PMID: identifiant
de la référence Pubmed : |
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 (22120177)  |
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| titre : |
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Stimulating healthy tissue regeneration by targeting the 5-HT₂B receptor in chronic liver disease. |
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| auteur(s) : |
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Mohammad Ebrahimkhani1, Fiona Oakley2, Lindsay Murphy2, Jelena Mann2, Anna Moles2, Maria Perugorria2, Elizabeth Ellis2, Anne Lakey2, Alastair Burt2, Angela Douglass2, Matthew Wright2, Steven White2, Fabrice Jaffré3, Luc Maroteaux3, Derek Mann ( ) 2 |
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| laboratoire : |
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| résumé : |
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Tissue homeostasis requires an effective, limited wound-healing response to injury. In chronic disease, failure to regenerate parenchymal tissue leads to the replacement of lost cellular mass with a fibrotic matrix. The mechanisms that dictate the balance of cell regeneration and fibrogenesis are not well understood. Here we report that fibrogenic hepatic stellate cells (HSCs) in the liver are negative regulators of hepatocyte regeneration. This negative regulatory function requires stimulation of the 5-hydroxytryptamine 2B receptor (5-HT(2B)) on HSCs by serotonin, which activates expression of transforming growth factor β1 (TGF-β1), a powerful suppressor of hepatocyte proliferation, through signaling by mitogen-activated protein kinase 1 (ERK) and the transcription factor JunD. Selective antagonism of 5-HT(2B) enhanced hepatocyte growth in models of acute and chronic liver injury. We also observed similar effects in mice lacking 5-HT(2B) or JunD or upon selective depletion of HSCs in wild-type mice. Antagonism of 5-HT(2B) attenuated fibrogenesis and improved liver function in disease models in which fibrosis was pre-established and progressive. Pharmacological targeting of 5-HT(2B) is clinically safe in humans and may be therapeutic in chronic liver disease. |
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| domaine : |
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Sciences du Vivant/Biochimie, Biologie Moléculaire
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langue du texte
intégral : |
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Anglais |
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| ISSN : |
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1546-170X |
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| type de publication : |
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Articles dans des revues avec comité de lecture |
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| DOI : |
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10.1038/nm.2490 |
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| journal : |
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Nat Med |
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| Audience : |
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internationale |
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| date de publication : |
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12/2011 |
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date de publication
électronique : |
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27/11/2011 |
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| volume : |
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17 |
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| numéro : |
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12 |
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| page, identifiant, ... : |
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1668-73 |
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| Descripteur(s) MeSH : |
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Animals – Cell Proliferation – Cells – Cultured – Chronic Disease – Electrophoresis – Polyacrylamide Gel – Hepatic Stellate Cells – Hepatocytes – Immunohistochemistry – Indoles – Liver Cirrhosis – Male – Mice – Inbred C57BL – Knockout – Mitogen-Activated Protein Kinase 1 – Proto-Oncogene Proteins c-jun – Rats – Sprague-Dawley – Receptor – Serotonin – 5-HT2B – Serotonin 5-HT2 Receptor Antagonists – Signal Transduction – Transforming Growth Factor beta1 – Urea – Wound Healing |
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| contrat, financement : |
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This work was funded by grants from the UK MRC (grant number G0700890 to DAM, MCW and FO), UK MRC (grant number G0900535 to FO), the Wellcome Trust (grant number WT084961MA to FO, DAM and MCW, and grant WT086755MA to MCW, ADB and DAM). Work in the lab of DAM is also funded by a European Commission FP7 program grant 'INFLACARE' (EC Contract No. 223151; http://InflaCare.forth.gr). L. Maroteaux's work has been supported by the Centre National de la Recherche Scientifique, the Institut National de la Santé et de la Recherche Médicale, the Université Pierre et Marie Curie, and by grants from the Fondation de France, the Fondation pour la Recherche Médicale, the French ministry of research (Agence Nationale pour la Recherche), and the European Commission (DEVANX). |
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| Projet Européen : |
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| Numéro Cordis |
201714 |
| Acronyme |
DEVANX |
| Titre |
Serotonin and GABA-B receptors in anxiety : from developmental risk factors to treatment. |
| Financé par |
HEALTH |
| Début |
2008-02-01 |
| Date de fin |
2012-07-31 |
| Identifiant de l'appel |
FP7-HEALTH-2007-A |
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