{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T03:41:48Z","timestamp":1793850108494,"version":"4.6.1"},"reference-count":56,"publisher":"American Society for Microbiology","issue":"12","license":[{"start":{"date-parts":[[2016,5,27]],"date-time":"2016-05-27T00:00:00Z","timestamp":1464307200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2016,6,15]],"date-time":"2016-06-15T00:00:00Z","timestamp":1465948800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2016,6,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>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-\u03b1. We examined the ability of inflammatory stimuli, including tumor necrosis factor alpha (TNF-\u03b1), lipopolysaccharide (LPS), interleukin-6 (IL-6) and IL-10 to upregulate hepatocyte USP18 expression and blunt the IFN-\u03b1 response. Human hepatoma cells and primary murine hepatocytes were treated with TNF-\u03b1\/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-\u03b1, but not IL-6 or IL-10, led to upregulated USP18 expression and induced an IFN-\u03b1 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-\u03b1 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.<\/jats:p><jats:p><jats:bold>IMPORTANCE<\/jats:bold>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.<\/jats:p>","DOI":"10.1128\/jvi.02557-15","type":"journal-article","created":{"date-parts":[[2016,3,24]],"date-time":"2016-03-24T03:34:38Z","timestamp":1458790478000},"page":"5549-5560","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":32,"title":["Lipopolysaccharide and Tumor Necrosis Factor Alpha Inhibit Interferon Signaling in Hepatocytes by Increasing Ubiquitin-Like Protease 18 (USP18) Expression"],"prefix":"10.1128","volume":"90","author":[{"given":"Sonya A.","family":"MacParland","sequence":"first","affiliation":[{"name":"Multi-Organ Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue-Zhong","family":"Ma","sequence":"additional","affiliation":[{"name":"Multi-Organ Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Limin","family":"Chen","sequence":"additional","affiliation":[{"name":"Multi-Organ Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada"},{"name":"Institute of Blood Transfusion, Chinese Academy of Medical Science, Chengdu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramzi","family":"Khattar","sequence":"additional","affiliation":[{"name":"Multi-Organ Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vera","family":"Cherepanov","sequence":"additional","affiliation":[{"name":"Toronto Centre for Liver Disease, McLaughlin-Rotman Centre for Global Health, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Selzner","sequence":"additional","affiliation":[{"name":"Multi-Organ Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordan J.","family":"Feld","sequence":"additional","affiliation":[{"name":"Toronto Centre for Liver Disease, McLaughlin-Rotman Centre for Global Health, University of Toronto, Toronto, Ontario, Canada"},{"name":"Toronto Western Hospital, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nazia","family":"Selzner","sequence":"additional","affiliation":[{"name":"Multi-Organ Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian D.","family":"McGilvray","sequence":"additional","affiliation":[{"name":"Multi-Organ Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature04082"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2007.06.001"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00974-13"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.510230203"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2004.11.025"},{"key":"e_1_3_2_7_2","first-page":"1944","article-title":"Safety of anti-tumor necrosis factor-alpha therapy in patients with rheumatoid arthritis and chronic hepatitis C virus infection","volume":"35","author":"Ferri C","year":"2008","unstructured":"Ferri C, Ferraccioli G, Ferrari D, Galeazzi M, Lapadula G, Montecucco C, Triolo G, Valentini G, Valesini G, The GISEA Group. 2008. 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