title: CD14+monocyte-derived galectin-9 induces natural killer cell cytotoxicity in chronic hepatitis C.
abstract: Natural killer (NK) cell activation is associated with both liver injury and persistent infection in chronic hepatitis C (CHC); however, the detailed mechanism of this activation has not yet been fully elucidated. Because galectin-9 (Gal-9) has been reported to be increased in the serum and liver tissue of CHC patients, we investigated the function of Gal-9 in NK cell activation in CHC. First, we evaluated the function of Gal-9 on NK cytotoxicity in vitro. Gal-9 treatment resulted in increased cytotoxicity of naïve NK cells, and the Gal-9-activated NK cells demonstrated cytotoxicity toward hepatoma cells and T cells. Additionally, coculturing peripheral blood mononuclear cells (PBMCs) with JFH-1/Huh7.5.1 cells increased both Gal-9 production and NK cell cytotoxicity. Next, we investigated the source of Gal-9 and the mechanism of Gal-9 production. Deletion of CD14+monocytes from PBMCs resulted in reduced Gal-9 production in the coculture with JFH-1/Huh7.5.1 cells. Gal-9 production was driven by coculturing of PBMCs with apoptotic hepatocytes. Blocking integrin αvβ3, a receptor for phosphatidylserine expressed on apoptotic cells, also resulted in decreased Gal-9 production. Finally, we found that serum Gal-9 levels were significantly higher in CHC patients than in healthy donors and patients who achieved sustained virologic response. Among CHC patients, serum Gal-9 levels were significantly higher in patients with elevated alanine aminotransferase (ALT) than in those with normal ALT.
  
  
  
  These results demonstrate that CD14+monocyte-derived Gal-9 increases NK cell cytotoxicity in HCV infection, which might be associated with liver injury and persistent infection. (Hepatology 2017;65:18-31).
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Nishio
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tatsumi
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Nawa
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Suda
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Teppei
authors.initials: T
authors.lastname: Yoshioka
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Onishi
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Aono
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Shigekawa
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Hayato
authors.identifier: 0000-0003-2488-7315
authors.initials: H
authors.lastname: Hikita
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Ryotaro
authors.initials: R
authors.lastname: Sakamori
authors.affiliation: Department of DNA-Chip Developmental Center for Infectious Diseases, Osaka University, Suita, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Okuzaki
authors.affiliation: Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Suita, Japan.
authors.forename: Takasuke
authors.initials: T
authors.lastname: Fukuhara
authors.affiliation: Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Suita, Japan.
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Matsuura
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Hiramatsu
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Takehara
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000920:Antibody-Dependent Cell Cytotoxicity; D005260:Female; D037161:Galectins / Q000502:physiology*; D019698:Hepatitis C, Chronic / Q000276:immunology*; D006801:Humans; D007694:Killer Cells, Natural / Q000502:physiology*; D018950:Lipopolysaccharide Receptors; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology*
chemical_list: D037161:Galectins; C105032:LGALS9 protein, human; D018950:Lipopolysaccharide Receptors