Biliary repair and carcinogenesis are mediated by IL-33–dependent cholangiocyte proliferation
Open accessAbstract
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.
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TREM-2 overexpression reduces IL-33 expression, and IL-33 has been shown to favor mouse BEC proliferation.
“In addition, TREM-2 overexpression reduces IL-33 expression, and IL-33 has been shown to favor mouse BEC proliferation [194].”
From Inflammation and immunity in liver homeostasis and disease: a nexus of hepatocytes, nonparenchymal cells and immune cells (2025) · cites this paper as [194]
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- Authors
- Li, J., Razumilava, N., Gores, G. J., Walters, S., Mizuochi, T., Mourya, R., Bessho, K., Wang, Y.-H., Glaser, S. S., Shivakumar, P., & Bezerra, J. A.
- Affiliations
- Cincinnati Children's Hospital Medical Center (US)
- Mayo Clinic (US)
- Texas A&M Health Science Center (US)
- Corresponding author
- Bezerra, Jorge A.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2014-06-02
- Volume
- 124
- Issue
- 7
- Pages
- 3241-3251
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC4071370
- OpenAlex
- W2031633372
- Cited by
- 202
- References
- 31
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 9 · 2023: 6 · 2022: 13 · 2021: 16 · 2020: 19 · 2019: 23 · 2018: 27 · 2017: 20 · 2016: 17 · 2015: 29 · 2014: 7
- FWCI
- 11.11
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Cincinnati Children's Hospital Medical Center
- National Institutes of Health (7r01dk083781-14, DK-83781, DK78392, DK59427)
- Tufts University School of Medicine
- Medical Research Council
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 83781, R01-DK083781, DK78392, R56DK059427, DK 59427, DK-789392, DK 64008, R01DK059427, R01DK054811, R01DK064008, R01DK076898, P30DK078392)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
- Health Sciences › Medicine › Surgery › Pediatric Hepatobiliary Diseases and Treatments
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Keywords
- IL-33, biliary atresia, cholangiocyte proliferation, ILC2, IL-13, biliary carcinogenesis, cholangiocarcinoma, YAP, Akt, Th2 immune response, biliary injury, liver fibrosis, liver metastasis
- MeSH terms
- Interleukin-33, Animals, Animals, Newborn, Biliary Atresia, Biliary Tract Neoplasms, Cell Line, Disease Models, Animal, Female, Humans, Interleukins, Male, Mice, Inbred BALB C, Bile Ducts, Extrahepatic, Cholangiocarcinoma, Mice, Knockout, Th2 Cells, Interleukin-13, Cell Line, Tumor, Cell Proliferation, Mice, Carcinogenesis
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