Cyclosporine suppresses cell growth and collagen production in hepatic stellate cells

Transplant Proc. 2005 Dec;37(10):4598-602. doi: 10.1016/j.transproceed.2005.10.104.


Background: In HCV-related graft hepatitis, immunosuppression has been implicated in rapid progression to cirrhosis, a serious clinical issue. We investigated the effects of cyclosporine or tacrolimus on cell growth and collagen production by hepatic stellate cells (HSC), which play a role in hepatic fibrosis.

Materials and methods: Cultured rat HSCs and human HSC-derived TWNT-4 cells were evaluated for proliferation, type I collagen, phosphorylation states of mitogen-activated protein kinases extracellular signal-regulated kinase 1/2; [MAPKs Erk1/2], c-Jun N-terminal kinase (JNK, p38), as well as the expression of collagen, matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) genes.

Results: Cyclosporine suppressed cell growth and collagen production in a concentration-dependent manner. At clinically relevant concentrations of 0.125 micromol (150 ng/mL) cyclosporine significantly reduced collagen production per cell by more than 50%. Similarly, tacrolimus also reduced both collagen concentration and cell number; however, tacrolimus at a clinically relevant concentration of 12.5 nmol (10 ng/mL) did not significantly reduce collagen production. Treatment with cyclosporine reduced type I collagen and TIMP-1 expression and enhanced MMP-1 expression. Cyclosporine also inhibited phosphorylation strongly for JNK and p38, and weakly inhibited for Erk1/2.

Conclusion: These findings demonstrated that cyclosporine suppresses cell growth and collagen production, suggesting that it may have an antifibrogenic effect.

MeSH terms

  • Animals
  • Cells, Cultured
  • Collagen / metabolism
  • Collagen Type I / biosynthesis*
  • Cyclosporine / pharmacology*
  • Dose-Response Relationship, Drug
  • Hepatocytes / drug effects
  • Hepatocytes / physiology*
  • Humans
  • Immunosuppressive Agents / pharmacology
  • Mice
  • Tacrolimus / pharmacology
  • Tissue Inhibitor of Metalloproteinase-1 / metabolism


  • Collagen Type I
  • Immunosuppressive Agents
  • Tissue Inhibitor of Metalloproteinase-1
  • Cyclosporine
  • Collagen
  • Tacrolimus