Immunosuppressant FK506 inhibits matrix metalloproteinase-9 induction in TNF-alpha-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-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-kappaB 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 IkappaB-alpha and resulted in the transcriptional activation of NF-kappaB. FK506 suppressed this TNF-alpha-induced NK-kappaB 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-kappaB pathway suggesting the anti-inflammatory properties of FK506.
Migita
Kiyoshi
K
Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Kubara 2-1001-1 Omura, Nagasaki, 856-8562, Japan. migita@nmc.hosp.go.jp
Maeda
Yumi
Y
Abiru
Seigo
S
Nakamura
Minoru
M
Komori
Atsumasa
A
Yokoyama
Terufumi
T
Takii
Yasushi
Y
Mori
Tsuyoshi
T
Yatsuhashi
Hiroshi
H
Eguchi
Katsumi
K
Ishibashi
Hiromi
H
D015153:Blotting, Western; D004790:Enzyme Induction / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D018093:Gelatinases / Q000096:biosynthesis; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007202:Indicators and Reagents; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D016328:NF-kappa B / Q000096:biosynthesis; D010957:Plasmids / Q000235:genetics; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D012967:Sodium Dodecyl Sulfate / Q000494:pharmacology; D013501:Surface-Active Agents / Q000494:pharmacology; D016559:Tacrolimus / Q000494:pharmacology*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D007166:Immunosuppressive Agents; D007202:Indicators and Reagents; D016328:NF-kappa B; D013501:Surface-Active Agents; D014409:Tumor Necrosis Factor-alpha; D012967:Sodium Dodecyl Sulfate; D012313:RNA; D018093:Gelatinases; D020780:Matrix Metalloproteinase 9; D016559:Tacrolimus