IFN-γ contributes to the hepatic inflammation in HFD-induced nonalcoholic steatohepatitis by STAT1β/TLR2 signaling pathway
IFN-γ contributes to the hepatic inflammation in HFD-induced nonalcoholic steatohepatitis by STAT1β/TLR2 signaling pathway
复制标题
IFN-γ通过STAT1β/TLR2信号通路促进HFD诱导的非酒精性脂肪性肝炎的肝脏炎症
DOI：
10.1016/j.molimm.2021.03.005
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发表时间：
2021-03-23
影响因子：
3.6
通讯作者：
Lu, Shemin
中科院分区：
文献类型：
--
作者：
Li, Jing;Chen, Qian;Lu, Shemin
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)的发生发展密切相关。然而，人们对其监管机制知之甚少。在这里，我们发现在NASH相关的大鼠肝脏标本中，干扰素-γ和TLR2的表达显著上调。同时，干扰素-γ对NR8383大鼠巨噬细胞TLR2及其靶基因的表达有正向调节作用，呈剂量和时间依赖性。重要的是，干扰素还调节相关的转录因子pSTAT1和IRF1。此外，我们还发现TLR2启动子区域1000-200bp的DNA片段负责STAT1的结合，特别是STAT1-BS3(与591相似，与-573bp相似)。进一步的研究证实，在这一过程中，STAT1β是必不可少的，而不是STAT1α。总体而言，我们的发现表明，干扰素-α通过STAT1β促进TLR2的转录及其靶基因的表达。这导致了NASH肝脏炎症的恶性循环，为NASH的治疗提供了新的潜在靶点。
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-gamma and TLR2 expression is significantly upregulated in NASH associated rat liver specimens. Meanwhile, IFN-gamma positively regulated the expression of TLR2 and its target genes in NR8383 rat macrophage cells in dose- & time-dependent manner. Importantly, IFN-gamma 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 (similar to 591 similar to-573 bp). Further investigation verified that STAT1 beta is essential in this process, rather than STAT1 alpha. Overall, our findings suggest that IFN-alpha promotes TLR2 transcription and its target genes expression by STAT1 beta. This leads to the hepatic inflammation vicious cycle in NASH and provides new potential targets for treating NASH.