chung, Yoon Hee
AU - Jeong, Ji Hoon
AU - Bach, Jae Hyung
AU - Park, Dae Hun
AU - Yamada, Kiyofumi
AU - Nabeshima, Toshitaka
AU - Yoneda, Yukio
AU - Kim, Hyoung Chun
N1 - Funding Information:
This study was supported by a Grant (#2011K00271) from the Brain Research Center from 21st Century Frontier Research Program funded by the Ministry of Science and Technology, Republic of Korea. This work was, in part, supported by grants from the Ministry of Health, Labor, and Welfare, Research on Risk of Chemical Substances, and the Ministry of Education, Culture, Sports, Science, and Technology, Academic Frontier Project. Xuan-Khanh Thi Nguyen and Jae-Hyung Bach were supported by the BK 21 Program. The English in this article was checked by at least two professional editors, both native speakers of English. For a certificate, please see http://www.textcheck.com/certificate/mj8OQD .
PY - 2012/4/1
Y1 - 2012/4/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84862778033&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84862778033&partnerID=8YFLogxK
U2 - 10.1016/j.freeradbiomed.2011.12.008
DO - 10.1016/j.freeradbiomed.2011.12.008
M3 - Article
C2 - 22245015
AN - SCOPUS:84862778033
SN - 0891-5849
VL - 52
SP - 1159
EP - 1174
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
IS - 7
ER -