title: 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.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Nataliya
authors.initials: N
authors.lastname: Razumilava
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Gores
authors.forename: Stephanie
authors.initials: S
authors.lastname: Walters
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Mizuochi
authors.forename: Reena
authors.initials: R
authors.lastname: Mourya
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Bessho
authors.forename: Yui-Hsi
authors.initials: YH
authors.lastname: Wang
authors.forename: Shannon S
authors.initials: SS
authors.lastname: Glaser
authors.forename: Pranavkumar
authors.initials: P
authors.lastname: Shivakumar
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Bezerra
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017734:Bile Ducts, Extrahepatic / Q000276:immunology / Q000473:pathology; D001656:Biliary Atresia / Q000209:etiology / Q000276:immunology* / Q000473:pathology*; D001661:Biliary Tract Neoplasms / Q000209:etiology / Q000276:immunology* / Q000473:pathology*; D063646:Carcinogenesis; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018281:Cholangiocarcinoma / Q000209:etiology / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D018793:Interleukin-13 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D000067596:Interleukin-33; D007378:Interleukins / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D018418:Th2 Cells / Q000276:immunology
chemical_list: C506536:IL33 protein, human; C506535:Il33 protein, mouse; D018793:Interleukin-13; D000067596:Interleukin-33; D007378:Interleukins