Open AccessElectroporative interleukin‐10 gene transfer ameliorates carbon tetrachloride‐induced murine liver fibrosis by MMP and TIMP modulation 1
Author(s) -
CHOU Wenying,
LU Chengnan,
LEE Tsunghsing,
WU Chialing,
HUNG Kungsheng,
CONCEJERO Allan M,
JAWAN Bruno,
WANG Chenghaung
Publication year - 2006
Publication title -
acta pharmacologica sinica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.514
H-Index - 90
eISSN - 1745-7254
pISSN - 1671-4083
DOI - 10.1111/j.1745-7254.2006.00304.x
Subject(s) - fibrosis , matrix metalloproteinase , ccl4 , genetic enhancement , hepatic fibrosis , interleukin , carbon tetrachloride , medicine , pathology , cancer research , immunology , cytokine , biology , chemistry , gene , biochemistry , organic chemistry
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 investi gate whether electroporative IL‐10 gene therapy has an hepatic fibrolytic effect on mice. Methods: Hepatic fibrosis was induced by administering carbon tetrachlo‐ride (CCl 4 ) 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 CCl 4 ‐induced liver fibrosis in mice. RT‐PCR revealed that IL‐10 gene therapy attenuated liver TGF‐β1, col lagen 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 CCl 4 intoxication. Conclusions: We demonstrated that IL‐10 gene therapy attenuated CCl 4 ‐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.