Abstract
Oxidative stress-induced cell damage is involved in many neurological diseases. Interferon regulatory factor 6 (IRF6), a member of the IRF family of transcription factors, is required for the differentiation of skin, breast epithelium, and oral epithelium. However, the regulation and function of IRF6 in central nervous system remain unknown. This study aimed to investigate the role of IRF6 in hydrogen peroxide (H2O2)-induced oxidative neuronal injury in HT22 mouse hippocampal cells. Treatment with H2O2 significantly increased the expression of IRF6 at both mRNA and protein levels, and knockdown of IRF6 using specific small interfering RNA reduced H2O2-induced cytotoxicity, as evidenced by increased cell viability and decreased apoptosis. Knockdown of IRF6 attenuated intracellular reactive oxygen species (ROS) generation and lipid peroxidation, and also preserved endogenous antioxidant enzyme activities. The inhibitory effect of IRF6 knockdown on mitochondrial dysfunction was demonstrated by reduced mitochondrial oxidative level, preserved mitochondrial membrane potential (MMP) and ATP generation, as well as attenuated mitochondrial swelling. In addition, down-regulation of IRF6 inhibited the activation of mitochondrial apoptotic factors, whereas IRF6 knockdown together with caspase inhibitors had no extra effect on cell viability and LDH release. These results suggest that knockdown of IRF6 has protective effects against H2O2-induced oxidative stress by reducing ROS accumulation and apoptosis, and these protective effects are dependent on preservation of mitochondrial function.
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Acknowledgments
This study has been funded by the Shaanxi Province Scientific and Technological Research and Development Program (No. 2004K14-G; No.2010, K01-154) and Shaanxi Province Natural Science Foundation Research Program (No. 2014JM4131). The authors would like to thank Dr. Terry Chen for his technical support for the experiments and the preparation of the manuscript.
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Guo, XM., Chen, B., Lv, JM. et al. Knockdown of IRF6 Attenuates Hydrogen Dioxide-Induced Oxidative Stress via Inhibiting Mitochondrial Dysfunction in HT22 Cells. Cell Mol Neurobiol 36, 1077–1086 (2016). https://doi.org/10.1007/s10571-015-0301-8
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DOI: https://doi.org/10.1007/s10571-015-0301-8