Mycophenolic acid, a possible Inhibitor of re-fibrosis in HCV-positive liver transplanted patients

Background and Aims: The rising number of liver-transplanted patients with chronic HCV-infection makes it necessary to establish a therapy which is profitable in immunosuppression, repression of virus activity, and overall survival. A keystone of liver fibrosis is the activation of human hepatic stellate cells (HSC). Therefore our aim was to analyze the influence of Immunosuppressiva on HSC activity. Methods: Thus we analyzed proliferation of cells by MTT, gene expression (Col1α, TGF-β, α-SMA, PDGF and PUMA), and protein expression (TGF-β, α-SMA, hyaluronic acid [HA]) after incubation of immortalized HSC (LX2-cells) with HCV±apoptotic bodies (AB) and immunosuppressiva (Cyclosporin A [CsA], Rapamycin, and Mycophenolic acid [MPA]) for both, 24 and 48 hours. Results: Incubation of LX2 with both, MPA and Rapamycin, results in inhibition of cell proliferation independent of HCV-activity of AB. No alteration in mRNA-levels (Col1α, TGF-β, α-SMA, PDGF, PUMA) and protein expressions (TGF-β, α-SMA, HA) could be found when CsA combined w/wo AB was used. Rapamycin caused an increase of gene expression in a time and HCV-activity independent manner and a general increase of TGF-β protein was observed. No changes in both protein levels, α-SMA and HA, were detectable. MPA decreased Col1α and increased TGF-β, α-SMA-mRNA-levels independent of HVC-activity of AB. Simultaneously PUMA-mRNA-level was improved if MPA was used. Apoptosis and HA-expression was upregulated if cells were treated with both, HCV positive AB and an MPA. At least a reduction of TGF-β-protein level was recordable. Conclusion: While an engulfment of AB causes a resistance of HSC against pro-apoptotic stimuli, an in vitro induction of apoptosis using MPA could be advantageous in therapy of patients liver-transplanted due to HCV. Thus by higher rates of apoptosis re-fibrosis could be prevented and patients would be immune suppressed effectively.