title: Toll-like receptor 2-mediated intestinal injury and enteric tumor necrosis factor receptor I contribute to liver fibrosis in mice.
abstract: OBJECTIVE
  Progression of liver fibrosis in experimental models depends on gut-derived bacterial products, but little is known about mechanisms of disruption of the mucosal barrier or translocation. We used a mouse model of cholestatic liver disease to investigate mechanisms of intestinal barrier disruption following liver injury.
  
  
  METHODS
  Liver fibrosis and bacterial translocation were assessed in Toll-like receptor 2 (TLR2)-deficient and tumor necrosis factor receptor I (TNFRI)-deficient mice subjected to bile duct ligation. Epithelial and lamina propria cells were isolated and analyzed by immunoblot analyses and flow cytometry. We analyzed bone marrow chimeras and mice with a conditional gain-of-function allele for the TNFRI receptor. By crossing TNFRI(flxneo/flxneo) mice with mice that expressed the VillinCre transgene specifically in intestinal epithelial cells, we created mice that express functional TNFRI specifically on intestinal epithelial cells (VillinCreTNFRI(flxneo/flxneo) mice).
  
  
  RESULTS
  Following bile duct ligation, TLR2-deficient mice had less liver fibrosis and intestinal translocation of bacteria and bacterial products than wild-type mice. Mice with hematopoietic cells that did not express TLR2 also had reduced bacterial translocation, indicating that TLR2 expression by hematopoietic cells regulates intestinal barrier function. The number of TLR2(+) monocytes that produce tumor necrosis factor α increased in the intestinal lamina propria of wild-type mice following bile duct ligation; bacterial translocation was facilitated by TNFRI-mediated signals on intestinal epithelial cells.
  
  
  CONCLUSIONS
  Intestinal inflammation and bacterial translocation contribute to liver fibrosis via TLR2 signaling on monocytes in the lamina propria and TNFRI signaling on intestinal epithelial cells in mice. Therefore, enteric TNFRI is an important mediator of cholestatic liver fibrosis.
authors: Department of Medicine, University of California San Diego, La Jolla, California.
authors: Phillipp
authors: P
authors: Hartmann
authors: Department of Medicine, University of California San Diego, La Jolla, California.
authors: Michael
authors: M
authors: Haimerl
authors: Department of Medicine, University of California San Diego, La Jolla, California.
authors: Magdalena
authors: M
authors: Mazagova
authors: Department of Medicine, University of California San Diego, La Jolla, California.
authors: David A
authors: DA
authors: Brenner
authors: Department of Medicine, University of California San Diego, La Jolla, California. Electronic address: beschnabl@ucsd.edu.
authors: Bernd
authors: B
authors: Schnabl
mesh_terms: D000818:Animals; D018988:Bacterial Translocation; D001652:Bile Ducts; D024722:Cardiac Myosins / Q000378:metabolism; D002452:Cell Count; D002779:Cholestasis / Q000150:complications; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000382:microbiology; D008026:Ligation; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism*; D018994:Myosin Light Chains / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D018709:Statistics, Nonparametric; D019108:Tight Junctions / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D020742:rhoA GTP-Binding Protein
chemical_list: D018994:Myosin Light Chains; D047888:Receptors, Tumor Necrosis Factor, Type I; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha; C107184:myosin light chain 2; D024722:Cardiac Myosins; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein