title: HCV-infected cells and differentiation increase monocyte immunoregulatory galectin-9 production.
abstract: The lectin galectin-9 may help establish and maintain chronic hepatitis C virus infection. Galectin-9 is elevated in the liver and sera of hepatitis C virus patients, induces apoptosis of hepatitis C virus-specific T cells, and increases inhibitory regulatory T cells. Kupffer cells stain strongly for galectin-9 protein in hepatitis C virus patients. In the current study, we determined stimuli that induce galectin-9 production by monocytes and macrophages in hepatitis C virus infection. With the use of real-time PCR and flow cytometry, we analyzed galectin-9 mRNA and protein from human monocytes cocultured with hepatitis C virus-infected cells or noninfectious hepatitis C virus subgenomic replicon cells. We focused on finding the stimuli for galectin-9 production. Additionally, we measured galectin-9 during monocyte-to-macrophage maturation. Finally, we examined galectin-9 in peripheral monocytes from hepatitis C virus patients using flow cytometry. Galectin-9 mRNA increased 8-fold when primary monocytes were exposed to hepatitis C virus--infected cells. Maximum induction required proximity or contact and did not require IFN-γ or hepatitis C virus virions. Coculture of monocytes with subgenomic replicon cells increased galectin-9 5-fold, and purified exosomes from infected cells stimulated galectin-9 production. Stimulation of monocyte TLR3, -7, and -8 increased galectin-9 production. Differentiation of monocytes to macrophages increased galectin-9, and nonclassic monocytes from hepatitis C virus patients had the highest levels of galectin-9. Hepatitis C virus-infected cells stimulated monocytes to produce galectin-9 in close proximity, possibly, in part, as a result of exosomes and endosomal TLRs. Differentiation of monocytes to macrophages increased galectin-9. Nonclassic monocytes from hepatitis C virus patients express the highest galectin-9 levels, suggesting they may contribute to elevated galectin-9 and adaptive immune inhibition in hepatitis C virus infection.
authors.affiliation: Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Denver VA Medical Center, Denver, Colorado, USA.
authors.forename: Noah M K
authors.initials: NM
authors.lastname: Harwood
authors.affiliation: Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Denver VA Medical Center, Denver, Colorado, USA.
authors.forename: Lucy
authors.initials: L
authors.lastname: Golden-Mason
authors.affiliation: Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Denver VA Medical Center, Denver, Colorado, USA.
authors.forename: Linling
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Denver VA Medical Center, Denver, Colorado, USA.
authors.forename: Hugo R
authors.initials: HR
authors.lastname: Rosen
authors.affiliation: Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Denver VA Medical Center, Denver, Colorado, USA andy.mengshol@ucdenver.edu.
authors.forename: John A
authors.initials: JA
authors.lastname: Mengshol
mesh_terms: D002450:Cell Communication; D002454:Cell Differentiation; D002478:Cells, Cultured; D055354:Exosomes; D037161:Galectins / Q000096:biosynthesis* / Q000235:genetics; D006526:Hepatitis C / Q000276:immunology*; D022781:Hepatocytes / Q000821:virology; D006801:Humans; D008264:Macrophages / Q000166:cytology; D009000:Monocytes / Q000166:cytology / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D051193:Toll-Like Receptors / Q000502:physiology
chemical_list: D037161:Galectins; C105032:LGALS9 protein, human; D012333:RNA, Messenger; D051193:Toll-Like Receptors
keywords: JFH-1; exosome; non-classical monocyte