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

Abstract

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.

Keywords: Hepatic inflammation; IFN-γ; IRF1; Nonalcoholic steatohepatitis (NASH); STAT1; Toll-like receptor 2 (TLR2).