Growth inhibitory properties of endothelin-1 in activated human hepatic stellate cells: a cyclic adenosine monophosphate-mediated pathway. Inhibition of both extracellular signal-regulated kinase and c-Jun kinase and upregulation of endothelin B receptors.

Mallat, Ariane; Préaux, Anne-Marie; Gal, Claudine Serradeil–Le; Raufaste, Danielle; Gallois, Cyrille; Brenner, David A.; Bradham, Cynthia A.; Maclouf, Jacques; Iourgenko, Vadim; Fouassier, Laura; Dhumeaux, Daniel; Mavier, Philippe; Lotersztajn, Sophie

doi:10.1172/jci119103

Cited by 105 publications

(90 citation statements)

References 62 publications

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“…Therefore, the present data further support a central role of COX-2 in hMF growth inhibition. According to our previous data, early COX-2-dependent cAMP will block early steps involved in hMF proliferation, such as extracellular signal-regulated kinase and c-Jun NH 2 -terminal kinase activations (4). The consequences of COX-2 induction by S1P remain to be determined but may involve regulation of more distal events, such as cell cycle components (34).…”

Section: Discussionmentioning

confidence: 92%

“…5), the major part of PGE 2 levels found in basal conditions derives from constitutive COX-2. The rapid increase in PGE 2 production in turn leads to elevation of cAMP, a growth inhibitory mediator that blocks early events involved in hMF proliferation (4). Recent studies indicate that S1P generally decreases cAMP production (9,10,12), but S1P-induced cAMP elevation has also been reported in a few instances (20,29,30).…”

Section: Discussionmentioning

confidence: 99%

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Antiproliferative Properties of Sphingosine 1-Phosphate in Human Hepatic Myofibroblasts

Davaille¹,

Gallois²,

Habib³

et al. 2000

Journal of Biological Chemistry

114

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Proliferation of hepatic myofibroblasts (hMF) is central for the development of fibrosis during liver injury, and factors that may limit their growth are potential antifibrotic agents. Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid with growth-regulating properties, either via Edg receptors or through intracellular actions. In this study, we examined the effects of S1P on the proliferation of human hMF. Human hMF expressed mRNAs for the S1P receptors Edg1, Edg3, and Edg5. These receptors were functional at nanomolar concentrations and coupled to pertussis toxin-sensitive and -insensitive G proteins, as demonstrated in guanosine 5-3-O-(thio)triphosphate binding assays. S1P potently inhibited hMF growth (IC 50 ‫؍‬ 1 M), in a pertussis toxininsensitive manner. Analysis of the mechanisms involved in growth inhibition revealed that S1P rapidly increased prostaglandin E 2 production and in turn cAMP, two growth inhibitory messengers for hMF; C 2 -ceramide and sphingosine, which inhibited hMF proliferation, did not affect cAMP levels. Production of cAMP by S1P was abolished by NS-398, a selective inhibitor of COX-2. Also, S1P potently induced COX-2 protein expression. Blocking COX-2 by NS-398 blunted the antiproliferative effect of S1P. We conclude that S1P inhibits proliferation of hMF, probably via an intracellular mechanism, through early COX-2-dependent release of prostaglandin E 2 and cAMP, and delayed COX-2 induction. Our results shed light on a novel role for S1P as a growth inhibitory mediator and point out its potential involvement in the negative regulation of liver fibrogenesis.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Antiproliferative Properties of Sphingosine 1-Phosphate in Human Hepatic Myofibroblasts

Davaille¹,

Gallois²,

Habib³

et al. 2000

Journal of Biological Chemistry

114

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“…For example, endothelin-1 causes a contraction of the sinusoidal fenestrae via the endothelin B receptor, 41 which can signal through cAMP. 42 This pathway also may be triggered by bile acids via TGR5. Whereas the relevance of SEC contractions for vascular resistance and overall portal pressure under healthy conditions remains controversial, 38,43 SEC have a central role as a donor of nitric oxide (NO).…”

Section: Discussionmentioning

confidence: 99%

The G-protein coupled bile salt receptor TGR5 is expressed in liver sinusoidal endothelial cells

et al. 2007

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Sinusoidal endothelial cells (SEC) constitute a permeable barrier between hepatocytes and blood. SEC are exposed to high concentrations of bile salts from the enterohepatic circulation. Whether SEC are responsive to bile salts is unknown. TGR5, a G-protein-coupled bile acid receptor, which triggers cAMP formation, has been discovered recently in macrophages. In this study, rat TGR5 was cloned and antibodies directed against the C-terminus of rat TGR5 were developed, which detected TGR5 as a glycoprotein in transfected HepG2-cells. B ile salts are required for cholesterol excretion and lipid absorption. 1 However, high concentrations of lipophilic bile salts have toxic effects. Bile salts alter membrane fluidity 2 and can act pro-or anti-apoptotic. [3][4][5][6] Many liver diseases are aggravated by the cholestatic potential of lipophilic bile salts. Therefore, several mechanisms exist to maintain bile salt homeostasis. These include the coordinated expression and action of bile salt transporters at the sinusoidal and canalicular membrane of liver parenchymal cells, 7 alternative pathways for bile salt synthesis and metabolism, 8,9 and the involvement of extrahepatic tissues (such as the gut and the kidneys) in bile salt excretion. [10][11][12] These mechanisms are closely regulated by nuclear receptors sensitive for bile salts, which control the expression of transporter proteins and enzymes. They comprise the farnesoid X receptor, 13-15 the pregnane X receptor, 16,17 and the vitamin D receptor. 18 Recently, a G-protein-coupled plasma membrane receptor responsive to bile salts has been discovered by highthroughput screening. This receptor, named TGR5, 19 M-BAR, or BG37, 20 stimulates adenylate cyclase on activation and increases the production of cyclic adenosine monophosphate (cAMP). Thereby, bile salts not only may be involved in the regulation of transcription but also may influence rapid, cAMP-dependent mechanisms in TGR5 expressing cells. So far, TGR5 expression has been demonstrated in enteroendocrine cells, 21 where bile salts stimulate the secretion of glucagon-like peptide-1 via TGR5 and in alveolar macrophages, 19 which secrete smaller amounts of cytokines in response to endotoxin, when bile salts are present. Recently, bile salts were shown to influence energy consumption in brown adipose tissue

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“…Stellate cells are a major source as well as a target of this cytokine during liver injury (286,289,376,377,495,535,539,545). ET-1 has a prominent contractile effect on stellate cells and myofibroblasts, which may contribute to portal hypertension in the cirrhotic liver (309,393,534).…”

Section: Production Of Growth Factors and Cytokinesmentioning

confidence: 99%

Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver

Friedman

2008

Physiological Reviews

2,356

2,549

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The hepatic stellate cell has surprised and engaged physiologists, pathologists, and hepatologists for over 130 years, yet clear evidence of its role in hepatic injury and fibrosis only emerged following the refinement of methods for its isolation and characterization. The paradigm in liver injury of activation of quiescent vitamin A-rich stellate cells into proliferative, contractile, and fibrogenic myofibroblasts has launched an era of astonishing progress in understanding the mechanistic basis of hepatic fibrosis progression and regression. But this simple paradigm has now yielded to a remarkably broad appreciation of the cell's functions not only in liver injury, but also in hepatic development, regeneration, xenobiotic responses, intermediary metabolism, and immunoregulation. Among the most exciting prospects is that stellate cells are essential for hepatic progenitor cell amplification and differentiation. Equally intriguing is the remarkable plasticity of stellate cells, not only in their variable intermediate filament phenotype, but also in their functions. Stellate cells can be viewed as the nexus in a complex sinusoidal milieu that requires tightly regulated autocrine and paracrine cross-talk, rapid responses to evolving extracellular matrix content, and exquisite responsiveness to the metabolic needs imposed by liver growth and repair. Moreover, roles vital to systemic homeostasis include their storage and mobilization of retinoids, their emerging capacity for antigen presentation and induction of tolerance, as well as their emerging relationship to bone marrow-derived cells. As interest in this cell type intensifies, more surprises and mysteries are sure to unfold that will ultimately benefit our understanding of liver physiology and the diagnosis and treatment of liver disease.

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Growth inhibitory properties of endothelin-1 in activated human hepatic stellate cells: a cyclic adenosine monophosphate-mediated pathway. Inhibition of both extracellular signal-regulated kinase and c-Jun kinase and upregulation of endothelin B receptors.

Cited by 105 publications

References 62 publications

Antiproliferative Properties of Sphingosine 1-Phosphate in Human Hepatic Myofibroblasts

Antiproliferative Properties of Sphingosine 1-Phosphate in Human Hepatic Myofibroblasts

The G-protein coupled bile salt receptor TGR5 is expressed in liver sinusoidal endothelial cells

Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver

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