IFN-γ contributes to the hepatic inflammation in HFD-induced nonalcoholic steatohepatitis by STAT1β/TLR2 signaling pathway

• Published in: Molecular immunology Vol. 134; pp. 118 - 128
• Main Authors: Li, Jing, Chen, Qian, Yi, Jing, Lan, Xi, Lu, Kaikai, Du, Xiaojuan, Guo, Zizhen, Guo, Yuanxu, Geng, Manman, Li, Dongmin, Lu, Shemin
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.06.2021
• Subjects: Hepatic inflammation; IFN-γ; IRF1; Nonalcoholic steatohepatitis (NASH); STAT1; Toll-like receptor 2 (TLR2); NAFLD; Toll-like receptor 2 (TLR2); STAT1; HFD; MFD; LFD; Hepatic inflammation; NASH; MCD; Nonalcoholic steatohepatitis (NASH); IFN-γ; IRF1; TLR2
• ISSN: 0161-5890; 1872-9142
• DOI: 10.1016/j.molimm.2021.03.005

•IFN-γ and TLR2 expression upregulated significantly in E3 rats NASH animal model.•IFN-γ positively regulated TLR2, TNF-α, IL6, p-STAT1 and IRF1 in cells consistently.•IFN-γ promotes TLR2 transcription and its target genes production by STAT1β. 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.