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The prostaglandin receptor EP4 suppresses colitis, mucosal damage and CD4 cell activation in the gut

Kenji Kabashima1, Tomomi Saji, Takahiko Murata

  • 1Department of Pharmacology, Faculty of Medicine, Kyoto University, Kyoto, Japan.

The Journal of Clinical Investigation
|April 3, 2002
PubMed

Insights

EP4 receptor deficiency exacerbates dextran sodium sulfate-induced colitis in mice by impairing mucosal integrity and increasing immune responses. EP4 signaling is crucial for maintaining intestinal homeostasis and preventing severe colitis.

Area of Science:

  • Gastroenterology
  • Immunology
  • Molecular Biology

Background:

  • Prostanoids play a role in inflammatory conditions, including colitis.
  • The specific roles of individual prostanoid receptors in dextran sodium sulfate (DSS)-induced colitis are not fully understood.

Purpose of the Study:

  • To investigate the function of each prostanoid receptor subtype in DSS-induced colitis.
  • To elucidate the role of the EP4 receptor in maintaining intestinal homeostasis and regulating immune responses during colitis.

Main Methods:

  • Utilized mice deficient in each of the eight prostanoid receptor types and subtypes.
  • Induced colitis using dextran sodium sulfate (DSS) at varying concentrations.
  • Administered EP4-selective agonist (AE1-734) and antagonist (AE3-208) to wild-type mice.
  • Assessed histological damage, immune cell infiltration, and gene expression profiles (DNA microarray) in colonic tissue.
  • Performed in vitro assays on lamina propria mononuclear cells to evaluate proliferation and cytokine production.

Main Results:

  • Only EP4-deficient mice exhibited severe DSS-induced colitis, characterized by impaired mucosal barrier function, epithelial loss, and immune cell aggregation.
  • Administration of an EP4 antagonist mimicked severe colitis, while an EP4 agonist ameliorated DSS-induced colitis.
  • EP4 deficiency led to elevated immune response gene expression and reduced mucosal repair gene expression.
  • In vitro, EP4 antagonism enhanced, while agonism suppressed, T-cell proliferation and Th1 cytokine production.

Conclusions:

  • EP4 receptor signaling is critical for maintaining intestinal mucosal integrity and downregulating excessive immune responses during colitis.
  • EP4 plays a protective role in DSS-induced colitis, preserving the gut barrier and modulating immune cell activity.
  • Targeting EP4 may represent a therapeutic strategy for managing inflammatory bowel diseases like colitis.

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