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

doi:10.1016/j.freeradbiomed.2011.12.008

Free Radical Biology and Medicine

Volume 52, Issue 7, 1 April 2012, Pages 1159-1174

https://doi.org/10.1016/j.freeradbiomed.2011.12.008 Get rights and content

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.

Graphical abstract

Highlights

► We observed that IL-6 is an endogenous neuroprotectant in response to trimethyltin (TMT) toxicity. ► IL-6 KO mice are more susceptible to TMT seizures than either TNF-α or IFN-γ KO mice. ► Recombinant IL-6 attenuates oxidative burden and neurodegeneration in TMT-treated IL-6 KO mice. ► We suggest that IL-6 activates Nrf2/PI3K-dependent signaling for neuroprotection.

Section snippets

Animals

We used IL-6^−/−, TNF-α^−/−, and IFN-γ^−/− mice of the C57BL/6 background strain as previously reported [20], [21], [22]. Breeding pairs were purchased from The Jackson Laboratory (Bar Harbor, ME, USA). Mice were bred and housed in an approved animal facility at Kangwon National University. Wild-type C57BL/6 mice were purchased from Orient Bio, Inc. (Charles River Technology, Seoul, Korea). All mice were treated in accordance with the NIH Guide for the Humane Care and Use of Laboratory Animals and

rIL-6 attenuates TMT-induced convulsive behaviors in IL-6^−/− mice

As shown in Fig. 1, we assessed TMT-induced convulsions in IL-6^−/− mice 1 and 2 days after TMT treatment. TMT-induced convulsions were higher in intensity in IL-6^−/− mice than in WT mice (P < 0.01). Pretreatment with rIL-6 attenuated the TMT-induced increase in convulsive behaviors in IL-6^−/− mice in a dose-dependent manner (saline vs 6 ng rIL-6, P < 0.05 at 1 day, P < 0.01 at 2 days; saline vs 3 ng rIL-6, P < 0.05 at 2 days).

rIL-6 dose-dependently attenuates TMT-induced oxidative damage in the hippocampus of IL-6^−/− mice

TMT induced several types of oxidative damage, and rIL-6 pretreatment

Discussion

Our examination of knockout mice clearly demonstrated that IL-6^−/− mice are more susceptible to TMT-induced convulsive behaviors than either TNF-α^−/− or IFN-γ^−/− mice (Supplementary Fig. 2). Although TMT treatment initially induced IL-6 gene expression in WT mice, this increase in expression disappeared within 2 days of TMT exposure (Supplementary Fig. 1). In both WT and IL-6^−/− mice, TMT treatment increased the level of oxidative stress in the hippocampus, as shown by formation of MDA, protein

Acknowledgments

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

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¹: These authors contributed equally to this work.

²: Present address: University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh, Vietnam.

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Original ContributionProtective potential of IL-6 against trimethyltin-induced neurotoxicity in vivo

Abstract

Graphical abstract

Highlights

Section snippets

Animals

rIL-6 attenuates TMT-induced convulsive behaviors in IL-6−/− mice

rIL-6 dose-dependently attenuates TMT-induced oxidative damage in the hippocampus of IL-6−/− mice

Discussion

Acknowledgments

Chemosphere

Brain Res.

Neuroscience

Neurochem. Int.

Brain Behav. Immun.

Mol. Cell. Neurosci.

Brain Res.

Neuroscience

Neurochem. Int.

J. Biol. Chem.

Free Radic. Biol. Med.

Biochim. Biophys. Acta

Biol. Psychiatry

Cell. Signalling

Brain Res.

J. Biol. Chem.

Neurochem. Int.

Neurochem. Int.

Neurobiol. Aging

Free Radic. Biol. Med.

J. Biol. Chem.

Brain Res.

Pharmacol. Biochem. Behav.

Prog. Neuropsychopharmacol. Biol. Psychiatry

Cell

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

rIL-6 attenuates TMT-induced convulsive behaviors in IL-6^−/− mice

rIL-6 dose-dependently attenuates TMT-induced oxidative damage in the hippocampus of IL-6^−/− mice