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

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

Research output: Contribution to journalArticle

103 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3241-3251
Number of pages11
JournalJournal of Clinical Investigation
Volume124
Issue number7
DOIs
StatePublished - Jul 1 2014

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Carcinogenesis
Biliary Atresia
Interleukin-13
Bile Ducts
Wounds and Injuries
Cytokines
Extrahepatic Bile Ducts
Cholangiocarcinoma
Liver
Hyperplasia
Interleukin-33
Liver Diseases
Fibrosis
Epithelium
Lymphocytes
Neoplasm Metastasis
Inflammation
Growth
Serum
Neoplasms

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Biliary repair and carcinogenesis are mediated by IL-33-dependent cholangiocyte proliferation. / Li, Jun; Razumilava, Nataliya; Gores, Gregory James; Walters, Stephanie; Mizuochi, Tatsuki; Mourya, Reena; Bessho, Kazuhiko; Wang, Yui Hsi; Glaser, Shannon S.; Shivakumar, Pranavkumar; Bezerra, Jorge A.

In: Journal of Clinical Investigation, Vol. 124, No. 7, 01.07.2014, p. 3241-3251.

Research output: Contribution to journalArticle

Li, J, Razumilava, N, Gores, GJ, Walters, S, Mizuochi, T, Mourya, R, Bessho, K, Wang, YH, Glaser, SS, Shivakumar, P & Bezerra, JA 2014, 'Biliary repair and carcinogenesis are mediated by IL-33-dependent cholangiocyte proliferation', Journal of Clinical Investigation, vol. 124, no. 7, pp. 3241-3251. https://doi.org/10.1172/JCI73742
Li, Jun ; Razumilava, Nataliya ; Gores, Gregory James ; Walters, Stephanie ; Mizuochi, Tatsuki ; Mourya, Reena ; Bessho, Kazuhiko ; Wang, Yui Hsi ; Glaser, Shannon S. ; Shivakumar, Pranavkumar ; Bezerra, Jorge A. / Biliary repair and carcinogenesis are mediated by IL-33-dependent cholangiocyte proliferation. In: Journal of Clinical Investigation. 2014 ; Vol. 124, No. 7. pp. 3241-3251.
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