Interleukin-1 beta up-regulates tissue inhibitor of matrix metalloproteinase-1 mRNA and phosphorylation of c-jun N-terminal kinase and p38 in hepatic stellate cells

DDC (diethyldithiocarbamate) could block collagen synthesis in HSC (hepatic stellate cells) through the inhibition of ROS (reactive oxygen species) derived from hepatocyte CYP2E1 (cytochrome P450 2E1). However, the effect of DDC on MMP-1 (matrix metalloproteinase-1), which is the main collagen degrading matrix metalloproteinase, has not been reported. In co-culture experiments, we found that DDC significantly enhanced MMP-1 expression in human HSC (LX-2) that were cultured with hepatocyte C3A cells either expressing or not expressing CYP2E1. The levels of both proenzyme and active MMP-1 enzyme were up-regulated in LX-2 cells, accompanied by elevated enzyme activity of MMP-1 and decreased collagen I, in both LX-2 cells and the culture medium. H2O2 treatment abrogated DDC-induced MMP-1 up-regulation and collagen I decrease, while catalase treatment slightly up-regulated MMP-1 expression. These data suggested that the decrease in ROS by DDC was partially responsible for the MMP-1 up-regulation. ERK1/2 (extracellular signal-regulated kinase 1/2), Akt (protein kinase B) and p38 were significantly activated by DDC. The ERK1/2 inhibitor (U0126) and Akt inhibitor (T3830) abrogated the DDC-induced MMP-1 up-regulation. In addition, a p38 inhibitor (SB203580) improved MMP-1 up-regulation through the stimulation of ERK1/2. Our data indicate that DDC significantly up-regulates the expression of MMP-1 in LX-2 cells which results in greater MMP-1 enzyme activity and decreased collagen I. The enhancement of MMP-1 expression by DDC was associated with H2O2 inhibition and coordinated regulation by the ERK1/2 and Akt pathways. These data provide some new insights into treatment strategies for hepatic fibrosis.

Download Full-text

Mechanical stretch induces matrix metalloproteinase 1 production in hepatic stellate cells

Gastroenterology ◽

10.1016/s0016-5085(08)81783-0 ◽

2001 ◽

Vol 120 (5) ◽

pp. A359 ◽

Cited By ~ 1

Author(s):

Takashi Goto ◽

Ken-Ichiro Mikami ◽

Kouithi Miura ◽

Kazuo Yoneyama ◽

Kunio Nakane ◽

...

Keyword(s):

Matrix Metalloproteinase ◽

Hepatic Stellate Cells ◽

Stellate Cells ◽

Mechanical Stretch ◽

Matrix Metalloproteinase 1

Download Full-text

Effect of siRNA-mediated down-regulation of receptor for advanced glycation end products on expression of matrix metalloproteinase-1 and tissue inhibitor of metalloproteinase-1 in rat hepatic stellate cells and hepatic fibrosis

World Chinese Journal of Digestology ◽

10.11569/wcjd.v23.i19.3012 ◽

2015 ◽

Vol 23 (19) ◽

pp. 3012

Author(s):

Yang Liu

Keyword(s):

Matrix Metalloproteinase ◽

Hepatic Fibrosis ◽

Advanced Glycation End Products ◽

Hepatic Stellate Cells ◽

Stellate Cells ◽

Tissue Inhibitor Of Metalloproteinase ◽

Advanced Glycation ◽

Matrix Metalloproteinase 1 ◽

Glycation End Products ◽

End Products

Download Full-text

Matrix metalloproteinase-1 induction by diethyldithiocarbamate is regulated via Akt and ERK/miR222/ETS-1 pathways in hepatic stellate cells

Bioscience Reports ◽

10.1042/bsr20160111 ◽

2016 ◽

Vol 36 (4) ◽

Cited By ~ 9

Author(s):

Tianhui Liu ◽

Ping Wang ◽

Min Cong ◽

Dong Zhang ◽

Lin Liu ◽

...

Keyword(s):

Matrix Metalloproteinase ◽

Hepatic Stellate Cells ◽

Molecular Mechanisms ◽

Stellate Cells ◽

Transcriptional Factor ◽

Signalling Pathways ◽

Akt Inhibitor ◽

Matrix Metalloproteinase 1 ◽

Prevention And Treatment ◽

Important Regulator

Matrix metalloproteinase-1 (MMP-1) plays an important role in fibrolysis by degrading excessively deposited collagen I and III. We previously demonstrated that diethyldithiocarbamate (DDC) up-regulates MMP-1 in hepatic stellate cells via the ERK1/2 and Akt signalling pathways. In the current study, we attempted to further explore the molecular mechanisms involved in the regulation of MMP-1. We treated a co-cultured system that included hepatocytes (C3A) and hepatic stellate cells (LX-2) with DDC. The data revealed that the transcriptional factor ETS-1, which is an important regulator of MMP-1, was up-regulated in LX-2 cells following DDC treatment. Furthermore, the up-regulation of MMP-1 by DDC has been abrogated through employing si-ETS-1 to block expression of ETS-1. We found that DDC significantly inhibited the expression of miR-222 in LX-2 cells. We transfected miR-222 mimic into LX-2 cells and then co-cultured the cells with C3A. The up-regulation of ETS-1 and MMP-1 in LX-2 cells treated with DDC were inhibited after miR-222 mimic transfection. These data indicate that DDC up-regulated MMP-1 in LX-2 cells through the miR-222/ETS-1 pathway. Finally, we treated the co-cultured system with an Akt inhibitor (T3830) and an ERK1/2 inhibitor (U0126). Both T3830 and U0126 blocked the suppression of miR-222 by DDC in LX-2. Collectively, these data indicate that DDC up-regulated MMP-1 in LX-2 cells through the Akt and ERK/miR-222/ETS-1 pathways. Our study provides experimental data that will aid the control of the process of fibrolysis in liver fibrosis prevention and treatment.

Download Full-text