Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Center, Xi'an, Shaanxi, 710061, PR China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education of China, Xi'an, Shaanxi, 710061, PR China; Key Laboratory for Molecular Genetic Mechanisms and Intervention Research on High Altitude Disease of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, 712082, PR China.
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Center, Xi'an, Shaanxi, 710061, PR China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education of China, Xi'an, Shaanxi, 710061, PR China.
Mol Immunol. 2021 Jun;134:118-128. doi: 10.1016/j.molimm.2021.03.005. Epub 2021 Mar 23.
Growing research evidence suggests that elevated TLR2 is closely related to the occurrence and development of nonalcoholic steatohepatitis (NASH). However, a little is known about its regulatory mechanism. Here, we found that IFN-γ and TLR2 expression is significantly upregulated in NASH associated rat liver specimens. Meanwhile, IFN-γ positively regulated the expression of TLR2 and its target genes in NR8383 rat macrophage cells in dose- & time-dependent manner. Importantly, IFN-γ also regulated the related transcriptional factors pSTAT1 and IRF1. Moreover, we identified that the DNA fragment from -1000 to -200 bp of the TLR2 promoter region is responsible for STAT1 binding, especially the STAT1-BS3 (-591∼-573 bp). Further investigation verified that STAT1β is essential in this process, rather than STAT1α. Overall, our findings suggest that IFN-γ promotes TLR2 transcription and its target genes expression by STAT1β. This leads to the hepatic inflammation vicious cycle in NASH and provides new potential targets for treating NASH.
越来越多的研究证据表明，TLR2 升高与非酒精性脂肪性肝炎（NASH）的发生和发展密切相关。然而，其调控机制知之甚少。在这里，我们发现 IFN-γ 和 TLR2 的表达在与 NASH 相关的大鼠肝组织标本中显著上调。同时，IFN-γ 以剂量和时间依赖的方式在 NR8383 大鼠巨噬细胞中正向调节 TLR2 及其靶基因的表达。重要的是，IFN-γ 还调节相关转录因子 pSTAT1 和 IRF1。此外，我们确定 TLR2 启动子区域从-1000 到-200bp 的 DNA 片段负责 STAT1 结合，特别是 STAT1-BS3（-591∼-573bp）。进一步的研究验证了 STAT1β 在这个过程中是必不可少的，而不是 STAT1α。总的来说，我们的研究结果表明，IFN-γ 通过 STAT1β 促进 TLR2 的转录及其靶基因的表达。这导致 NASH 中的肝脏炎症恶性循环，并为治疗 NASH 提供了新的潜在靶点。
