{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:15:30Z","timestamp":1791296130871,"version":"4.1.0"},"reference-count":27,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":1614,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2011,4]]},"abstract":"<jats:sec>\n            <jats:title\/>\n            <jats:p>\n                                 <jats:bold>Activation of innate immunity (natural killer [NK] cell\/interferon-\u03b3 [IFN-\u03b3]) has been shown to play an important role in antiviral and antitumor defenses as well as antifibrogenesis. However, little is known about the regulation of innate immunity during chronic liver injury. Here, we compared the functions of NK cells in early and advanced liver fibrosis induced by a 2-week or a 10-week carbon tetrachloride (CCl4) challenge, respectively. Injection of polyinosinic-polycytidylic acid (poly I:C) or IFN-\u03b3 induced NK cell activation and NK cell killing of hepatic stellate cells (HSCs) in the 2-week CCl4 model. Such activation was diminished in the 10-week CCl4 model. Consistent with these findings, the inhibitory effect of poly I:C and IFN-\u03b3 on liver fibrosis was markedly reduced in the 10-week versus the 2-week CCl4 model.<\/jats:bold>\n                                 <jats:bold>\n                                    In vitro\n                                 <\/jats:bold>\n                                 <jats:bold>coculture experiments demonstrated that 4-day cultured (early activated) HSCs induce NK cell activation via an NK group 2 member D\/retinoic acid-induced early gene 1-dependent mechanism. Such activation was reduced when cocultured with 8-day cultured (intermediately activated) HSCs due to the production of transforming growth factor-\u03b2 (TGF-\u03b2) by HSCs. Moreover, early activated HSCs were sensitive, whereas intermediately activated HSCs were resistant to IFN-\u03b3-mediated inhibition of cell proliferation, likely due to elevated expression of suppressor of cytokine signaling 1 (SOCS1). Disruption of the SOCS1 gene restored the IFN-\u03b3 inhibition of cell proliferation in intermediately activated HSCs. Production of retinol metabolites by HSCs contributed to SOCS1 induction and subsequently inhibited IFN-\u03b3 signaling and functioning, whereas production of TGF-\u03b2 by HSCs inhibited NK cell function and cytotoxicity against HSCs.<\/jats:bold>\n                                 <jats:bold>\n                                    Conclusion:\n                                 <\/jats:bold>\n                                 <jats:bold>The antifibrogenic effects of NK cell\/IFN-\u03b3 are suppressed during advanced liver injury, which is likely due to increased production of TGF-\u03b2 and expression of SOCS1 in intermediately activated HSCs. (HEPATOLOGY 2011;)<\/jats:bold>\n                              <\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.24190","type":"journal-article","created":{"date-parts":[[2011,1,12]],"date-time":"2011-01-12T23:51:22Z","timestamp":1294876282000},"page":"1373-1382","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":139,"title":["Suppression of innate immunity (natural killer cell\/interferon-\u03b3) in the advanced stages of liver fibrosis in mice"],"prefix":"10.1097","volume":"53","author":[{"given":"Won-Il","family":"Jeong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ogyi","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang-Gun","family":"Suh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-Seok","family":"Byun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"So-Young","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Earl","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ja-Kyung","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyojin","family":"Ko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew M.","family":"Miller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"R1-31-20241104","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1002\/hep.22034","article-title":"Liver: an organ with predominant innate immunity.","volume":"47","author":"Gao","year":"2008","journal-title":"HEPATOLOGY"},{"key":"R2-31-20241104","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.clim.2008.08.008","article-title":"NK and NKT cells in liver injury and fibrosis.","volume":"130","author":"Notas","year":"2009","journal-title":"Clin Immunol"},{"key":"R3-31-20241104","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1136\/gut.2010.211136","article-title":"Amelioration of hepatic fibrosis by NK cell activation.","volume":"60","author":"Muhanna","year":"2010","journal-title":"Gut"},{"key":"R4-31-20241104","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1053\/j.gastro.2005.10.055","article-title":"Natural killer cells ameliorate liver fibrosis by killing activated stellate cells in NKG2D-dependent and tumor necrosis factor-related apoptosis-inducing ligand-dependent manners.","volume":"130","author":"Radaeva","year":"2006","journal-title":"Gastroenterology"},{"key":"R5-31-20241104","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.jhep.2005.12.025","article-title":"Anti-fibrotic activity of NK cells in experimental liver injury through killing of activated HSC.","volume":"45","author":"Melhem","year":"2006","journal-title":"J Hepatol"},{"key":"R6-31-20241104","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.1002\/hep.21419","article-title":"STAT1 inhibits liver fibrosis in mice by inhibiting stellate cell proliferation and stimulating NK cell cytotoxicity.","volume":"44","author":"Jeong","year":"2006","journal-title":"HEPATOLOGY"},{"key":"R7-31-20241104","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1053\/j.gastro.2007.09.034","article-title":"Abrogation of the antifibrotic effects of natural killer cellsinterferon-gamma contributes to alcohol acceleration of liver fibrosis.","volume":"134","author":"Jeong","year":"2008","journal-title":"Gastroenterology"},{"key":"R8-31-20241104","doi-asserted-by":"crossref","first-page":"G809","DOI":"10.1152\/ajpgi.00212.2007","article-title":"Retinoic acid signaling sensitizes hepatic stellate cells to NK cell killing via upregulation of NK cell activating ligand RAE1.","volume":"293","author":"Radaeva","year":"2007","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"R9-31-20241104","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1053\/j.gastro.2008.03.003","article-title":"Mechanisms of hepatic 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fibrosis or cirrhosis.","volume":"45","author":"Pockros","year":"2007","journal-title":"HEPATOLOGY"},{"key":"R16-31-20241104","doi-asserted-by":"crossref","first-page":"22086","DOI":"10.1074\/jbc.M102737200","article-title":"Suppressor of cytokine signaling-1 attenuates the duration of interferon gamma signal transduction in vitro and in vivo.","volume":"276","author":"Brysha","year":"2001","journal-title":"J Biol Chem"},{"key":"R17-31-20241104","doi-asserted-by":"crossref","first-page":"5541","DOI":"10.4049\/jimmunol.175.8.5541","article-title":"Inhibition of NK cell activity through TGF-beta 1 by down-regulation of NKG2D in a murine model of head and neck cancer.","volume":"175","author":"Dasgupta","year":"2005","journal-title":"J Immunol"},{"key":"R18-31-20241104","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1002\/hep.1840160325","article-title":"Inhibition of rat hepatic lipocyte activation in culture by 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