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 language | English |
|---|---|
| Pages (from-to) | 1159-1174 |
| Number of pages | 16 |
| Journal | Free Radical Biology and Medicine |
| Volume | 52 |
| Issue number | 7 |
| DOIs | |
| Publication status | Published - 01-04-2012 |
| Externally published | Yes |
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All Science Journal Classification (ASJC) codes
- Biochemistry
- Physiology (medical)
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Protective potential of IL-6 against trimethyltin-induced neurotoxicity in vivo. / Tran, Hoang Yen Phi; Shin, Eun Joo; Saito, Kuniaki; Nguyen, Xuan Khanh Thi; Chung, Yoon Hee; Jeong, Ji Hoon; Bach, Jae Hyung; Park, Dae Hun; Yamada, Kiyofumi; Nabeshima, Toshitaka; Yoneda, Yukio; Kim, Hyoung Chun.
In: Free Radical Biology and Medicine, Vol. 52, No. 7, 01.04.2012, p. 1159-1174.Research output: Contribution to journal › Article
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
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
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U2 - 10.1016/j.freeradbiomed.2011.12.008
DO - 10.1016/j.freeradbiomed.2011.12.008
M3 - Article
VL - 52
SP - 1159
EP - 1174
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
SN - 0891-5849
IS - 7
ER -