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Immunol."],"abstract":"<jats:p><jats:italic>IFNL3\/IFNL4<\/jats:italic> polymorphisms are inversely associated with the risk of chronic hepatitis C virus (HCV) infection and cirrhosis, two major risk factors for developing hepatocellular carcinoma (HCC). To further explore these inverse associations and their molecular underpinnings, we analyzed <jats:italic>IFNL3\/IFNL4<\/jats:italic> polymorphisms represented by the <jats:italic>IFNL4<\/jats:italic> genotype (presence of rs368234815-dG or rs12979860-T alleles) in HCV patients: 2969 from Japan and 2931 from Taiwan. <jats:italic>IFNL4<\/jats:italic> genotype was associated with an increased risk of HCV-related HCC (OR=1.28, 95%CI=1.07-1.52, P=0.0058) in the general population of Japanese patients, but not in Taiwanese patients who achieved treatment-induced viral clearance. <jats:italic>IFNL4<\/jats:italic> genotype was also associated with a decreased risk of cirrhosis (OR=0.66, 95%CI=0.46-0.93, P=0.018, in Taiwanese patients). We then engineered HepG2 cells to inducibly express IFN-\u03bb4 in the presence or absence of interferon lambda receptor 1 (IFNLR1). Induction of IFN-\u03bb4 resulted in its intracellular accumulation, mainly in lysosomes and late endosomes, and increased ER stress, leading to apoptosis and reduced proliferation. We identified the very-low-density lipoprotein receptor (<jats:italic>VLDLR<\/jats:italic>), which facilitates HCV entry into hepatocytes, as a transcript induced by IFN-\u03bb4 but not IFN-\u03bb3. Our results suggest that the molecular mechanisms underlying the anti-cirrhotic but pro-HCV associations observed for <jats:italic>IFNL3\/IFNL4<\/jats:italic> polymorphisms are, at least in part, contributed by intracellular accumulation of IFN-\u03bb4 causing ER stress in hepatic cells.<\/jats:p>","DOI":"10.3389\/fimmu.2021.692263","type":"journal-article","created":{"date-parts":[[2021,8,23]],"date-time":"2021-08-23T08:06:07Z","timestamp":1629705967000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Intracellular Accumulation of IFN-\u03bb4 Induces ER Stress and Results in Anti-Cirrhotic but Pro-HCV Effects"],"prefix":"10.3389","volume":"12","author":[{"given":"Olusegun O.","family":"Onabajo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei-Hsuan","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oscar","family":"Florez-Vargas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adeola","family":"Obajemu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chizu","family":"Tanikawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joselin M.","family":"Vargas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu-Fen","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ci","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Han","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen-Yang","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. 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