Immunosuppressant FK506 inhibits matrix metalloproteinase-9 induction in TNF-α-stimulated human hepatic stellate cells

Activated hepatic stellate cells (HSCs) play a key role in the pathogenesis of hepatic inflammation and fibrosis through the production of matrix metalloproteinases (MMPs). Cytokines and growth factors are thought to activate HSCs. TNF-α has pleiotropic functions in hepatitis, but its role in liver fibrosis remains elusive. In this study we investigated the regulation of tumor necrosis factor-α (TNF-α) in the expression of MMPs by HSCs. We also examined whether the immunosuppressant FK506 influences the MMPs expression in human HSCs. Human HSCs, LI90, were treated with TNF-α in the presence of FK506. Release of MMPs into culture media, levels of MMP-9 mRNA and activation of NF-κB were compared between the cells cultured with or without FK506. Stimulation of human HSCs, LI90 cells, with TNF-α caused the induction of pro-MMP-9. Further, TNF-α stimulation induced the degradation of IκB-α and resulted in the transciptional activation of NF-κB. FK506 suppressed this TNF-α-induced NK-κB activation, alone with pro-MMP-9 mRNA and protein induction, in HSC. TNF-α contributes to the perpetuation of liver fibrosis through MMP-9 production from HSCs and that FK506 inhibits the induction of MMP-9 through NF-κB pathway suggesting the anti-inflammatory properties of FK506.