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

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.