Platelet-derived Growth Factor-BB and Thrombin Generate Positive and Negative Signals for Human Hepatic Stellate Cell Proliferation

Mallat, Ariane; Gallois, Cyrille; Tao, Jiangchuan; Habib, Aı̈da; Maclouf, Jacques; Mavier, Philippe; Préaux, Anne-Marie; Lotersztajn, Sophie

doi:10.1074/jbc.273.42.27300

Cited by 96 publications

(95 citation statements)

References 40 publications

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“…As shown in Figure 8A, pretreatment with ibuprofen exerted a dose-related abrogation of the inhibitory effect of NO donors on PDGF-induced DNA synthesis. In addition, pretreatment with ibuprofen significantly enhanced the mitogenic effect of PDGF, similar to the data of Mallat et al 51 Accordingly, the observed inhibition of PDGF-induced ERK activity exerted by NTG and SNAP was completely abolished when cells were preincubated with ibuprofen ( Figure 8B). Finally, to characterize the involvement of the adenylate cyclase/ cAMP pathway, we examined intracellular cAMP synthesis in response to NO donors in the absence and presence of ibuprofen.…”

Section: Pge 2 Synthesis Blockade Abrogates the Inhibitory Effect Of supporting

confidence: 89%

“…Along these lines, established experimental evidence obtained in activated human HSCs has clearly shown that activation of this signaling pathway is associated with effects on PDGF action and signaling similar to those observed in the presence of NO donors. [51][52][53] In agreement with this alternative working hypothesis, PGE 2 synthesis blockade obtained by using the COX inhibitor ibuprofen results in a decrease in NO donor-induced cAMP synthesis and in abrogation of the inhibitory effect of NO donors on both PDGF action and intracellular signaling.…”

Section: Discussionsupporting

confidence: 69%

“…In addition, a 2-fold increase in PGE 2 synthesis was also observed after stimulation with PDGF-BB, thus confirming recently reported observations in this cell type. 51 …”

Section: Effect Of No Donors On Pge 2 Synthesismentioning

confidence: 99%

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Nitrovasodilators inhibit platelet-derived growth factor-induced proliferation and migration of activated human hepatic stellate cells

Failli¹,

et al. 2000

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Background & Aims:Nitrovasodilators have been proposed for the treatment of portal hypertension alone or in combination with ␤-blockers. In addition to their vasodilatory properties, nitric oxide (NO) donors may exert direct antifibrogenic properties. We evaluated the effect of nitroglycerin (NTG) and S-nitroso-N-acetyl penicillamine (SNAP) on the mitogenic and chemotactic properties of platelet-derived growth factor (PDGF)-BB and the modulation of the relative intracellular signaling pathways in fully activated human hepatic stellate cells (HSCs), a cell type that plays an active role in liver fibrogenesis and portal hypertension. Methods & Results: Both NTG and SNAP induced a dosedependent decrease in PDGF-induced DNA synthesis and cell migration, which was associated with a decrease in PDGF-induced intracellular Ca 2؉ increase and extracellular signal-regulated kinase (ERK) activity. These effects were not related to activation of the classic soluble guanylate cyclase (sGC)/guanosine 3 ,5 -cyclic monophosphate pathway; accordingly, Western blot analysis of HSC lysates revealed the absence of the ␣ 1 ␤ 1 ubiquitous subunits of sGC, whereas they were detectable in quiescent HSCs, freshly isolated from normal human liver. Conversely, both NTG and SNAP induced a more than 10 -20-fold increase in prostaglandin E 2 in cell supernatants within 1 minute, associated with an increase in intracellular adenosine 3 ,5 -cyclic monophosphate levels. Accordingly, the inhibitory effects of NO donors on PDGF action and signaling were eliminated after preincubation with ibuprofen. Conclusions: These results suggest that NO donors may exert a direct antifibrogenic action by inhibiting proliferation, motility, and contractility of HSCs in addition to a reduction of fibrillar extracellular matrix accumulation.

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Section: Pge 2 Synthesis Blockade Abrogates the Inhibitory Effect Of supporting

confidence: 89%

Section: Discussionsupporting

confidence: 69%

See 1 more Smart Citation

Nitrovasodilators inhibit platelet-derived growth factor-induced proliferation and migration of activated human hepatic stellate cells

Failli¹,

et al. 2000

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“…Indeed, we found that the antiproliferative effects of ET-1 and TNF-␣ involve COX-2 (6). We also showed that the mitogenic effects of PDGF-BB and thrombin result from a balance between a promitogenic and a COX-2-dependent growth inhibitory pathway (5). Therefore, the present data further support a central role of COX-2 in hMF growth inhibition.…”

Section: Discussionsupporting

confidence: 69%

Antiproliferative Properties of Sphingosine 1-Phosphate in Human Hepatic Myofibroblasts

Davaille¹,

Gallois²,

Habib³

et al. 2000

Journal of Biological Chemistry

Self Cite

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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“…IL-1β-induced COX-2 expression was enhanced by IGF-I treatment in rat renal mesangial cells (23). However, other recent studies showed that IGF-I failed to induce COX-2 expression in HT-29 colon cancer cells, hepatic stellate cells, and human vein vascular endothelial cells (13,24,25), and IGF-I treatment even decreased COX-2 expression in osteoblasts (26). Thus, the effects of IGF-I on COX-2 expression appear to be cell-type specific, which may reflect its ability to promote organ-specific tumorigenesis (2-4).…”

Section: Discussionmentioning

confidence: 99%

Insulin-like growth factor-I induces cyclooxygenase-2 expression via PI3K, MAPK and PKC signaling pathways in human ovarian cancer cells☆

Cao

Liu

Dixon

et al. 2007

Cellular Signalling

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Elevated levels of insulin-like growth factor-I (IGF-I) are associated with ovarian carcinogenesis and progression. However, the molecular mechanisms by which IGF-I contributes to ovarian cancer development remain to be elucidated. Cyclooxygenase-2 (COX-2) is a crucial player in the pathogenesis of human malignancies. Herein we showed that IGF-I efficiently induced COX-2 expression and PGE 2 biosynthesis at physiologically relevant concentrations in human ovarian cancer cells. IGF-I treatment significantly increased COX-2 transcriptional activation. IGF-I also stabilized COX-2 mRNA through the COX-2 3′-untranslated region (3′-UTR), which appeared independent of the conserved AU-rich elements. We next investigated the signaling pathways involved in IGF-I-induced COX-2 expression. We found that PI3K inhibitor wortmannin or LY294002 blocked COX-2 expression induced by IGF-I. Wortmannin treatment or a dominant negative PI3K mutant significantly inhibited IGF-I-induced COX-2 mRNA stabilization, but only slightly decreased COX-2 transcriptional activation. We showed that ERK1/2 and p38 MAPKs were required for IGF-I-induced COX-2 expression and that activation of both pathways by IGF-I increased COX-2 transcriptional activation and its mRNA stability. IGF-I stimulated PKC activation in the cells and pretreatment with PKC inhibitor bisindolylmaleimide prevented IGF-I-induced COX-2 transcriptional activation and mRNA stabilization, and inhibited COX-2 mRNA and protein expression. Taken together, our data demonstrate that IGF-I induces COX-2 expression in human ovarian cancer cells, which is mediated by three parallel signaling cascades -PI3K, MAPK, and PKC pathways that differentially regulate COX-2 expression at transcriptional and posttranscriptional levels.

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Platelet-derived Growth Factor-BB and Thrombin Generate Positive and Negative Signals for Human Hepatic Stellate Cell Proliferation

Cited by 96 publications

References 40 publications

Nitrovasodilators inhibit platelet-derived growth factor-induced proliferation and migration of activated human hepatic stellate cells

Nitrovasodilators inhibit platelet-derived growth factor-induced proliferation and migration of activated human hepatic stellate cells

Antiproliferative Properties of Sphingosine 1-Phosphate in Human Hepatic Myofibroblasts

Insulin-like growth factor-I induces cyclooxygenase-2 expression via PI3K, MAPK and PKC signaling pathways in human ovarian cancer cells☆

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