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This Article Full Text Full Text (PDF) All Versions of this Article: 294/3/G748    most recent 00208.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Yu, J. Articles by Dranoff, J. A. PubMed PubMed Citation Articles by Yu, J. Articles by Dranoff, J. A.

LIVER AND BILIARY TRACT

IL-6 downregulates transcription of NTPDase2 via specific promoter elements

¹Yale University School of Medicine and Yale Liver Center, New Haven, Connecticut; ²Centre de Recherche en Rhumatologie et Immunologie and ³Ontogeny-Reproduction Research Unit, Centre Hospitalier Universitaire de Québec, Université Laval, Quebec, Quebec, Canada

Submitted 8 May 2007 ; accepted in final form 9 January 2008

Bile ductular proliferation is markedly upregulated in biliary fibrosis and cirrhosis. However, the mechanisms regulating this upregulation in bile ductular proliferation have not been defined. Recently, we demonstrated that expression of the ectonucleotidase nucleoside triphosphate diphosphohydrolase-2 (NTPDase2/Entpd2) by portal fibroblasts (PF) is a critical regulator of bile ductular proliferation. Since interleukin 6 (IL-6) is markedly upregulated in biliary cirrhosis, our aims were to determine the role and mechanism of IL-6 in the regulation of NTPDase2 by PF. We found that IL-6 downregulated NTPDase2 protein expression in a concentration-dependent and time-dependent fashion but did not alter PF -smooth muscle actin expression. IL-6 markedly downregulated NTPDase2 mRNA expression. Expression of the IL-6 receptor gp130 but not the IL-6 receptor gp80 was detected in PF. Two transcription start sites were identified in rat Entpd2 by the method of RNA ligase-mediated rapid amplification of 5' cDNA ends. The minimal promoter construct, but not shorter constructs, was downregulated by IL-6. Three putative IL-6 response elements were identified in silico and mutated. Mutation of all three response elements, but not fewer elements, completely abolished the IL-6 response. Thus IL-6 transcriptionally downregulates NTPDase2 expression by PF via actions at specific promoter elements independently of myofibroblastic differentiation. This effect may represent a novel signaling pathway by which bile ductular proliferation is dysregulated in biliary cirrhosis and thus provides a potential therapeutic approach for the regulation of bile ductular growth.

bile duct epithelia; ecto-adenosine triphosphatase; P2Y; biliary cirrhosis; interleukin-6; nucleoside triphosphate diphosphohydrolase-2