TGF-β1 modulates matrix metalloproteinase-13 expression in hepatic stellate cells by complex mechanisms involving p38MAPK, PI3-kinase, AKT, and p70S6k

2004 ◽  
Vol 287 (5) ◽  
pp. G974-G987 ◽  
Author(s):  
Carmen G. Lechuga ◽  
Zamira H. Hernández-Nazara ◽  
José-Alfredo Domínguez Rosales ◽  
Elena R. Morris ◽  
Ana Rosa Rincón ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Hepatic Stellate Cells ◽  
Type I Collagen ◽  
De Novo ◽  
Stellate Cells ◽  
Type I ◽  
Collagen Mrna ◽  
Matrix Metalloproteinase 13 ◽  
De Novo Protein Synthesis ◽  
Tgf Β1

Transforming growth factor-β1 (TGF-β1), the main cytokine involved in liver fibrogenesis, induces expression of the type I collagen genes in hepatic stellate cells by a transcriptional mechanism, which is hydrogen peroxide and de novo protein synthesis dependent. Our recent studies have revealed that expression of type I collagen and matrix metalloproteinase-13 (MMP-13) mRNAs in hepatic stellate cells is reciprocally modulated. Because TGF-β1 induces a transient elevation of α1(I) collagen mRNA, we investigated whether this cytokine was able to induce the expression of MMP-13 mRNA during the downfall of the α1(I) collagen mRNA. In the present study, we report that TGF-β1 induces a rapid decline in steady-state levels of MMP-13 mRNA at the time that it induces the expression of α1(I) collagen mRNA. This change in MMP-13 mRNA expression occurs within the first 6 h postcytokine administration and is accompanied by a twofold increase in gene transcription and a fivefold decrease in mRNA half-life. This is followed by increased expression of MMP-13 mRNA, which reaches maximal values by 48 h. Our results also show that this TGF-β1-mediated effect is de novo protein synthesis-dependent and requires the activity of p38MAPK, phosphatidylinositol 3-kinase, AKT, and p70S6k. Altogether, our data suggest that regulation of MMP-13 by TGF-β1 is a complex process involving transcriptional and posttranscriptional mechanisms.

scholarly journals Reciprocal Modulation of Matrix Metalloproteinase-13 and Type I Collagen Genes in Rat Hepatic Stellate Cells

2003 ◽  
Vol 162 (6) ◽  
pp. 1771-1780 ◽  
Author(s):  
Benjamin Schaefer ◽  
Ana María Rivas-Estilla ◽  
Noemí Meraz-Cruz ◽  
Miguel Arturo Reyes-Romero ◽  
Zamira H. Hernández-Nazara ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Hepatic Stellate Cells ◽  
Type I Collagen ◽  
Stellate Cells ◽  
Type I ◽  
Matrix Metalloproteinase 13 ◽  
Collagen Genes

scholarly journals EFFECT OF COLLAGEN I GEL ON APOPTOSIS OF RAT HEPATIC STELLATE CELLS

2013 ◽  
Vol 56 (2) ◽  
pp. 73-79
Author(s):  
Lenka Bittnerová ◽  
Alena Jiroutová ◽  
Emil Rudolf ◽  
Martina Řezáčová ◽  
Jiří Kanta
Keyword(s):  
Hepatic Stellate Cells ◽  
Type I Collagen ◽  
Collagen Gel ◽  
Stellate Cells ◽  
Type I ◽  
Function Type ◽  
Fibrotic Liver ◽  
Normal Rat ◽  
And Function

Activated hepatic stellate cells (HSC) are a major source of fibrous proteins in cirrhotic liver. Inducing or accelerating their apoptosis is a potential way of liver fibrosis treatment. Extracellular matrix (ECM) surrounding cells in tissue affects their differentiation, migration, proliferation and function. Type I collagen is the main ECM component in fibrotic liver. We have examined how this protein modifies apoptosis of normal rat HSC induced by gliotoxin, cycloheximide and cytochalasin D in vitro and spontaneous apoptosis of HSC isolated from CCl4-damaged liver. We have found that type I collagen gel enhances HSC apoptosis regardless of the agent triggering this process.

Mechanical stretch modulates TGF-β1 and α1(I) collagen expression in fetal human intestinal smooth muscle cells

1999 ◽  
Vol 277 (5) ◽  
pp. G1074-G1080 ◽  
Author(s):  
Jorge A. Gutierrez ◽  
Hilary A. Perr
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Type I Collagen ◽  
Intestinal Smooth Muscle ◽  
Type I ◽  
Collagen Mrna ◽  
Collagen Expression ◽  
Collagen Protein ◽  
Mrna Content ◽  
Tgf Β1

Intestinal muscle undergoes stretch intermittently during peristalsis and persistently proximal to obstruction. The influence of this pervasive biomechanical force on developing smooth muscle cell function remains unknown. We adapted a novel in vitro system to study whether stretch modulates transforming growth factor-β1 (TGF-β1) and type I collagen protein and component α1 chain [α1(I) collagen] expression in fetal human intestinal smooth muscle cells. Primary confluent cells at 20-wk gestation, cultured on flexible silicone membranes, were subjected to two brief stretches or to 18 h tonic stretch. Nonstretched cultures served as controls. TGF-β1 protein was measured by ELISA and type I collagen protein was assayed by Western blot. TGF-β1 and α1(I) collagen mRNA abundance was determined by Northern blot analysis, quantitated by phosphorimaging, and normalized to 18S rRNA. Transcription was examined by nuclear run-on assay. Tonic stretch increased TGF-β1 protein 40%, type I collagen protein 100%, TGF-β1 mRNA content 2.16-fold, and α1(I) collagen mRNA 3.80-fold and enhanced transcription of TGF-β1 and α1(I) collagen by 3.1- and 4.25-fold, respectively. Brief stretch stimulated a 50% increase in TGF-β1 mRNA content but no change in α1(I) collagen. Neutralizing anti-TGF-β1 ablated stretch-mediated effects on α1(I) collagen. Therefore, stretch upregulates transcription for TGF-β1, which stimulates α1(I) collagen gene expression in smooth muscle from developing gut.

Hematopoietic Origin of Hepatic Stellate Cell.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1679-1679
Author(s):  
Eri Miyata ◽  
Masahiro Masuya ◽  
Fumihiko Ishikawa ◽  
Shuro Yoshida ◽  
Keizo Kato ◽  
...  
Keyword(s):  
Stem Cells ◽  
Liver Injury ◽  
Hematopoietic Stem Cells ◽  
Hepatic Stellate Cells ◽  
Type I Collagen ◽  
Stellate Cells ◽  
Gradual Transition ◽  
Type I ◽  
Chimeric Mice ◽  
Hematopoietic Stem

Abstract Hepatic stellate cells are believed to play a key role in the development of liver fibrosis. They undergo a gradual transition from a quiescent, fat-storing phenotype to an activated myofibroblast-like phenotype and then produce high amount of extracellular matrix such as collagen by liver injury. They express mesenchymal markers such as vimentin and desmin, or neural/neuroectodermal markers such as glial fibrillary acidic protein (GFAP). Based on the characteristic phenotype, the embryonic origin of stellate cells is thought to be the septum transversum mesenchyme or neural crest. However, their origin in the adult liver is still unknown. Recently, several studies have reported that crude bone marrow (BM) cells can give rise to hepatic stellate cells. However, since adult BM cells are thought to contain hematopoietic stem cells and mesenchymal stem cells, it is important to clarify which type of stem cells is the true source of hepatic stellate cells. We hypothesized that hepatic stellate cells are derived from hematopoietic stem cells. To test this hypothesis, we generated chimeric mice by transplantation of singe enhanced green fluorescent protein (EGFP)-marked hematopoietic stem cells (Lin− Sca-1+ c-kit+ CD34− cells) into lethally irradiated nontransgenic mice and examined the histology of liver tissues obtained from chimeric mice with carbon tetrahydrochloride (CCl4)-induced injury. Following 12 weeks treatment of CCl4, hepatic nodules and bridging fibrosis developed in all livers. We detected EGFP+ cells in the liver and some of them contained intracytoplasmic lipid droplets, which were proved by oil red O staining. Immunohistochemical analysis demonstrated that 60% of EGFP+ cells were negative for leukocyte common antigen (CD45); however, they expressed vimentin, GFAP and ADAMTS-13, which is a circulating zinc metalloproteinase synthesized in hepatic stellate cells. Moreover, nonparenchymal cell populations were isolated from the livers of chimeric mice with CCl4 treatment and were incubated on noncoated glass slides for 3 days. EGFP+ cells were also positive for type I collagen. These phenotypes are consistent with those of hepatic stellate cells. Our findings suggest that hematopoietic stem cells contribute to the generation of hepatic stellate cells upon liver injury.

Direct Hepatotoxic Effect of KC Chemokine in the Liver Without Infiltration of Neutrophils

2005 ◽  
Vol 230 (8) ◽  
pp. 573-586 ◽  
Author(s):  
Lela Stefanovic ◽  
David A. Brenner ◽  
Branko Stefanovic
Keyword(s):  
Hepatic Stellate Cells ◽  
Type I Collagen ◽  
Feedback Regulation ◽  
Fold Increase ◽  
Stellate Cells ◽  
Polymerase Chain Reaction Analysis ◽  
Type I ◽  
Hepatotoxic Effect ◽  
Polymerase Chain

KC is a mouse homolog of human chemokine gro-α (CXCL1), expression of which is increased in liver diseases. We show that activated, but not quiescent, hepatic stellate cells (HSCs) express KC. Hepatic stellate cells constitutively express the KC receptor, CXCR2. Addition of recombinant KC to HSCs undergoing activation in culture Increases secretion and processing of Type I collagen. Overexpression of endogenous KC in the mouse liver could be achieved by an intraperitoneal injection CCl4 followed after 24 hrs by an injection of recombinant KC into circulation. This protocol resulted in about a 14-fold increase in concentration of KC protein in the liver. Overexpression of KC was associated with upregulation of the mRNA for CXCR2 and MIP-2 and with necrosis and increased synthesis of Type I collagen. This suggests that KC has a direct hepatotoxic effect, which led to a massive liver necrosis after 48 hrs. No accumulation of neutrophils was seen in the livers as judged by histology and reverse transcriptase-polymerase chain reaction analysis of myeloperoxidase mRNA. Autostimulation of KC and CXCR2 expression by recombinant KC protein in the mice with preexisting liver injury indicates a positive feedback regulation. Such regulation and direct hepatotoxicity of KC with increased collagen synthesis represent novel findings about the role of KC/gro-α in liver pathology.

scholarly journals Stimulation of Pro-MMP-2 Production and Activation by Native Form of Extracellular Type I Collagen in Cultured Hepatic Stellate Cells

2003 ◽  
Vol 28 (6) ◽  
pp. 505-513 ◽  
Author(s):  
Da-Ren Wang ◽  
Mitsuru Sato ◽  
Li-Na Li ◽  
Mitsutaka Miura ◽  
Naosuke Kojima ◽  
...  
Keyword(s):  
Hepatic Stellate Cells ◽  
Type I Collagen ◽  
Stellate Cells ◽  
Type I ◽  
Native Form ◽  
Stimulation Of
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