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Published online before print March 1, 2007
Eur Respir J 2007, doi:10.1183/09031936.00131606
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ORIGINAL ARTICLE

Activation of EP4 and EP2 receptors inhibits TNF{alpha} release from human alveolar macrophages

M.J. Ratcliffe 1, A. Walding 1, P.A. Shelton 1, A. Flaherty 2, I.G. Dougall 1

1 Depts of Molecular Biology and
2 Medicinal Chemistry, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough LE11 5RH.


  Abstract

Prostaglandin E2 (PGE2) has been shown to inhibit mediator release from human alveolar macrophages (AMs), but the prostanoid receptor(s) mediating this response have not been documented. To investigate this we conducted a range of pharmacological and expression based studies in monocyte derived macrophages (MDMs) and AMs.

MDMs were obtained by in vitro differentiation of monocytes from the peripheral blood of healthy human volunteers. Human AMs were obtained by perfusion of lung tissue from carcinoma resection patients.

In MDMs, PGE2 potently inhibited lipopolysaccharide-induced TNF{alpha} release (p[A]50= 8.51±0.11, maximum inhibition=95.9%±4.8%). In human AMs, PGE2 also inhibited TNF{alpha} release but the concentration-effect curve observed was very flat and inhibition was incomplete. The shape of the PGE2 curve in AMs suggested that its effects were mediated by activation of a heterogeneous receptor population. Expression studies combined with the use of various EP receptor agonists and a selective EP4-receptor antagonist (Ono-AE2-227) confirmed that the inhibitory effects of PGE2 in both AMs and MDMs were mediated by activation of EP4 and EP2 receptors.

These data indicate that both EP4 and EP2 selective agonists may have anti-inflammatory properties in lung diseases where macrophages play a role.

Keywords:  Alveolar, cytokine, human, macrophage, PGE2, prostaglandin




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Copyright © 2007 by the European Respiratory Society.