Journal
LIFE SCIENCES
Volume 78, Issue 21, Pages 2510-2515Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.lfs.2005.10.003
Keywords
FK506; hepatic stellate cells; NF-kappa B; matrix metalloproteinase; TNF-alpha
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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-alpha has pleiotropic functions in hepatitis, but its role in liver fibrosis remains elusive. In this study we investigated the regulation of tumor necrosis factor-alpha (TNF-alpha) 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-alpha in the presence of FK506. Release of MMPs into culture media, levels of MMP-9 mRNA and activation of NF-kappa B were compared between the cells cultured with or without FK506. Stimulation of human HSCs, LI90 cells, with TNF-alpha caused the induction of pro-MMP-9. Further, TNF-alpha stimulation induced the degradation of I kappa B-alpha and resulted in the transciptional activation of NF-kappa B. FK506 suppressed this TNF-alpha-induced NK-kappa B activation, alone with pro-MMP-9 mRNA and protein induction, in HSC. TNF-alpha contributes to the perpetuation of liver fibrosis through MMP-9 production from HSCs and that FK506 inhibits the induction of MMP-9 through NF-kappa B pathway suggesting the anti-inflammatory properties of FK506. (c) 2005 Elsevier Inc. All rights reserved.
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