title: Vitamin D receptor and Jak-STAT signaling crosstalk results in calcitriol-mediated increase of hepatocellular response to IFN-α.
abstract: Recent clinical research suggests a role for vitamin D in the response to IFN-α-based therapy of chronic hepatitis C. Therefore, we aimed to explore the underlying mechanisms in vitro. Huh-7.5 cells harboring subgenomic hepatitis C virus (HCV) replicons or infected with cell culture-derived HCV were exposed to bioactive 1,25-dihydroxyvitamin D3 (calcitriol) with or without IFN-α. In these experiments, calcitriol alone had no effect on the HCV life cycle. However, calcitriol enhanced the inhibitory effect of IFN-α on HCV replication. This effect was based on a calcitriol-mediated increase of IFN-α-induced gene expression. Further mechanistic studies revealed a constitutive inhibitory interaction between the inactive vitamin D receptor (VDR) and Stat1, which was released upon stimulation with calcitriol and IFN-α. As a consequence, IFN-α-induced binding of phosphorylated Stat1 to its DNA target sequences was enhanced by calcitriol. Importantly, and in line with these observations, silencing of the VDR resulted in an enhanced hepatocellular response to IFN-α. Our findings identify the VDR as a novel suppressor of IFN-α-induced signaling through the Jak-STAT pathway.
authors.affiliation: Division of Gastroenterology and Hepatology, Vaud University Hospital Center, University of Lausanne, CH-1011 Lausanne, Switzerland; Department of Medicine 1, J.W. Goethe University Hospital, D-60590 Frankfurt, Germany; and Christian.Lange@kgu.de Darius.Moradpour@chuv.ch.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Lange
authors.affiliation: Division of Gastroenterology and Hepatology, Vaud University Hospital Center, University of Lausanne, CH-1011 Lausanne, Switzerland;
authors.forename: Jérôme
authors.initials: J
authors.lastname: Gouttenoire
authors.affiliation: Department of Biomedicine, University Hospital Basel, CH-4031 Basel, Switzerland.
authors.forename: François H T
authors.initials: FH
authors.lastname: Duong
authors.affiliation: Division of Gastroenterology and Hepatology, Vaud University Hospital Center, University of Lausanne, CH-1011 Lausanne, Switzerland;
authors.forename: Kenichi
authors.initials: K
authors.lastname: Morikawa
authors.affiliation: Department of Biomedicine, University Hospital Basel, CH-4031 Basel, Switzerland.
authors.forename: Markus H
authors.initials: MH
authors.lastname: Heim
authors.affiliation: Division of Gastroenterology and Hepatology, Vaud University Hospital Center, University of Lausanne, CH-1011 Lausanne, Switzerland; Christian.Lange@kgu.de Darius.Moradpour@chuv.ch.
authors.forename: Darius
authors.initials: D
authors.lastname: Moradpour
mesh_terms: D002117:Calcitriol / Q000494:pharmacology; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D016174:Hepacivirus / Q000502:physiology*; D006526:Hepatitis C / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D053612:Janus Kinases / Q000235:genetics / Q000276:immunology*; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D018167:Receptors, Calcitriol / Q000235:genetics / Q000276:immunology*; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D014779:Virus Replication / Q000187:drug effects / Q000276:immunology*; D014815:Vitamins / Q000494:pharmacology
chemical_list: D016898:Interferon-alpha; D018167:Receptors, Calcitriol; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D014815:Vitamins; D053612:Janus Kinases; D002117:Calcitriol