Biliary repair and carcinogenesis are mediated by IL-33–dependent cholangiocyte proliferation
Jun Li, … , Pranavkumar Shivakumar, Jorge A. Bezerra
Jun Li, … , Pranavkumar Shivakumar, Jorge A. Bezerra
Published June 2, 2014
Citation Information: J Clin Invest. 2014;124(7):3241-3251. https://doi.org/10.1172/JCI73742.
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Research Article Oncology

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

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.

Authors

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

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Figure 6

ILC2s mediate IL-33–induced cholangiocyte proliferation.

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ILC2s mediate IL-33–induced cholangiocyte proliferation. (A) Representat...
(A) Representative dot plots show that Rag2–/–gc–/– mice lack Lin–ST2+ population after 4 days of IL-33 injections (B6 strain used as control). (B) Quantification of Lin–ST2+ cells from total hepatic mononuclear cells from 3 independent experiments. (C) Quantification of BrdU uptake by CK19+ and CK19– cells in EHBDs by immunofluorescence staining 1 day after administration of IL-33 into Rag2–/–gc–/– mice compared with B6 controls. (D) BrdU staining showing the recovery of proliferation in EHBDs of Rag2–/–gc–/– mice following adoptive transfer of B6/SJL/CD45.1+ Lin–ST2+ cells after IL-33, with (E) quantification of BrdU uptake. (F) BrdU uptake in EHBDs of Rag2–/–gc–/– mice after i.p. administration of PBS or 5 × 106 bone marrow cells from Rora+/+ or Rorasg/sg mice into Rag2–/–gc–/– mice, followed by IL-33 treatment i.p. for 6 weeks. Mean ± SD. *P < 0.05; **P < 0.01; ***P < 0.001. Scale bars: 50 μm.