Role of NF-κB in the Antiproliferative Effect of Endothelin-1 and Tumor Necrosis Factor-α in Human Hepatic Stellate Cells

Gallois, Cyrille; Habib, Aı̈da; Tao, Jiangchuan; Moulin, Stéphanie; Maclouf, Jacques; Mallat, Ariane; Lotersztajn, Sophie

doi:10.1074/jbc.273.36.23183

Cited by 155 publications

(133 citation statements)

References 59 publications

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“…It should be noted that NS-398 decreased basal PGE 2 production, in agreement with our previous data showing that COX-2 is constitutively expressed in hMF (see Fig. 5A) and accounts for basal PGE 2 production in these cells (6). Therefore, these results demonstrate that S1P stimulates an early COX-2-dependent production of PGE 2 , leading to cAMP synthesis.…”

Section: Cox-2 Mediates the Growth Inhibitory Effects Of Sphingosine supporting

confidence: 81%

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Antiproliferative Properties of Sphingosine 1-Phosphate in Human Hepatic Myofibroblasts

Davaille¹,

Gallois²,

Habib³

et al. 2000

Journal of Biological Chemistry

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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: Cox-2 Mediates the Growth Inhibitory Effects Of Sphingosine supporting

confidence: 81%

“…Whole cell extracts were prepared, and Western blotting analysis was performed as described previously (6).…”

Section: Methodsmentioning

confidence: 99%

Antiproliferative Properties of Sphingosine 1-Phosphate in Human Hepatic Myofibroblasts

Davaille¹,

Gallois²,

Habib³

et al. 2000

Journal of Biological Chemistry

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114

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“…Most studies of liver fibrosis reported until now have considered that activated HSC was the principal fibrogenic cell type contributing to ECM accumulation. 58 However, other cell types such as portal fibroblasts may, after activation, acquire fibrogenic potential. 59,60 In our study, a heterogeneous population of hIHFs was isolated from human livers using collagenase perfusion, because most (but not all) of these cells store vitamin A in the same way as stellate cells, when quiescent.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-4 induces the activation and collagen production of cultured human intrahepatic fibroblasts via the STAT-6 pathway

Aoudjehane

Pissaia

Scatton

et al. 2008

Laboratory Investigation

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Interleukin-4 (IL-4) is overexpressed in liver grafts in a context of severe recurrent hepatitis C, during which the development of fibrosis is dramatically accelerated. In this study, we examined the effects of IL-4 on the activation and collagen production of cultured human intrahepatic (myo)fibroblasts (hIHFs), and investigated the underlying mechanisms. The myofibroblastic nature of cells was evaluated morphologically using activation markers (smooth muscle a-actin, vimentin and prolyl 4-hydroxylase). Quiescent hIHFs were obtained by cell incubation in serum-free medium or cell culture on Matrigel. We first analyzed IL-4 receptor expression, STAT-6 activation by IL-4, and STAT-6 inhibition by an anti-IL-4 antibody or by STAT-6 small-interfering RNA (siRNA) transfection. We then focused on collagen production, using quantitative real-time PCR to analyze the effect of IL-4 on the mRNA expression of collagens I, III and IV, and on collagen levels in supernatants of hIHFs, using the Sircol collagen assay. hIHFs cultured in plastic wells appeared to be morphologically activated. The expression of activation markers was reduced by serum deprivation or culture on Matrigel, and restored by IL-4 incubation. The IL-4 receptor was expressed by hIHFs, and STAT-6 was activated following incubation with IL-4. Both anti-IL-4 antibody and STAT-6 siRNA transfection inhibited this activation. The treatment of hIHFs with IL-4 increased the mRNA expression of collagens I, III and IV (Po0.05) and elevated collagen levels in supernatants (P ¼ 0.01 vs untreated cells). Therefore, IL-4 exerts profibrotic effects by activating hIHFs and inducing collagen production and secretion. This effect requires IL4-R binding and STAT-6 activation. IL-4 may thus be involved in accelerated course of fibrogenesis during recurrent hepatitis C.

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“…Glucocorticoids are one class of agents that sometimes, but not always, inhibits myofibroblast formation and proliferation (32,33), perhaps by blockade of TGF-␤ production (34). Other therapies to blunt fibrosis are under study, but none has been shown to be efficacious and nontoxic (35).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of cardiac myofibroblast formation and collagen synthesis by activation and overexpression of adenylyl cyclase

Swaney

Roth

Olson

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

192

179

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Transformation of fibroblasts to myofibroblasts, characterized by expression of ␣-smooth muscle actin (␣-SMA) and production of extracellular matrix (ECM) components, is a key event in connective tissue remodeling. Approaches to inhibit this transformation are needed in tissues, such as the heart, where excessive ECM production by cardiac fibroblasts (CFs) causes fibrosis, myocardial stiffening, and cardiac dysfunction. We tested whether adenylyl cyclase (AC) activation (increased cAMP levels) modulates the transformation of adult rat CF to myofibroblasts, as assessed by immunofluorescent microscopy, immunoblotting, and collagen synthesis. A 24-h incubation of CF with TGF-␤ or angiotensin II increased ␣-SMA expression, which was inhibited by the AC agonist forskolin and a cAMP analog that activates protein kinase A. Treatment with forskolin blunted serum-, TGF-␤-, and angiotensin II-stimulated collagen synthesis. CFs engineered to overexpress type 6 AC had enhanced forskolin-promoted cAMP formation, greater inhibition by forskolin of TGF-␤-stimulated ␣-SMA expression, and a decrease in the EC 50 of forskolin to reduce serum-stimulated collagen synthesis. The AC stimulatory agonist adrenomedullin inhibited collagen synthesis in CF that overexpressed AC6 but not in controls. Thus, AC stimulation blunts collagen synthesis and, in parallel, the transformation of adult rat CF to myofibroblasts. AC overexpression enhances these effects, ''uncovering'' an inhibition by adrenomedullin. These findings implicate cAMP as an inhibitor of ECM formation by means of blockade of the transformation of CF to myofibroblasts and suggest that increasing AC expression, thereby enhancing cAMP generation through stimulation of receptors expressed on CF, could provide a means to attenuate and prevent cardiac fibrosis and its sequelae.cardiac fibroblast ͉ cyclic AMP ͉ extracellular matrix ͉ fibrosis ͉ heart failure

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Role of NF-κB in the Antiproliferative Effect of Endothelin-1 and Tumor Necrosis Factor-α in Human Hepatic Stellate Cells

Cited by 155 publications

References 59 publications

Antiproliferative Properties of Sphingosine 1-Phosphate in Human Hepatic Myofibroblasts

Antiproliferative Properties of Sphingosine 1-Phosphate in Human Hepatic Myofibroblasts

Interleukin-4 induces the activation and collagen production of cultured human intrahepatic fibroblasts via the STAT-6 pathway

Inhibition of cardiac myofibroblast formation and collagen synthesis by activation and overexpression of adenylyl cyclase

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