Electroporative interleukin-10 gene transfer ameliorates carbon tetrachloride-induced murine liver fibrosis by MMP and TIMP modulation

Wen Ying Chou, Cheng Nan Lu, Tsung Hsing Lee, Chia Ling Wu, Kung Sheng Hung, Allan M. Concejero, Bruno Jawan, Cheng Haung Wang

Research output: Contribution to journalArticle

24 Citations (Scopus)

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 tetrachlo-ride (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 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.

Original languageEnglish
Pages (from-to)469-476
Number of pages8
JournalActa Pharmacologica Sinica
Volume27
Issue number4
DOIs
Publication statusPublished - Apr 2006
Externally publishedYes

Fingerprint

Gene transfer
Tissue Inhibitor of Metalloproteinases
Matrix Metalloproteinase Inhibitors
Carbon Tetrachloride
Matrix Metalloproteinases
Liver Cirrhosis
Liver
Interleukin-10
Modulation
Tissue
Gene therapy
Genetic Therapy
Genes
Polymerase chain reaction
Transcription
Reverse Transcription
Fibrosis
Chemical activation
Polymerase Chain Reaction
Electroporation

Keywords

  • Cyclooxygenase 2
  • Gelatinase A
  • Gene therapy
  • Interleukin-10
  • Liver cirrhosis
  • Tissue inhibitor of metalloproteinases

ASJC Scopus subject areas

  • Chemistry(all)
  • Pharmacology

Cite this

Electroporative interleukin-10 gene transfer ameliorates carbon tetrachloride-induced murine liver fibrosis by MMP and TIMP modulation. / Chou, Wen Ying; Lu, Cheng Nan; Lee, Tsung Hsing; Wu, Chia Ling; Hung, Kung Sheng; Concejero, Allan M.; Jawan, Bruno; Wang, Cheng Haung.

In: Acta Pharmacologica Sinica, Vol. 27, No. 4, 04.2006, p. 469-476.

Research output: Contribution to journalArticle

Chou, Wen Ying ; Lu, Cheng Nan ; Lee, Tsung Hsing ; Wu, Chia Ling ; Hung, Kung Sheng ; Concejero, Allan M. ; Jawan, Bruno ; Wang, Cheng Haung. / Electroporative interleukin-10 gene transfer ameliorates carbon tetrachloride-induced murine liver fibrosis by MMP and TIMP modulation. In: Acta Pharmacologica Sinica. 2006 ; Vol. 27, No. 4. pp. 469-476.
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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 tetrachlo-ride (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 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.",
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T1 - Electroporative interleukin-10 gene transfer ameliorates carbon tetrachloride-induced murine liver fibrosis by MMP and TIMP modulation

AU - Chou, Wen Ying

AU - Lu, Cheng Nan

AU - Lee, Tsung Hsing

AU - Wu, Chia Ling

AU - Hung, Kung Sheng

AU - Concejero, Allan M.

AU - Jawan, Bruno

AU - Wang, Cheng Haung

PY - 2006/4

Y1 - 2006/4

N2 - 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 tetrachlo-ride (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 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.

AB - 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 tetrachlo-ride (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 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.

KW - Cyclooxygenase 2

KW - Gelatinase A

KW - Gene therapy

KW - Interleukin-10

KW - Liver cirrhosis

KW - Tissue inhibitor of metalloproteinases

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