NIM811, a nonimmunosuppressive cyclosporine analogue, suppresses collagen production and enhances collagenase activity in hepatic stellate cells

Motoyuki Kohjima, Munechika Enjoji, Nobito Higuchi, Kazuhiro Kotoh, Masaki Kato, Ryoiichi Takayanagi, Makoto Nakamuta

Research output: Contribution to journalArticle

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Abstract

Background/Aims: A recent decrease in patient survival has been reported among hepatitis C virus (HCV)-infected liver transplant recipients and this may be attributable to progression of fibrosis. We reported previously that cyclosporine suppressed the proliferation of, and collagen production in, hepatic stellate cells (HSCs). Here, we investigated the effects of NIM811, a cyclosporine analogue, on cell growth, collagen production and collagenase activity in HSCs. Methods: Rat HSCs and human HSC-derived TWNT-4 cells were cultured for the study. The expression of collagen, matrix metalloproteinase 1 (MMP-1) and tissue inhibitor of metalloproteinase-1 (TIMP-1) and collagenase activity was evaluated. Cell proliferation and apoptosis were measured. Phosphorylation of mitogen-activated protein kinases (MAPKs), Smad2 and Smad3 was evaluated. The expression of the tumour growth factor-β (TGF-β)-receptor and Smad7 genes was also evaluated. Results: NIM811, as well as cyclosporine, suppressed the transcription and synthesis of collagen and stimulated the production of MMP-1 with a concomitant enhancement of collagenase activity, although it did not change the expression of TIMP-1. NIM811 inhibited proliferation without induction of apoptosis. In the MAPKs and TGF-β signalling pathways, NIM811 enhanced the phosphorylation of JNK and p38, but not extracellular signal-regulated kinases 1 and 2, and suppressed the phosphorylation of Smad2 and Smad3, accompanied by increased Smad7 transcription and decreased TGF-β-receptor transcription. Conclusion: These findings demonstrate that NIM811 not only suppresses collagen production and proliferation but also increases collagenase activity. These effects are accompanied by inhibition of TGF-β signalling pathways.

Original languageEnglish
Pages (from-to)1273-1281
Number of pages9
JournalLiver International
Volume27
Issue number9
DOIs
Publication statusPublished - Nov 1 2007

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Hepatic Stellate Cells
Collagenases
Cyclosporine
Collagen
Matrix Metalloproteinase 1
Tissue Inhibitor of Metalloproteinase-1
Growth Factor Receptors
Phosphorylation
Mitogen-Activated Protein Kinases
Neoplasms
Intercellular Signaling Peptides and Proteins
Apoptosis
Matrix Metalloproteinase Inhibitors
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Hepacivirus
Cultured Cells
Fibrosis
Cell Proliferation
(melle-4)cyclosporin

All Science Journal Classification (ASJC) codes

  • Hepatology

Cite this

NIM811, a nonimmunosuppressive cyclosporine analogue, suppresses collagen production and enhances collagenase activity in hepatic stellate cells. / Kohjima, Motoyuki; Enjoji, Munechika; Higuchi, Nobito; Kotoh, Kazuhiro; Kato, Masaki; Takayanagi, Ryoiichi; Nakamuta, Makoto.

In: Liver International, Vol. 27, No. 9, 01.11.2007, p. 1273-1281.

Research output: Contribution to journalArticle

Kohjima, Motoyuki ; Enjoji, Munechika ; Higuchi, Nobito ; Kotoh, Kazuhiro ; Kato, Masaki ; Takayanagi, Ryoiichi ; Nakamuta, Makoto. / NIM811, a nonimmunosuppressive cyclosporine analogue, suppresses collagen production and enhances collagenase activity in hepatic stellate cells. In: Liver International. 2007 ; Vol. 27, No. 9. pp. 1273-1281.
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T1 - NIM811, a nonimmunosuppressive cyclosporine analogue, suppresses collagen production and enhances collagenase activity in hepatic stellate cells

AU - Kohjima, Motoyuki

AU - Enjoji, Munechika

AU - Higuchi, Nobito

AU - Kotoh, Kazuhiro

AU - Kato, Masaki

AU - Takayanagi, Ryoiichi

AU - Nakamuta, Makoto

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N2 - Background/Aims: A recent decrease in patient survival has been reported among hepatitis C virus (HCV)-infected liver transplant recipients and this may be attributable to progression of fibrosis. We reported previously that cyclosporine suppressed the proliferation of, and collagen production in, hepatic stellate cells (HSCs). Here, we investigated the effects of NIM811, a cyclosporine analogue, on cell growth, collagen production and collagenase activity in HSCs. Methods: Rat HSCs and human HSC-derived TWNT-4 cells were cultured for the study. The expression of collagen, matrix metalloproteinase 1 (MMP-1) and tissue inhibitor of metalloproteinase-1 (TIMP-1) and collagenase activity was evaluated. Cell proliferation and apoptosis were measured. Phosphorylation of mitogen-activated protein kinases (MAPKs), Smad2 and Smad3 was evaluated. The expression of the tumour growth factor-β (TGF-β)-receptor and Smad7 genes was also evaluated. Results: NIM811, as well as cyclosporine, suppressed the transcription and synthesis of collagen and stimulated the production of MMP-1 with a concomitant enhancement of collagenase activity, although it did not change the expression of TIMP-1. NIM811 inhibited proliferation without induction of apoptosis. In the MAPKs and TGF-β signalling pathways, NIM811 enhanced the phosphorylation of JNK and p38, but not extracellular signal-regulated kinases 1 and 2, and suppressed the phosphorylation of Smad2 and Smad3, accompanied by increased Smad7 transcription and decreased TGF-β-receptor transcription. Conclusion: These findings demonstrate that NIM811 not only suppresses collagen production and proliferation but also increases collagenase activity. These effects are accompanied by inhibition of TGF-β signalling pathways.

AB - Background/Aims: A recent decrease in patient survival has been reported among hepatitis C virus (HCV)-infected liver transplant recipients and this may be attributable to progression of fibrosis. We reported previously that cyclosporine suppressed the proliferation of, and collagen production in, hepatic stellate cells (HSCs). Here, we investigated the effects of NIM811, a cyclosporine analogue, on cell growth, collagen production and collagenase activity in HSCs. Methods: Rat HSCs and human HSC-derived TWNT-4 cells were cultured for the study. The expression of collagen, matrix metalloproteinase 1 (MMP-1) and tissue inhibitor of metalloproteinase-1 (TIMP-1) and collagenase activity was evaluated. Cell proliferation and apoptosis were measured. Phosphorylation of mitogen-activated protein kinases (MAPKs), Smad2 and Smad3 was evaluated. The expression of the tumour growth factor-β (TGF-β)-receptor and Smad7 genes was also evaluated. Results: NIM811, as well as cyclosporine, suppressed the transcription and synthesis of collagen and stimulated the production of MMP-1 with a concomitant enhancement of collagenase activity, although it did not change the expression of TIMP-1. NIM811 inhibited proliferation without induction of apoptosis. In the MAPKs and TGF-β signalling pathways, NIM811 enhanced the phosphorylation of JNK and p38, but not extracellular signal-regulated kinases 1 and 2, and suppressed the phosphorylation of Smad2 and Smad3, accompanied by increased Smad7 transcription and decreased TGF-β-receptor transcription. Conclusion: These findings demonstrate that NIM811 not only suppresses collagen production and proliferation but also increases collagenase activity. These effects are accompanied by inhibition of TGF-β signalling pathways.

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