Biliary repair and carcinogenesis are mediated by IL-33-dependent cholangiocyte proliferation. Academic Article uri icon

abstract

  • Injury to the biliary epithelium triggers inflammation and fibrosis, which can result in severe liver diseases and may progress to malignancy. Development of a type 1 immune response has been linked to biliary injury pathogenesis; however, a subset of patients with biliary atresia, the most common childhood cholangiopathy, exhibit increased levels of Th2-promoting cytokines. The relationship among different inflammatory drivers, epithelial repair, and carcinogenesis remains unclear. Here, we determined that the Th2-activating cytokine IL-33 is elevated in biliary atresia patient serum and in the livers and bile ducts of mice with experimental biliary atresia. Administration of IL-33 to WT mice markedly increased cholangiocyte proliferation and promoted sustained cell growth, resulting in dramatic and rapid enlargement of extrahepatic bile ducts. The IL-33-dependent proliferative response was mediated by an increase in the number of type 2 innate lymphoid cells (ILC2s), which released high levels of IL-13 that in turn promoted cholangiocyte hyperplasia. Induction of the IL-33/ILC2/IL-13 circuit in a murine biliary injury model promoted epithelial repair; however, induction of this circuit in mice with constitutive activation of AKT and YAP in bile ducts induced cholangiocarcinoma with liver metastases. These findings reveal that IL-33 mediates epithelial proliferation and suggest that activation of IL-33/ILC2/IL-13 may improve biliary repair and disruption of the circuit may block progression of carcinogenesis.

published proceedings

  • J Clin Invest

altmetric score

  • 10.5

author list (cited authors)

  • Li, J., Razumilava, N., Gores, G. J., Walters, S., Mizuochi, T., Mourya, R., ... Bezerra, J. A

citation count

  • 149

complete list of authors

  • Li, Jun||Razumilava, Nataliya||Gores, Gregory J||Walters, Stephanie||Mizuochi, Tatsuki||Mourya, Reena||Bessho, Kazuhiko||Wang, Yui-Hsi||Glaser, Shannon S||Shivakumar, Pranavkumar||Bezerra, Jorge A

publication date

  • June 2014