4.8 Article

A Role for RUNX3 in Inflammation-Induced Expression of IL23A in Gastric Epithelial Cells

Journal

CELL REPORTS
Volume 8, Issue 1, Pages 50-58

Publisher

CELL PRESS
DOI: 10.1016/j.celrep.2014.06.003

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Funding

  1. Translational and Clinical Research Flagship Programme
  2. National Research Foundation Singapore
  3. Singapore Ministry of Education under Research Centres of Excellence Initiative
  4. National University of Singapore Graduate School for Integrative Sciences and Engineering scholarship

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RUNX3 functions as a tumor suppressor in the gastric epithelium, where its inactivation is frequently observed during carcinogenesis. We identified IL23A as a RUNX3 target gene in gastric epithelial cells. This was confirmed in a series of in vitro analyses in gastric epithelial cell lines. In elucidating the underlying regulatory network, we uncovered a prominent role for the TNF-alpha/NF-kappa B pathway in activating IL23A transcription. Moreover, the activating effect of TNF-alpha was markedly augmented by the infection of Helicobacter pylori, the primary cause of human gastritis. Of note, H. pylori utilized the CagA/SHP2 pathway to activate IL23A, as well as the induction of the NOD1 pathway by iE-DAP. Importantly, RUNX3 synergized strongly with these physiologically relevant stimuli to induce IL23A. Lastly, we present evidence for the secretion of IL23A by gastric epithelial cells in a form that is distinct from canonical IL-23 (IL23A/IL12B).

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