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

Abstract

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.

• Authors: Kiyoshi Migita, Yumi Maeda, Seigo Abiru, Minoru Nakamura, Atsumasa Komori, Terufumi Yokoyama, Yasushi Takii, Tsuyoshi Mori, Hiroshi Yatsuhashi, Katsumi Eguchi, Hiromi Ishibashi
• Journal: Life sciences (Life Sci) Vol. 78 Issue 21 Pg. 2510-5 (Apr 18 2006) ISSN: 0024-3205 [Print] Netherlands
• PMID: 16303143 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Immunosuppressive Agents
• Indicators and Reagents
• NF-kappa B
• Surface-Active Agents
• Tumor Necrosis Factor-alpha
• Sodium Dodecyl Sulfate
• RNA
• Gelatinases
• Matrix Metalloproteinase 9
• Tacrolimus

Topics

• Blotting, Western
• Enzyme Induction (drug effects)
• Enzyme-Linked Immunosorbent Assay
• Gelatinases (biosynthesis)
• Hepatocytes (drug effects, metabolism)
• Humans
• Immunosuppressive Agents (pharmacology)
• Indicators and Reagents
• Liver (cytology, metabolism)
• Matrix Metalloproteinase 9 (biosynthesis)
• NF-kappa B (biosynthesis)
• Plasmids (genetics)
• RNA (biosynthesis, isolation & purification)
• Sodium Dodecyl Sulfate (pharmacology)
• Surface-Active Agents (pharmacology)
• Tacrolimus (pharmacology)
• Transfection
• Tumor Necrosis Factor-alpha (pharmacology)