{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T10:55:48Z","timestamp":1791197748866,"version":"4.1.0"},"reference-count":44,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":3349,"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":[[2006,7]]},"abstract":"<jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      <jats:bold>Steatohepatitis enhances the severity of liver injury caused by acute inflammation. The purpose of this study was to test the hypothesis that fatty liver due to chronic choline-deficient diet exacerbates concanavalin A (ConA)-induced liver hepatitis, which is predominantly facilitated by T cells. Male C57BL\/6 mice were fed either control choline-sufficient diet (CSD) or choline-deficient diet (CDD) for 6 weeks before ConA administration. Mice were sacrificed 3, 9, and 24 hours after ConA injection. Liver injury measured by aspartate aminotransferase (AST), alanine aminotransferase (ALT), pathology, and terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) staining was minimal in mice fed either diet before ConA exposure. However, ConA-induced liver injury was significantly greater in CDD-fed mice compared with control-fed mice. Liver cytokines were assessed by quantitative real-time polymerase chain reaction (PCR). The expression of T helper (Th) 1 cytokines tumor necrosis factor alpha (TNF-\u03b1), interleukin 12 (IL-12), and interferon gamma (IFN-\u03b3) were dramatically elevated after ConA in CDD-fed mice compared with control-fed mice. CDD also enhanced ConA-induced STAT4 activation, but not STAT6. Notably, regulators of T-cell differentiation were strongly shifted toward a predominant Th1 profile. T-bet, regulator of the Th1 response, was up-regulated in CDD-fed mice, whereas Th2 regulator GATA-3 was significantly suppressed in CDD-fed mice after ConA. Moreover, the expression of suppressor of cytokine signaling (SOCS)-1, SOCS-3, and repressor of GATA-3 (ROG) favored a predominant Th1 cytokine response in CDD-fed mice.<\/jats:bold>\n                      <jats:bold>In conclusion<\/jats:bold>\n                      <jats:bold>, these data support the hypothesis that hepatosteatosis caused by CDD is associated with more severe ConA-induced hepatitis due to a predominant shift toward Th1 response.<\/jats:bold>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/hep.21221","type":"journal-article","created":{"date-parts":[[2006,6,27]],"date-time":"2006-06-27T03:26:57Z","timestamp":1151378817000},"page":"216-227","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":88,"title":["Favored T helper 1 response in a mouse model of hepatosteatosis is associated with enhanced T cell\u2013mediated 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Tcelldependent experimental liver injury in mice inducible by concanavalin A.","volume":"90","author":"Tiegs","year":"1992","journal-title":"J Clin Invest"},{"key":"R12-27-20241201","first-page":"176","article-title":"Experimental hepatitis and role of cytokines.","volume":"60","author":"Tiegs","year":"1997","journal-title":"Acta Gastroenterol Belg"},{"key":"R13-27-20241201","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/S1074-7613(00)80533-6","article-title":"Cytokines induce the development of functionally heterogeneous T helper cell subsets.","volume":"8","author":"OGarra","year":"1998","journal-title":"Immunity"},{"key":"R14-27-20241201","first-page":"13","article-title":"T helper differentiation proceeds through Stat1dependent, Stat4dependent and Stat4independent phases.","volume":"238","author":"Murphy","year":"1999","journal-title":"Curr Top Microbiol 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