{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T02:53:22Z","timestamp":1783133602720,"version":"3.54.6"},"reference-count":50,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,1,24]],"date-time":"2022-01-24T00:00:00Z","timestamp":1642982400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["SCHL377\/2-4 & 6-2"],"award-info":[{"award-number":["SCHL377\/2-4 & 6-2"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["BR4014\/5-1 & 8-1"],"award-info":[{"award-number":["BR4014\/5-1 & 8-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["TRR60"],"award-info":[{"award-number":["TRR60"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>The role of non-parenchymal liver cells as part of the hepatic, innate immune system in the defense against hepatotropic viruses is not well understood. Here, primary human Kupffer cells, liver sinusoidal endothelial cells and hepatic stellate cells were isolated from liver tissue obtained after tumor resections or liver transplantations. Cells were stimulated with Toll-like receptor 1\u20139 ligands for 6\u201324 h. Non-parenchymal liver cells expressed and secreted inflammatory cytokines (IL6, TNF and IL10). Toll-like receptor- and cell type-specific downstream signals included the phosphorylation of NF-\u03baB, AKT, JNK, p38 and ERK1\/2. However, only supernatants of TLR3-activated Kupffer cells, liver sinusoidal endothelial cells and hepatic stellate cells contained type I and type III interferons and mediated an antiviral activity in the interferon-sensitive subgenomic hepatitis C virus replicon system. The antiviral effect could not be neutralized by antibodies against IFNA, IFNB nor IFNL, but could be abrogated using an interferon alpha receptor 2-specific neutralization. Interestingly, TLR3 responsiveness was enhanced in liver sinusoidal endothelial cells isolated from hepatitis C virus-positive donors, compared to uninfected controls. In conclusion, non-parenchymal liver cells are potent activators of the hepatic immune system by mediating inflammatory responses. Furthermore, liver sinusoidal endothelial cells were identified to be hyperresponsive to viral stimuli in chronic hepatitis C virus infection.<\/jats:p>","DOI":"10.3390\/v14020218","type":"journal-article","created":{"date-parts":[[2022,1,25]],"date-time":"2022-01-25T20:42:26Z","timestamp":1643143346000},"page":"218","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Antiviral Toll-like Receptor Signaling in Non-Parenchymal Liver Cells Is Restricted to TLR3"],"prefix":"10.3390","volume":"14","author":[{"given":"Melanie","family":"Werner","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Schefczyk","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Trippler","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juergen W.","family":"Treckmann","sequence":"additional","affiliation":[{"name":"Department of General-, Visceral- and Transplantation-Surgery, University Hospital of Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1750-5318","authenticated-orcid":false,"given":"Hideo A.","family":"Baba","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Hospital of Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guido","family":"Gerken","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany"},{"name":"Helios Hospital, Gastroenterology, Hepatology and Palliative Medicine, Robert-Koch-Stra\u00dfe 2, 42549 Velbert, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joerg F.","family":"Schlaak","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany"},{"name":"AMEOS Hospital, St. Clemens, Internal Medicine\u2014Hepatology, Gastroenterology, Infectiology and Diabetology, Wilhelmstr. 34, 46145 Oberhausen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7125-3246","authenticated-orcid":false,"given":"Ruth","family":"Broering","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1007\/BF00224305","article-title":"The pit cell: Description of a new type of cell occurring in rat liver sinusoids and peripheral blood","volume":"173","author":"Wisse","year":"1976","journal-title":"Cell Tissue Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1083\/jcb.72.2.441","article-title":"Distribution of organelles and membranes between hepatocytes and nonhepatocytes in the rat liver parenchyma. 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