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

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.

• Authors: 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
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 52 Issue 7 Pg. 1159-74 (Apr 01 2012) ISSN: 1873-4596 [Electronic] United States
• PMID: 22245015 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Interleukin-6
• NF-E2-Related Factor 2
• Nfe2l2 protein, mouse
• RNA, Messenger
• Reactive Oxygen Species
• Trimethyltin Compounds
• Tumor Necrosis Factor-alpha
• trimethyltin
• Malondialdehyde
• Interferon-gamma
• Proto-Oncogene Proteins c-akt
• Caspase 3
• Glutathione

Topics

• Animals
• Blotting, Western
• Caspase 3 (genetics, metabolism)
• Female
• Fluorescent Antibody Technique
• Glutathione (metabolism)
• Interferon-gamma (physiology)
• Interleukin-6 (physiology)
• Male
• Malondialdehyde (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• NF-E2-Related Factor 2 (physiology)
• Neurons (drug effects, metabolism, pathology)
• Neurotoxicity Syndromes (etiology, metabolism, prevention & control)
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• RNA, Messenger (genetics)
• Reactive Oxygen Species (metabolism)
• Real-Time Polymerase Chain Reaction
• Trimethyltin Compounds (toxicity)
• Tumor Necrosis Factor-alpha (physiology)