Abstract
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-β1, collagen α1, fibronectin, and cell adhesion molecule mRNA upregulation. Following gene transfer, both the activation of α-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.
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Project supported by research grant CMRPG-840451 from the Chang Gung Memorial Hospital.
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Chou, Wy., Lu, Cn., Lee, Th. et al. Electroporative interleukin-10 gene transfer ameliorates carbon tetrachloride-induced murine liver fibrosis by MMP and TIMP modulation. Acta Pharmacol Sin 27, 469–476 (2006). https://doi.org/10.1111/j.1745-7254.2006.00304.x
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DOI: https://doi.org/10.1111/j.1745-7254.2006.00304.x
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