title: Early growth response factor-1 limits biliary fibrosis in a model of xenobiotic-induced cholestasis in mice.
abstract: Hepatic expression of the transcription factor early growth response-1 (Egr-1) is increased in livers of patients with cholestatic liver disease. Bile acid induction of inflammatory genes in hepatocytes is Egr-1 dependent, and Egr-1 expression is increased in livers of mice after bile duct ligation. Of importance, Egr-1 deficiency reduces liver inflammation and injury in that model. However, it is not known whether Egr-1 promotes inflammation in other models of cholestasis. We tested the hypothesis that Egr-1 contributes to liver inflammation in mice exposed chronically to the bile duct epithelial cell (BDEC) toxicant alpha-naphthylisothiocyanate (ANIT). Egr-1-knockout (Egr-1(-/-)) mice and wild-type mice were fed a diet containing 0.025% ANIT for 2 weeks. Expression of Egr-1 mRNA and protein was significantly increased in livers of mice fed ANIT diet. Egr-1 deficiency did not significantly affect ANIT diet-induced hepatocellular injury, inflammatory gene induction, BDEC hyperplasia, or hepatic neutrophil accumulation. In contrast, the deposition of Type 1 collagen was significantly increased in livers of Egr-1(-/-) mice fed ANIT diet compared with wild-type mice fed ANIT diet. Interestingly, this increase in liver fibrosis occurred in association with elevated expression of the β6 integrin (Itgb6) gene, suggesting the potential for increased local activation of transforming growth factor beta. Taken together, the results indicate that Egr-1 does not contribute to liver injury or inflammation in mice fed a diet containing ANIT. Rather, these studies indicate that Egr-1 deficiency worsens liver fibrosis in conjunction with enhanced expression of the profibrogenic Itgb6 gene.
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
authors.forename: Bradley P
authors.initials: BP
authors.lastname: Sullivan
authors.forename: Wei
authors.initials: W
authors.lastname: Cui
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Copple
authors.forename: James P
authors.initials: JP
authors.lastname: Luyendyk
mesh_terms: D015058:1-Naphthylisothiocyanate / Q000633:toxicity; D000818:Animals; D001659:Biliary Tract / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D002779:Cholestasis / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D004195:Disease Models, Animal; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D039641:Integrin beta Chains / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D039641:Integrin beta Chains; D012333:RNA, Messenger; C508961:Tgfb1 protein, mouse; C560825:Timp1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; D053773:Transforming Growth Factor beta1; C072170:integrin beta6; D015058:1-Naphthylisothiocyanate
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