Upregulation of Interferon Regulatory Factor 6 Promotes Neuronal Apoptosis After Traumatic Brain Injury in Adult Rats

Abstract

The interferon regulatory factor (IRF) family was first discovered as a set of transcriptional regulators of the type I interferon system in 1988. In mammals, the IRF family includes nine members that play important roles in the immune system, oncogenesis, and apoptosis. However, the distribution and the function of IRF6 in the central nervous system are limited. In this study, we established an adult rat traumatic brain injury (TBI) model. Compared to the sham brain cortex, Western blot and immunohistochemistry showed significant upregulation of IRF6 in the ipsilateral brain cortex after TBI. Immunofluorescence double-labeling showed that IRF6 completely co-localized with neurons, not astrocytes or oligodendrocytes. Furthermore, we detected that the neuronal apoptosis marker active caspase-3 co-localized with IRF6 in neurons. Additionally, IRF6 knockdown in PC12 cells in vitro resulted in a decrease in active caspase-3 expression and an increase in Bcl-2 and p-Akt expression. We conclude that IRF6 might promote neuronal apoptosis by inhibiting Akt phosphorylation after TBI.

Knockdown of IRF6 Attenuates Hydrogen Dioxide-Induced Oxidative Stress via Inhibiting Mitochondrial Dysfunction in HT22 Cells

“…Our results here showed that the expression levels of IRF6 mRNA and protein were both significantly increased by H 2 O 2 treatment, indicating that the process of transcription was also involved in IRF6 regulation in our in vitro conditions. In consistent with our data, a recent study demonstrated that the expression of IRF6 in cortical neurons, but not in astrocytes or oligodendrocytes, was up-regulated after traumatic brain injury, which was also confirmed in in vitro injury model using PC12 cells (Lin et al 2015). Together with our observations, these data strongly suggested that IRF6 might play important roles in oxidative stress associated neuronal injury.…”

“…The mitochondria-associated intrinsic apoptotic pathway is mediated by disruption of mitochondrial membrane integrity, the opening of mPTP, and the release of cytochrome c, which further activates caspase-9 and in turn causes the cleavage of caspase-3 (Hacker and Paschen 2007;Dai et al 2014a, b). Recently, up-regulation of IRF6 was shown to promote neuronal apoptosis after traumatic brain injury (Lin et al 2015). Consistently, we found that down-regulation of IRF6 inhibits the activation of mitochondrial apoptotic factors, including caspase-9, caspase-3, and Bax.…”

“…Among the IRF family, IRF1 and IRF8 were found to be associated with neuronal apoptosis under ischemic conditions in the central nervous system (Xiang et al 2014;Alexander et al 2003). Moreover, the pro-apoptotic activity of IRF6 in traumatic brain injury was recently discovered in rats (Lin et al 2015). These findings could be explained by the similar structure of IRF6 and IRF8, exhibiting homology to the C-terminal domains of SMAD family members and containing an IRF-associated domain 1 (IDA1), although all IRF family members contain five well-conserved tryptophan repeats and a helix-turn-helix DBD (Kondo et al 2002;Yanai et al 2012).…”

“…However, the regulation and function of IRF6 in the central nervous system remain unknown. Recently, Lin et al found that IRF6 is constitutively expressed in the brain, especially in cortical neurons, and that the expression of IRF6 is dramatically increased after traumatic brain injury (Lin et al 2015). They speculated that IRF6 might promote neuronal apoptosis by inhibiting pro-survival Akt signaling cascades.…”

Interferon Regulatory Factor 6 Has a Protective Role in the Host Response to Endotoxic Shock

“…The carboxy-terminal domain exhibits increased diversity and confers specificity to each of the IRF family members. Although IRFs were initially described as mediating the interferon response after viral infections [ 1 ], this family is now recognized as playing a wider role in embryonic development, health and diseases like cancer [ 2 , 3 ], metabolism and traumatic brain injury [ 4 ]. Of particular interest is the involvement of multiple family members in the regulation of immune responses and immune cell development (for review, [ 5 ]).…”