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

¹ Depts of Molecular Biology, and ² Medicinal Chemistry, AstraZeneca Research & Development Charnwood, Loughborough, UK.

CORRESPONDENCE: M. J. Ratcliffe, Dept of Molecular Biology, AstraZeneca Research and Development Charnwood, Bakewell Road, Loughborough, LE11 5RH, UK. Fax: 44 1509645557. E-mail: Marianne.ratcliffe{at}astrazeneca.com

Keywords: Alveolar, cytokine, human, macrophage, prostaglandin E₂

Received: October 9, 2006
Accepted February 18, 2007

Prostaglandin (PG)E₂ has been shown to inhibit mediator release from human alveolar macrophages (AMs), but the prostanoid receptor(s) mediating this response have not yet been documented. To investigate this, the present authors 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 tumour necrosis factor (TNF)- release (p[A]₅₀ 8.51±0.11, maximum inhibition 95.9±4.8%). In human AMs, PGE₂ also inhibited TNF- release but the observed concentration–effect curve 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 E-prostanoid (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 E-prostanoid₄ and E-prostanoid₂ selective agonists may have anti-inflammatory properties in lung diseases where macrophages play a role.

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