title: Lipopolysaccharide and Tumor Necrosis Factor Alpha Inhibit Interferon Signaling in Hepatocytes by Increasing Ubiquitin-Like Protease 18 (USP18) Expression.
abstract: Inflammation may be maladaptive to the control of viral infection when it impairs interferon (IFN) responses, enhancing viral replication and spread. Dysregulated immunity as a result of inappropriate innate inflammatory responses is a hallmark of chronic viral infections such as, hepatitis B virus and hepatitis C virus (HCV). Previous studies from our laboratory have shown that expression of an IFN-stimulated gene (ISG), ubiquitin-like protease (USP)18 is upregulated in chronic HCV infection, leading to impaired hepatocyte responses to IFN-α. We examined the ability of inflammatory stimuli, including tumor necrosis factor alpha (TNF-α), lipopolysaccharide (LPS), interleukin-6 (IL-6) and IL-10 to upregulate hepatocyte USP18 expression and blunt the IFN-α response. Human hepatoma cells and primary murine hepatocytes were treated with TNF-α/LPS/IL-6/IL-10 and USP18, phosphorylated (p)-STAT1 and myxovirus (influenza virus) resistance 1 (Mx1) expression was determined. Treatment of Huh7.5 cells and primary murine hepatocytes with LPS and TNF-α, but not IL-6 or IL-10, led to upregulated USP18 expression and induced an IFN-α refractory state, which was reversed by USP18 knockdown. Liver inflammation was induced in vivo using a murine model of hepatic ischemia/reperfusion injury. Hepatic ischemia/reperfusion injury led to an induction of USP18 expression in liver tissue and promotion of lymphocytic choriomeningitis replication. These data demonstrate that certain inflammatory stimuli (TNF-α and LPS) but not others (IL-6 and IL-10) target USP18 expression and thus inhibit IFN signaling. These findings represent a new paradigm for how inflammation alters hepatic innate immune responses, with USP18 representing a potential target for intervention in various inflammatory states.
  
  
  
  Inflammation may prevent the control of viral infection when it impairs the innate immune response, enhancing viral replication and spread. Blunted immunity as a result of inappropriate innate inflammatory responses is a common characteristic of chronic viral infections. Previous studies have shown that expression of certain interferon-stimulated genes is upregulated in chronic HCV infection, leading to impaired hepatocyte responses. In this study, we show that multiple inflammatory stimuli can modulate interferon stimulated gene expression and thus inhibit hepatocyte interferon signaling via USP18 induction. These findings represent a new paradigm for how inflammation alters hepatic innate immune responses, with the induction of USP18 representing a potential target for intervention in various inflammatory states.
authors.affiliation: Multi-Organ Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Sonya A
authors.initials: SA
authors.lastname: MacParland
authors.affiliation: Multi-Organ Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Xue-Zhong
authors.initials: XZ
authors.lastname: Ma
authors.affiliation: Multi-Organ Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada.|Institute of Blood Transfusion, Chinese Academy of Medical Science, Chengdu, China.
authors.forename: Limin
authors.initials: L
authors.lastname: Chen
authors.affiliation: Multi-Organ Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Ramzi
authors.initials: R
authors.lastname: Khattar
authors.affiliation: Toronto Centre for Liver Disease, McLaughlin-Rotman Centre for Global Health, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Vera
authors.initials: V
authors.lastname: Cherepanov
authors.affiliation: Multi-Organ Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Markus
authors.initials: M
authors.lastname: Selzner
authors.affiliation: Toronto Centre for Liver Disease, McLaughlin-Rotman Centre for Global Health, University of Toronto, Toronto, Ontario, Canada.|Toronto Western Hospital, Toronto, Ontario, Canada.
authors.forename: Jordan J
authors.initials: JJ
authors.lastname: Feld
authors.affiliation: Multi-Organ Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Nazia
authors.initials: N
authors.lastname: Selzner
authors.affiliation: Multi-Organ Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada ian.mcgilvray@uhn.on.ca.
authors.forename: Ian D
authors.initials: ID
authors.lastname: McGilvray
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D010450:Endopeptidases / Q000235:genetics* / Q000378:metabolism; D016174:Hepacivirus / Q000502:physiology; D019698:Hepatitis C, Chronic / Q000276:immunology; D022781:Hepatocytes / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000821:virology; D016898:Interferon-alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016753:Interleukin-10 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D007511:Ischemia / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000098:blood supply / Q000276:immunology* / Q000293:injuries / Q000473:pathology; D051379:Mice; D064547:Myxovirus Resistance Proteins / Q000235:genetics / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D043222:Ubiquitin Thiolesterase / Q000235:genetics* / Q000378:metabolism
chemical_list: C508609:IL10 protein, human; C508600:IL6 protein, human; D016898:Interferon-alpha; D015850:Interleukin-6; D008070:Lipopolysaccharides; D064547:Myxovirus Resistance Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D010450:Endopeptidases; C118306:Usp18 protein, mouse; C485560:USP18 protein, human; D043222:Ubiquitin Thiolesterase