Acta Pharmacologica Sinica 2006 April; 27 (4): 469-476; doi: 10.1111/j.1745-7254.2006.00304.x

Aim: Liver fibrosis represents a process of healing and scarring in response to chronic liver injury. Effective therapies for liver fibrosis are lacking. Interleukin-10 (IL-10) is a cytokine that downregulates pro-inflammatory responses and has a modulatory effect on hepatic fibrogenesis. The aim of this study was to investigate whether electroporative IL-10 gene therapy has an hepatic fibrolytic effect on mice.

Methods: Hepatic fibrosis was induced by administering carbon tetrachloride (CCl₄) for 10 weeks in mice. The human IL-10 expression plasmid was delivered via electroporation after hepatic fibrosis was established. Histopathology, reverse transcription polymerase chain reaction (RT-PCR), immunoblotting, and gelatin zymography were used to investigate the possible mechanisms of action of IL-10.

Results: Human IL-10 gene therapy reversed CCl₄-induced liver fibrosis in mice. RT-PCR revealed that IL-10 gene therapy attenuated liver TGF-b1, collagen a1, fibronectin, and cell adhesion molecule mRNA upregulation. Following gene transfer, both the activation of a-smooth muscle actin and cyclooxygenase-2 were significantly attenuated. Furthermore, IL-10 significantly inhibited matrix metalloproteinase-2 (MMP-2) and tissue inhibitors of matrix metalloproteinase (TIMP) activation after CCl₄ intoxication.

Conclusions: We demonstrated that IL-10 gene therapy attenuated CCl₄-induced liver fibrosis in mice. IL-10 prevented upregulated fibrogenic and pro-inflammatory gene responses. Its collagenolytic effect may be attributed to MMP and TIMP modulation. IL-10 gene therapy may be an effective therapeutic modality against liver fibrosis with potential clinical use.

Keywords: interleukin-10; gene therapy; liver cirrhosis; gelatinase A; tissue inhibitor of metallopro-teinases; cyclooxygenase 2