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Activation of E-prostanoid4 and E-prostanoid2 receptors inhibits TNF-alpha release from human alveolar macrophages

M J Ratcliffe1, A Walding, P A Shelton

  • 1Dept of Molecular Biology, AstraZeneca Research and Development Charnwood, Bakewell Road, Loughborough, LE11 5RH, UK. Marianne.ratcliffe@astrazeneca.com

The European Respiratory Journal
|March 3, 2007
PubMed

Insights

Prostaglandin E2 (PGE2) inhibits mediator release from macrophages via EP2 and EP4 receptors. This finding suggests potential anti-inflammatory therapies for lung diseases involving macrophages.

Area of Science:

  • Immunology
  • Cell Biology
  • Pharmacology

Background:

  • Prostaglandin E2 (PGE2) is known to inhibit mediator release from human alveolar macrophages (AMs).
  • The specific prostanoid receptors responsible for this effect have not been identified.

Purpose of the Study:

  • To investigate the prostanoid receptors mediating PGE2's inhibitory effects on mediator release in human macrophages.
  • To explore the potential anti-inflammatory properties of E-prostanoid (EP) receptor agonists in lung diseases.

Main Methods:

  • Pharmacological studies and expression-based analyses were performed on monocyte-derived macrophages (MDMs) and AMs.
  • PGE2's effect on lipopolysaccharide-induced tumor necrosis factor-alpha (TNF-α) release was measured.
  • EP receptor agonists and a selective EP4 antagonist (Ono-AE2-227) were used to identify mediating receptors.

Main Results:

  • PGE2 potently inhibited TNF-α release in MDMs.
  • PGE2 also inhibited TNF-α release in AMs, though with a flatter concentration-effect curve.
  • Expression studies and pharmacological interventions confirmed that EP2 and EP4 receptors mediate PGE2's inhibitory effects in both cell types.

Conclusions:

  • PGE2 inhibits TNF-α release from human AMs and MDMs through the activation of EP2 and EP4 receptors.
  • Selective EP2 and EP4 receptor agonists may possess anti-inflammatory properties beneficial for lung diseases involving macrophage activity.

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