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

Richard L. Gieseck III, Thirumalai R. Ramalingam, Kevin M. Hart, Kevin M. Vannella, David A. Cantu, Wei-Yu Lu, Sofía Ferreira-González, Stuart J. Forbes, Ludovic Vallier, Thomas A. Wynn

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Pages (from-to)145–158
Number of pages14
JournalImmunity
Volume45
Issue number1
Early online date12 Jul 2016
DOIs
Publication statusPublished - 19 Jul 2016

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