title: Bile acids induce inflammatory genes in hepatocytes: a novel mechanism of inflammation during obstructive cholestasis.
abstract: Inflammation contributes to liver injury during cholestasis. The mechanism by which cholestasis initiates an inflammatory response in the liver, however, is not known. Two hypotheses were investigated in the present studies. First, activation of Toll-like receptor 4 (TLR4), either by bacterial lipopolysaccharide or by damage-associated molecular pattern molecules released from dead hepatocytes, triggers an inflammatory response. Second, bile acids act as inflammagens, and directly activate signaling pathways in hepatocytes that stimulate production of proinflammatory mediators. Liver inflammation was not affected in lipopolysaccharide-resistant C3H/HeJ mice after bile duct ligation, indicating that Toll-like receptor 4 is not required for initiation of inflammation. Treatment of hepatocytes with bile acids did not directly cause cell toxicity but increased the expression of numerous proinflammatory mediators, including cytokines, chemokines, adhesion molecules, and other proteins that influence immune cell levels and function. Up-regulation of several of these genes in hepatocytes and in the liver after bile duct ligation required early growth response factor-1, but not farnesoid X receptor. In addition, early growth response factor-1 was up-regulated in the livers of patients with cholestasis and correlated with levels of inflammatory mediators. These data demonstrate that Toll-like receptor 4 is not required for the initiation of acute inflammation during cholestasis. In contrast, bile acids directly activate a signaling network in hepatocytes that promotes hepatic inflammation during cholestasis.
authors.affiliation: Department of Pharmacology, Toxicology, and Experimental Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
authors.forename: Katryn
authors.initials: K
authors.lastname: Allen
authors.forename: Hartmut
authors.initials: H
authors.lastname: Jaeschke
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Copple
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism* / Q000494:pharmacology; D002470:Cell Survival; D054410:Chemokine CCL7 / Q000235:genetics; D054426:Chemokine CXCL2 / Q000235:genetics; D002779:Cholestasis / Q000150:complications* / Q000378:metabolism / Q000473:pathology*; D051766:Early Growth Response Protein 1 / Q000235:genetics; D005786:Gene Expression Regulation; D006505:Hepatitis / Q000209:etiology / Q000235:genetics* / Q000276:immunology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D008070:Lipopolysaccharides / Q000276:immunology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000276:immunology; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D058258:Serpin E2 / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000276:immunology; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics; D020666:ras-GRF1 / Q000235:genetics; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D054410:Chemokine CCL7; D054426:Chemokine CXCL2; D051766:Early Growth Response Protein 1; D018799:Intercellular Adhesion Molecule-1; D008070:Lipopolysaccharides; D018160:Receptors, Cytoplasmic and Nuclear; D058258:Serpin E2; D051197:Toll-Like Receptor 4; D019010:Vascular Cell Adhesion Molecule-1; D020666:ras-GRF1; D000099150:Receptor, Farnesoid X-Activated; C515451:Ccl7 protein, mouse; C404915:Cxcl2 protein, mouse; C486109:Egr1 protein, mouse; C513037:Rasgrf1 protein, mouse; C511869:Serpine2 protein, mouse; C493487:Tlr4 protein, mouse