title: Interleukin-13 Activates Distinct Cellular Pathways Leading to Ductular Reaction, Steatosis, and Fibrosis.
abstract: Fibroproliferative diseases are driven by dysregulated tissue repair responses and are a major cause of morbidity and mortality because they affect nearly every organ system. Type 2 cytokine responses are critically involved in tissue repair; however, the mechanisms that regulate beneficial regeneration versus pathological fibrosis are not well understood. Here, we have shown that the type 2 effector cytokine interleukin-13 simultaneously, yet independently, directed hepatic fibrosis and the compensatory proliferation of hepatocytes and biliary cells in progressive models of liver disease induced by interleukin-13 overexpression or after infection with Schistosoma mansoni. Using transgenic mice with interleukin-13 signaling genetically disrupted in hepatocytes, cholangiocytes, or resident tissue fibroblasts, we have revealed direct and distinct roles for interleukin-13 in fibrosis, steatosis, cholestasis, and ductular reaction. Together, these studies show that these mechanisms are simultaneously controlled but distinctly regulated by interleukin-13 signaling. Thus, it may be possible to promote interleukin-13-dependent hepatobiliary expansion without generating pathological fibrosis. VIDEO ABSTRACT.
authors.affiliation: Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20852, USA; Wellcome Trust-Medical Research Council Stem Cell Institute, Anne McLaren Laboratory, Department of Surgery, University of Cambridge, Cambridge CB2 0SZ, UK.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Gieseck
authors.affiliation: Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20852, USA.
authors.forename: Thirumalai R
authors.initials: TR
authors.lastname: Ramalingam
authors.affiliation: Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20852, USA.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Hart
authors.affiliation: Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20852, USA.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Vannella
authors.affiliation: Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20852, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Cantu
authors.affiliation: Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK.
authors.forename: Wei-Yu
authors.initials: WY
authors.lastname: Lu
authors.affiliation: Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK.
authors.forename: Sofía
authors.initials: S
authors.lastname: Ferreira-González
authors.affiliation: Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK.
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Forbes
authors.affiliation: Wellcome Trust-Medical Research Council Stem Cell Institute, Anne McLaren Laboratory, Department of Surgery, University of Cambridge, Cambridge CB2 0SZ, UK; Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Vallier
authors.affiliation: Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20852, USA. Electronic address: twynn@niaid.nih.gov.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Wynn
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis; D049109:Cell Proliferation; D002478:Cells, Cultured; D005234:Fatty Liver / Q000276:immunology*; D005347:Fibroblasts / Q000276:immunology*; D005355:Fibrosis; D006801:Humans; D018793:Interleukin-13 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008099:Liver / Q000473:pathology*; D008105:Liver Cirrhosis, Biliary / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012550:Schistosoma mansoni / Q000276:immunology*; D012555:Schistosomiasis mansoni / Q000276:immunology*; D015398:Signal Transduction; D018418:Th2 Cells / Q000276:immunology
chemical_list: D001647:Bile Acids and Salts; D018793:Interleukin-13