Abstract
It has been reported that neuroinflammation occurs in the central nervous system (CNS) in patients with neuropathic pain, Alzheimer's disease and autism spectrum disorder. The 18-kDa translocator protein TSPO is used as an imaging target in positron emission tomography to detect neuroinflammation, and its expression is correlated with microglial activation. However, the mechanism underlying the transcriptional regulation of Tspo induced by inflammation is not clear. Here, we revealed that lipopolysaccharide (LPS) -induced Tspo expression was activated by the AP-1 complex in a mouse microglial cell line, BV-2. Knockdown of c-Fos and c-Jun, the components of AP-1, reduced LPS-induced Tspo expression. Furthermore, the enrichment of Sp1 in the proximal promoter region of Tspo was increased in the presence of LPS. In addition, the binding of histone deacetylase 1 (HDAC1) to the enhancer region, which contains the AP-1 site, was decreased by LPS treatment, but there were no significant differences in HDAC1 binding to the proximal promoter region with or without LPS. These results indicated that HDAC1 is involved not in the proximal promoter region but in the enhancer region. Our study revealed that inflammatory signals induce the recruitment of AP-1 to the enhancer region and Sp1 to the proximal promoter region of the Tspo gene and that Sp1 may regulate the basal expression of Tspo.
Highlights
Microglia are resident immune cells of the central nervous system (CNS) and play a pivotal role in maintaining the neuronal environment
We showed that recruitment of both c-Fos and c-Jun, which are components of the AP-1 complex, to the enhancer region of the Tspo gene was increased upon LPS treatment in the microglial cell line BV-2
Our experiments clearly demonstrated that AP-1, Sp1 and histone deacetylase 1 (HDAC1) are involved in the transactivation of Tspo expression
Summary
Microglia are resident immune cells of the central nervous system (CNS) and play a pivotal role in maintaining the neuronal environment. We showed that recruitment of both c-Fos and c-Jun, which are components of the AP-1 complex, to the enhancer region of the Tspo gene was increased upon LPS treatment in the microglial cell line BV-2 This evidence was supported by the observation that Tspo expression was reduced by knockdown of c-Fos and c-Jun. In addition, we found that the concentration of histone deacetylase 1 (HDAC1) at the AP-1 binding site in the Tspo enhancer region was decreased by LPS treatment. We found that the concentration of histone deacetylase 1 (HDAC1) at the AP-1 binding site in the Tspo enhancer region was decreased by LPS treatment These data suggest that LPS-induced Tspo gene expression in BV-2 was upregulated by AP-1 activation and that the release of HDAC1 from the AP-1 site was increased by LPS treatment
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