Damage to the biliary epithelium induces inflammation and fibrosis, which can lead to severe liver disease and malignancy. Many biliary injury-associated diseases are associated with induction of a Th1 response; however, some patients with biliary atresia present with increased levels of Th2-associated cytokines, and it is not clear if a particular inflammatory response following biliary injury promotes epithelial repair or carcinogenesis. Jun Li and colleagues at the University of Cincinnati College of Medicine revealed that the cytokine IL-33, a Th2-promoting cytokine, is upregulated in biliary atresia patient serum as well as the bile ducts and serum of mice with experimental biliary atresia. In WT mice, administration of IL-33 promoted biliary epithelial cell proliferation and a dramatic enlargement of the bile ducts. The authors demonstrated that type 2 innate lymphoid cells (ILC2s) increase in resposne to IL-33 and release high levels of IL-13, which subsequently promotes cholangiocyte hyperplasia. Interestingly, in a biliary injury model, induction of this IL-33/ILC2/IL-13 circuit promoted epithelial repair but induced metastatic cholangiocarcinoma in animals with constitutive activation of oncogenic mediators in bile ducts. The resullts from this study suggest that activating the IL-33/ILC2/IL-13 pathway may improve biliary repair. The accompanying image demostrates induction of biliary epithelium (green) proliferation (BrdU incorporation, red) in response to IL-33 (left panel). Nuclei stained blue with DAPI.
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.
Jun Li, Nataliya Razumilava, Gregory J. Gores, Stephanie Walters, Tatsuki Mizuochi, Reena Mourya, Kazuhiko Bessho, Yui-Hsi Wang, Shannon S. Glaser, Pranavkumar Shivakumar, Jorge A. Bezerra