Biliary repair and carcinogenesis are mediated by IL-33-dependent cholangiocyte proliferation

J Clin Invest. 2014 Jul;124(7):3241-51. doi: 10.1172/JCI73742. Epub 2014 Jun 2.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Animals, Newborn
  • Bile Ducts, Extrahepatic / immunology
  • Bile Ducts, Extrahepatic / pathology
  • Biliary Atresia / etiology
  • Biliary Atresia / immunology*
  • Biliary Atresia / pathology*
  • Biliary Tract Neoplasms / etiology
  • Biliary Tract Neoplasms / immunology*
  • Biliary Tract Neoplasms / pathology*
  • Carcinogenesis
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation
  • Cholangiocarcinoma / etiology
  • Cholangiocarcinoma / immunology
  • Cholangiocarcinoma / pathology
  • Disease Models, Animal
  • Female
  • Humans
  • Interleukin-13 / deficiency
  • Interleukin-13 / genetics
  • Interleukin-13 / physiology
  • Interleukin-33
  • Interleukins / physiology*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Th2 Cells / immunology

Substances

  • IL33 protein, human
  • Il33 protein, mouse
  • Interleukin-13
  • Interleukin-33
  • Interleukins