Interleukin-13 Activates Distinct Cellular Pathways Leading to Ductular Reaction, Steatosis, and Fibrosis

Immunity. 2016 Jul 19;45(1):145-58. doi: 10.1016/j.immuni.2016.06.009. Epub 2016 Jul 12.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Bile Acids and Salts / biosynthesis
  • Cell Proliferation
  • Cells, Cultured
  • Fatty Liver / immunology*
  • Fibroblasts / immunology*
  • Fibrosis
  • Humans
  • Interleukin-13 / genetics
  • Interleukin-13 / immunology
  • Interleukin-13 / metabolism*
  • Liver / pathology*
  • Liver Cirrhosis, Biliary / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Schistosoma mansoni / immunology*
  • Schistosomiasis mansoni / immunology*
  • Signal Transduction
  • Th2 Cells / immunology

Substances

  • Bile Acids and Salts
  • Interleukin-13