TGF-β activates NLRP3 inflammasome by an autocrine production of TGF-β in LX-2 human hepatic stellate cells.
Hwansu KangEunhui SeoYoon Sin OhHee-Sook JunPublished in: Molecular and cellular biochemistry (2022)
Inflammation contributes to the pathogenesis of liver disease, and inflammasome activation has been identified as a major contributor to the amplification of liver inflammation. Transforming growth factor-beta (TGF-β) is a key regulator of liver physiology, contributing to all stages of liver disease. We investigated whether TGF-β is involved in inflammasome-mediated fibrosis in hepatic stellate cells. Treatment with TGF-β increased priming of NLRP3 inflammasome signaling by increasing NLRP3 levels and activating TAK1-NF-kB signaling. Moreover, TGF-β increased the expression of p-Smad2/3-NOX4 in LX-2 cells and consequently increased ROS content, which is a trigger for NLRP3 inflammasome activation. Elevated expression of NEK7 and active caspase-1 was also shown in TGF-β-induced LX-2 cells, and this level was reduced by (5Z)-oxozeaenol, a TAK inhibitor. Finally, TGF-β-treated cells significantly increased TGF-β secretion levels, and their production was inhibited by IL-1β receptor antagonist treatment. In conclusion, TGF-β may represent an endogenous danger signal to the active NLRP3 inflammasome, by which IL-1β mediates TGF-β expression in an autocrine manner. Therefore, targeting the NLRP3 inflammasome may be a promising approach for the development of therapies for TGF-β-induced liver fibrosis.
Keyphrases
- transforming growth factor
- nlrp inflammasome
- epithelial mesenchymal transition
- induced apoptosis
- cell cycle arrest
- signaling pathway
- oxidative stress
- cell death
- liver fibrosis
- endothelial cells
- inflammatory response
- cell proliferation
- dna damage
- drug delivery
- binding protein
- high resolution
- mass spectrometry
- toll like receptor