Down-Regulation of IRF6 Protects Cortical Neurons Against Traumatic Neuronal Injury Through Activating Akt-eNOS Pathway.
Interferon regulatory factor 6 (IRF6) is a novel and unique member of the IRF family of transcription factors, and the regulation and function of IRF6 remain unknown. Recently, IRF6 was shown to be upregulated after TBI and could promote neuronal apoptosis under oxidative stress conditions. This study aimed to investigate the role of IRF6 in traumatic neuronal injury (TNI) in primary cultured mouse cortical neurons. We found that the expression of IRF6 was significantly increased within 48 after TNI, and peaked at 24 h. Knockdown of IRF6 using specific targeted small interfering RNA (siRNA) attenuated TNI-induced loss of neuronal viability and release of lactate dehydrogenase. The results of TUNEL staining showed that IRF6 knockdown markedly reduced neuronal apoptosis, which was accompanied by decreased activity of caspase-3. Furthermore, downregulation of IRF6 inhibited lipid peroxidation, promoted the activity of endogenous antioxidative enzymes, and differently regulated the expression of inflammatory cytokines after TNI. In addition, IRF6 knockdown significantly increased phosphorylation of Akt and endothelial nitric oxide synthase (eNOS), whereas blocking Akt-eNOS pathway via selective antagonists partly prevented the protective effects of IRF6 knockdown. These data show that downregulation of IRF6 affords protection against TNI through Akt-eNOS pathway-mediated antioxidative and anti-inflammatory activity.
Department of Neurosurgery, Shaanxi Provincial People's Hospital, Affiliated Hospital of Xi'an Medical University, The Third Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710068, Shaanxi, China. houmingshan_xjtu@163.com.
Ming-Shan
MS
Hou
Department of Neurosurgery, Shaanxi Provincial People's Hospital, Affiliated Hospital of Xi'an Medical University, The Third Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710068, Shaanxi, China.
Jie
J
Cao
Department of Neurosurgery, Shaanxi Provincial People's Hospital, Affiliated Hospital of Xi'an Medical University, The Third Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710068, Shaanxi, China.
Bo
B
Chen
Department of Neurosurgery, Shaanxi Provincial People's Hospital, Affiliated Hospital of Xi'an Medical University, The Third Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710068, Shaanxi, China.
Xiao-Bin
XB
Liu
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D015536:Down-Regulation; D050835:Interferon Regulatory Factors / Q000235:genetics* / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
C528250:IRF6 protein, mouse; D050835:Interferon Regulatory Factors; D020011:Protective Agents; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D051057:Proto-Oncogene Proteins c-akt
Akt; IRF6; Oxidative stress; TBI; eNOS