Role of NF-kappaB in the antiproliferative effect of endothelin-1 and tumor necrosis factor-alpha in human hepatic stellate cells. Involvement of cyclooxygenase-2.
During chronic liver diseases, hepatic stellate cells (HSC) acquire an activated myofibroblast-like phenotype and proliferate and synthesize fibrosis components. Endothelin-1 (ET-1), which inhibited the growth of human myofibroblastic HSC, increased the formation of two NF-kappaB DNA binding complexes; this effect was also observed with tumor necrosis factor-alpha (TNF-alpha). The complexes were identified as the p50/p50 and p50/p65 NF-kappaB dimers. Activation of NF-kappaB was associated with the degradation of the inhibitory protein IkappaB-alpha; no IkappaB-beta was detected. Activation of NF-kappaB and degradation of IkappaB-alpha were prevented by the NF-kappaB inhibitors sodium salicylate and MG-132. In addition to cyclooxygenase-1 (COX-1), COX-2 is also constitutively expressed in human HSC, and the use of dexamethasone and of SC-58125, a selective COX-2 inhibitor, revealed that COX-2 accounts for basal COX activity. Moreover, COX-2 mRNA and protein were up-regulated by ET-1 and TNF-alpha, whereas COX-1 was unaffected. Induction of COX-2 and stimulation of COX activity by ET-1 and TNF-alpha were prevented by sodium salicylate and MG-132, suggesting that activation of NF-kappaB by either factor is needed for stimulation of COX-2. Finally, SC-58125 and dexamethasone reduced the growth inhibitory effect of ET-1 and TNF-alpha, indicating that activation of COX-2 is required for inhibition of HSC proliferation. Taken together, our results suggest that NF-kappaB, by inducing COX-2 expression, may play an important role in the negative regulation of human myofibroblastic HSC proliferation.
Unité INSERM 99, Hôpital Henri Mondor, 94010 Créteil, 75010 Paris, France.
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Gallois
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Habib
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Tao
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Moulin
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Maclouf
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Mallat
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Lotersztajn
D017667:Adipocytes / Q000187:drug effects*; D000970:Antineoplastic Agents / Q000494:pharmacology; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D019281:Dimerization; D019332:Endothelin-1 / Q000494:pharmacology*; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D020672:I-kappa B Proteins; D007527:Isoenzymes / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology; D008099:Liver / Q000166:cytology*; D008565:Membrane Proteins; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000819:agonists; D012980:Sodium Salicylate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation; D014757:Viper Venoms / Q000494:pharmacology
D000970:Antineoplastic Agents; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004268:DNA-Binding Proteins; D019332:Endothelin-1; D020672:I-kappa B Proteins; D007527:Isoenzymes; D007976:Leupeptins; D008565:Membrane Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D011720:Pyrazoles; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D014409:Tumor Necrosis Factor-alpha; D014757:Viper Venoms; C057354:sarafotoxins s6; D000072000:NF-KappaB Inhibitor alpha; C090859:1-((4-methylsulfonyl)phenyl)-3-trifluoromethyl-5-(4-fluorophenyl)pyrazole; D003907:Dexamethasone; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D012980:Sodium Salicylate