Loss of Runx3 Function in Leukocytes Is Associated With Spontaneously Developed Colitis and Gastric Mucosal Hyperplasia

Proc Natl Acad Sci U S A. 2004 Nov 9;101(45):16016-21. doi: 10.1073/pnas.0407180101. Epub 2004 Oct 28.

Abstract

RUNX transcription factors are key regulators of lineage-specific gene expression and might be involved in autoimmune diseases. Runx3 plays a role during the development of sensory neurons and T cells and regulates transforming growth factor beta (TGF-beta) signaling in dendritic cells. Here, we report that at 4 weeks of age, Runx3 knockout (KO) mice spontaneously develop inflammatory bowel disease (IBD) characterized by leukocyte infiltration, mucosal hyperplasia, formation of lymphoid clusters, and increased production of IgA. Additionally, at a considerably older age (8 months), the KO mice also develop progressive hyperplasia of the gastric mucosa associated with disturbed epithelial differentiation and cellular hyaline degeneration. Analysis of cytokines in the colonic mucosa of Runx3 KO mice revealed a mixed T helper 1/T helper 2 response. By using immunohistochemistry and RNA in situ hybridization, Runx3 expression in the gastrointestinal tract is detected in lymphoid and myeloid populations but not in the epithelium. The data indicate that loss of leukocytic cell-autonomous function of Runx3 results in IBD and gastric lesion in the KO mice. IBD in humans is viewed as a complex genetic disorder. Several susceptibility loci were identified on different human chromosomes including the chromosomal region 1p36 where RUNX3 resides. It is thus tempting to speculate that mutations in RUNX3 may constitute an IBD risk factor in humans.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Colitis / etiology*
  • Colitis / genetics
  • Colitis / pathology
  • Colitis / physiopathology
  • Core Binding Factor Alpha 3 Subunit
  • Cytokines / metabolism
  • DNA-Binding Proteins / deficiency*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology
  • Gastric Mucosa / immunology
  • Gastric Mucosa / pathology*
  • Humans
  • Hyperplasia
  • Immunohistochemistry
  • In Situ Hybridization
  • Inflammatory Bowel Diseases / etiology
  • Inflammatory Bowel Diseases / genetics
  • Inflammatory Bowel Diseases / pathology
  • Inflammatory Bowel Diseases / physiopathology
  • Leukocytes / pathology
  • Leukocytes / physiology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Th1 Cells / immunology
  • Th1 Cells / pathology
  • Th2 Cells / immunology
  • Th2 Cells / pathology
  • Transcription Factors / deficiency*
  • Transcription Factors / genetics
  • Transcription Factors / physiology

Substances

  • Core Binding Factor Alpha 3 Subunit
  • Cytokines
  • DNA-Binding Proteins
  • Runx3 protein, human
  • Runx3 protein, mouse
  • Transcription Factors