TGF-β1 contributes to the hepatic inflammation in animal models with nonalcoholic steatohepatitis by Smad3/TLR2 signaling pathway

Mol Immunol. 2022 Dec:152:129-139. doi: 10.1016/j.molimm.2022.10.014. Epub 2022 Nov 2.

Abstract

Non-alcoholic fatty liver disease (NAFLD) is increasingly affecting human health and the economy worldwide due to various factors. Here, we found that the expression of TGF-β1 and TLR2 was significantly up-regulated in liver samples from both rats and mice nonalcoholic steatohepatitis (NASH) models. By constructing corresponding cell model, we found that TGF-β1 challenge can positively regulate the expression of TLR2 and p-Smad2/3, and the dual luciferase reporter gene system and EMSA assay confirmed the existence of Smad3 binding site (-916 ∼ -906) in the promoter region of TLR2. The overexpression and interference changes of Smad2/3 further verified the above experimental results. Taken together, these findings suggest that TGF-β1 promotes TLR2 transcription and its target gene expression via Smad3, leading to malignant exacerbation of liver inflammation in NASH, which provides new insights into the treatment of NASH.

Keywords: Nonalcoholic steatohepatitis (NASH); Smad3; Toll-like receptor 2 (TLR2); Transforming growth factor-β1 (TGF-β1).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Humans
  • Inflammation
  • Mice
  • Models, Animal
  • Non-alcoholic Fatty Liver Disease* / metabolism
  • Rats
  • Signal Transduction
  • Smad3 Protein* / metabolism
  • Toll-Like Receptor 2* / genetics
  • Toll-Like Receptor 2* / metabolism
  • Transforming Growth Factor beta1* / metabolism

Substances

  • Smad3 Protein
  • SMAD3 protein, human
  • TLR2 protein, human
  • Tlr2 protein, mouse
  • Toll-Like Receptor 2
  • Transforming Growth Factor beta1