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Liver fibrosis, in particular, is a major pathogenic consequence of HCV infection, and transforming growth factor \u03b21 (TGF-\u03b21) plays a key role in its pathogenesis. Several HCV proteins have been suggested to either augment or suppress the expression of TGF-\u03b21 by HCV-infected cells. Here, we report that TGF-\u03b21 levels are elevated in HCV-infected hepatocytes cultured<jats:italic>in vitro<\/jats:italic>and in liver tissue of HCV patients. Notably, the level of TGF-\u03b21 in media from<jats:italic>in vitro<\/jats:italic>-cultured HCV-infected hepatocytes was high enough to activate primary hepatic stellate cells isolated from rats. This indicates that TGF-\u03b21 secreted by HCV-infected hepatocytes is likely to play a key role in the liver fibrosis observed in HCV patients. Moreover, we showed that HCV E2 protein triggers the production of TGF-\u03b21 by HCV-infected cells through overproduction of glucose-regulated protein 94 (GRP94).<\/jats:p><jats:p><jats:bold>IMPORTANCE<\/jats:bold>Hepatic fibrosis is a critical step in liver cirrhosis caused by hepatitis C virus infection. It is already known that immune cells, including Kupffer cells, mediate liver fibrosis. Recently, several papers have suggested that HCV-infected hepatocytes also significantly produce TGF-\u03b21. Here, we provide the first examination of TGF-\u03b21 levels in the hepatocytes of HCV patients. Using an HCV culture system, we showed that HCV infection increases TGF-\u03b21 production in hepatocytes. Furthermore, we confirmed that the amount of TGF-\u03b21 secreted by HCV-infected hepatocytes was sufficient to activate primary hepatic stellate cells. To understand the molecular basis of TGF-\u03b21 production in HCV-infected hepatocytes, we used HCV replicons and various stable cell lines. Finally, we elucidated that HCV E2 triggered TGF-\u03b21 secretion via GRP94 mediated NF-\u03baB activation. This study contributes to the understanding of liver fibrosis by HCV and suggests a new potential target (GRP94) for blocking liver cirrhosis in HCV patients.<\/jats:p>","DOI":"10.1128\/jvi.02976-15","type":"journal-article","created":{"date-parts":[[2015,12,31]],"date-time":"2015-12-31T02:54:03Z","timestamp":1451530443000},"page":"3044-3055","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":26,"title":["New Mechanism of Hepatic Fibrogenesis: Hepatitis C Virus Infection Induces Transforming Growth Factor \u03b21 Production through Glucose-Regulated Protein 94"],"prefix":"10.1128","volume":"90","author":[{"given":"Min Hyeok","family":"Jee","sequence":"first","affiliation":[{"name":"POSTECH Biotech Center, Department of Life Sciences, Pohang University of Science and Technology, Pohang, Kyungbuk, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ka Young","family":"Hong","sequence":"additional","affiliation":[{"name":"POSTECH Biotech Center, Department of Life Sciences, Pohang University of Science and Technology, Pohang, Kyungbuk, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji Hoon","family":"Park","sequence":"additional","affiliation":[{"name":"POSTECH Biotech Center, Department of Life Sciences, Pohang University of Science and Technology, Pohang, Kyungbuk, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae Seung","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Kyungbuk, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hee Sun","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Kyungbuk, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song Hee","family":"Lee","sequence":"additional","affiliation":[{"name":"POSTECH Biotech Center, Department of Life Sciences, Pohang University of Science and Technology, Pohang, Kyungbuk, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung Key","family":"Jang","sequence":"additional","affiliation":[{"name":"POSTECH Biotech Center, Department of Life Sciences, Pohang University of Science and Technology, Pohang, Kyungbuk, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1111\/j.1365-2893.2006.00838.x","article-title":"The role of chemokines as inflammatory mediators in chronic hepatitis C virus infection","volume":"14","author":"Zeremski M","year":"2007","unstructured":"Zeremski M, Petrovic LM, Talal AH. 2007. 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