title: Expression of Interferon Lambda 4 Is Associated with Reduced Proliferation and Increased Cell Death in Human Hepatic Cells.
abstract: Interferon lambda 4 (IFN-λ4) is a novel type-III interferon that can be generated only in individuals carrying a ΔG frame-shift allele of an exonic genetic variant (rs368234815-ΔG/TT). The rs368234815-ΔG allele is strongly associated with decreased clearance of hepatitis C virus (HCV) infection. Here, we further explored the biological function of IFN-λ4 expressed in human hepatic cells-a hepatoma cell line HepG2 and fresh primary human hepatocytes (PHHs). We performed live confocal imaging, cell death and proliferation assays, mRNA expression profiling, protein detection, and antibody blocking assays using transient and inducible stable in vitro systems. Not only did we observe significant intracellular retention of IFN-λ4 but also detected secreted IFN-λ4 in the culture media of expressing cells. Secreted IFN-λ4 induced strong activation of the interferon-stimulated genes (ISGs) in IFN-λ4-expressing and surrounding cells in transwell assays. Specifically, in PHHs, secreted IFN-λ4 induced expression of the CXCL10 transcript and a corresponding pro-inflammatory chemokine, IP-10. In IFN-λ4-expressing HepG2 cells, we also observed decreased proliferation and increased cell death. All IFN-λ4-induced phenotypes--activation of ISGs, decreased proliferation, and increased cell death--could be inhibited by an anti-IFN-λ4-specific antibody. Our study offers new insights into biology of IFN-λ4 and its possible role in HCV clearance.
authors.affiliation: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health , Bethesda, Maryland.
authors.forename: Olusegun O
authors.initials: OO
authors.lastname: Onabajo
authors.affiliation: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health , Bethesda, Maryland.
authors.forename: Patricia
authors.initials: P
authors.lastname: Porter-Gill
authors.affiliation: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health , Bethesda, Maryland.
authors.forename: Ashley
authors.initials: A
authors.lastname: Paquin
authors.affiliation: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health , Bethesda, Maryland.
authors.forename: Nina
authors.initials: N
authors.lastname: Rao
authors.affiliation: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health , Bethesda, Maryland.
authors.forename: Luyang
authors.initials: L
authors.lastname: Liu
authors.affiliation: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health , Bethesda, Maryland.
authors.forename: Wei
authors.initials: W
authors.lastname: Tang
authors.affiliation: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health , Bethesda, Maryland.
authors.forename: Nathan
authors.initials: N
authors.lastname: Brand
authors.affiliation: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health , Bethesda, Maryland.
authors.forename: Ludmila
authors.initials: L
authors.lastname: Prokunina-Olsson
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000276:immunology*; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology*; D054357:Chemokine CXCL10 / Q000096:biosynthesis; D056945:Hep G2 Cells; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000276:immunology*; D022781:Hepatocytes / Q000276:immunology* / Q000821:virology; D006801:Humans; D007378:Interleukins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D008113:Liver Neoplasms / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D018121:Receptors, Cytokine / Q000096:biosynthesis / Q000235:genetics; D017471:Receptors, Interferon; D000095022:Interferon Lambda
chemical_list: D000911:Antibodies, Monoclonal; D054357:Chemokine CXCL10; D007378:Interleukins; D034741:RNA, Small Interfering; D018121:Receptors, Cytokine; D017471:Receptors, Interferon; C114753:CXCL10 protein, human; C579163:IFNL4 protein, human; D000095022:Interferon Lambda; C579640:IFNLR1 protein, human; C104577:IP10-Mig receptor