Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Th2 signals induce epithelial injury in mice and are compatible with the biliary atresia phenotype
Jun Li, … , Gilda Porta, Jorge A. Bezerra
Jun Li, … , Gilda Porta, Jorge A. Bezerra
Published October 17, 2011
Citation Information: J Clin Invest. 2011;121(11):4244-4256. https://doi.org/10.1172/JCI57728.
View: Text | PDF
Research Article Gastroenterology

Th2 signals induce epithelial injury in mice and are compatible with the biliary atresia phenotype

  • Text
  • PDF
Abstract

Biliary atresia (BA) is a destructive cholangiopathy of childhood in which Th1 immunity has been mechanistically linked to the bile duct inflammation and obstruction that culminate in liver injury. Based on reports of decreased Th1 cytokines in some patients and the development of BA in mice lacking CD4+ T cells, we hypothesized that Th1-independent mechanisms can also activate effector cells and induce BA. Here, we tested this hypothesis using Stat1–/– mice, which lack the ability to mount Th1 immune responses. Infection of Stat1–/– mice with rhesus rotavirus type A (RRV) on postnatal day 1 induced a prominent Th2 response, duct epithelial injury and obstruction within 7 days, and atresia shortly thereafter. A high degree of phosphorylation of the Th2 transcription factor Stat6 was observed; however, concurrent inactivation of Stat1 and Stat6 in mice did not prevent BA after RRV infection. In contrast, depletion of macrophages or combined loss of Il13 and Stat1 reduced tissue infiltration by lymphocytes and myeloid cells, maintained epithelial integrity, and prevented duct obstruction. In concordance with our mouse model, humans at the time of BA diagnosis exhibited differential hepatic expression of Th2 genes and serum Th2 cytokines. These findings demonstrate compatibility between Th2 commitment and the pathogenesis of BA, and suggest that patient subgrouping in future clinical trials should account for differences in Th2 status.

Authors

Jun Li, Kazuhiko Bessho, Pranavkumar Shivakumar, Reena Mourya, Sujit Kumar Mohanty, Jorge L. dos Santos, Irene K. Miura, Gilda Porta, Jorge A. Bezerra

×

Figure 2

Naive CD4+ T cells deficient in Stat1 differentiate into Th2 cells.

Options: View larger image (or click on image) Download as PowerPoint
Naive CD4+ T cells deficient in Stat1 differentiate into Th2 cells.
   
...
Flow cytometry of naive CD4+CD25– T cells cultured with anti-CD3/CD28 antibodies with or without different combinations of cytokines and antibodies for 3 days (A–F). Stat1–/– CD4+ T cells lack IFN-γ production under Th1-polarized conditions (A and B) and generate more IL-13 in Th0 and Th2 (C and D) and IL-4 under Th2 (E and F) conditions. Numbers in plots indicate percentage of CD4+ T cells that are also positive for IFN-γ, IL-13, or IL-4; data in B, D, and F are from 3 experiments. In G and H, the adoptive transfer of CD4+ T cells to Rag2–/– recipients soon after birth was followed by RRV injection 12 hours later. Hepatic mononuclear cells were analyzed by flow cytometry for percentage of IFN-γ, IL-13, and IL-4 gated on CD4+ T cells at 10 days after RRV challenge. Data are shown as representative dot plots (G) and average of 3 experiments (H). *P < 0.05; **P < 0.01. Values are expressed as mean ± SEM.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts