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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 \u03b1-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\u2032 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.<\/jats:p>","DOI":"10.1152\/ajpgi.00208.2007","type":"journal-article","created":{"date-parts":[[2008,1,18]],"date-time":"2008-01-18T01:35:02Z","timestamp":1200620102000},"page":"G748-G756","source":"Crossref","is-referenced-by-count":26,"title":["IL-6 downregulates transcription of NTPDase2 via specific promoter elements"],"prefix":"10.1152","volume":"294","author":[{"given":"Jin","family":"Yu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c9lise G.","family":"Lavoie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Sheung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacques J.","family":"Tremblay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean","family":"S\u00e9vigny","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan A.","family":"Dranoff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"R1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.58.3.3"},{"key":"R2","doi-asserted-by":"publisher","DOI":"10.1067\/mlc.2000.108151"},{"key":"R3","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.1994.266.5.G922"},{"key":"R4","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcmd.2005.12.025"},{"key":"R5","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.1995.0582"},{"key":"R6","doi-asserted-by":"publisher","DOI":"10.1046\/j.1460-9568.2003.02567.x"},{"key":"R7","doi-asserted-by":"publisher","DOI":"10.1002\/glia.10309"},{"key":"R8","doi-asserted-by":"publisher","DOI":"10.1002\/9780470032244.ch4"},{"key":"R9","unstructured":"Chapdelaine P, Delahaye S, Gauthier E, Tremblay RR, Dube JY.A one-hour procedure for the preparation of genomic DNA from frozen tissues.Biotechniques14: 163\u2013164, 1993."},{"key":"R10","doi-asserted-by":"publisher","DOI":"10.1136\/jim-52-07-42"},{"key":"R11","doi-asserted-by":"publisher","DOI":"10.1053\/jhep.2002.36823"},{"key":"R12","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.2001.281.4.G1059"},{"key":"R13","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00294.2003"},{"key":"R14","doi-asserted-by":"publisher","DOI":"10.1038\/12447"},{"key":"R15","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00293.2006"},{"key":"R16","doi-asserted-by":"publisher","DOI":"10.1016\/0300-9084(91)90073-A"},{"key":"R17","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.25.15358"},{"key":"R18","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-006-0070-9"},{"key":"R19","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.12.5.2282"},{"key":"R20","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.14.1.116"},{"key":"R21","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M412371200"},{"key":"R22","doi-asserted-by":"crossref","unstructured":"Kershenobich Stalnikowitz D, Weissbrod AB.Liver fibrosis and inflammation. 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