title: Analysis of the transcriptome and immune function of monocytes during IFNα-based therapy in chronic HCV revealed induction of TLR7 responsiveness.
abstract: Although in vitro studies have been performed to dissect the mechanism of action of IFNα, detailed in vivo studies on the long-term effects of IFNα on monocytes have not been performed. Here we examined peripheral blood from 14 chronic HCV patients at baseline and 12 weeks after start of IFNα-based therapy. Monocytes were phenotyped by flow-cytometry and their function evaluated upon TLR stimulation and assessed by multiplex cytokine assays. During therapy of HCV patients, monocytes displayed a hyperactive state as evidenced by increased TLR-induced pro-inflammatory cytokine levels, as well as enhanced CD69 and CD83 mRNA and protein expression. Moreover, monocytes from 8 patients at baseline and 12 weeks after start of IFNα-based therapy were transcriptomically profiled by high throughput RNA-sequencing. Detailed RNA-seq analysis of monocytes showed significant ISG mRNA induction during therapy. Importantly, IFNα-based therapy activated TLR7 signaling pathways, as demonstrated by up-regulated expression of TLR7, MyD88, and IRF7 mRNA, whereas other TLR family members as well as CD1c, CLEC4C, and CLEC9A were not induced. The induction of TLR7 responsiveness of monocytes by IFNα in vivo in HCV patients is relevant for the development of TLR7 agonists that are currently under development as a promising immunotherapeutic compounds to treat chronic viral hepatitis.
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, The Netherlands.
authors.forename: Jun
authors.initials: J
authors.lastname: Hou
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, The Netherlands.
authors.forename: Zwier M A
authors.initials: ZM
authors.lastname: Groothuismink
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, The Netherlands.
authors.forename: Ludi
authors.initials: L
authors.lastname: Koning
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, The Netherlands.
authors.forename: Robert
authors.initials: R
authors.lastname: Roomer
authors.affiliation: Center for Biomics, Erasmus MC, University Medical Center Rotterdam, The Netherlands.
authors.forename: Wilfred F J
authors.initials: WF
authors.lastname: van IJcken
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, The Netherlands.
authors.forename: Kim
authors.initials: K
authors.lastname: Kreefft
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, The Netherlands.
authors.forename: Bi-Sheng
authors.initials: BS
authors.lastname: Liu
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, The Netherlands; Liver Clinic University Health Network, Division of Gastroenterology, University of Toronto, Canada.
authors.forename: Harry L A
authors.initials: HL
authors.lastname: Janssen
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, The Netherlands.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: de Knegt
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, The Netherlands. Electronic address: p.a.boonstra@erasmusmc.nl.
authors.forename: Andre
authors.initials: A
authors.lastname: Boonstra
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage*; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D005260:Female; D016174:Hepacivirus / Q000187:drug effects / Q000502:physiology; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000235:genetics* / Q000276:immunology; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000276:immunology*; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000276:immunology*; D059467:Transcriptome / Q000187:drug effects*; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D016207:Cytokines; D016898:Interferon-alpha; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7
keywords: Gene expression; Interferon; Monocytes; TLR7; Viral hepatitis