Purinergic P2X 7 receptor function in lung alveolar macrophages: Pharmacologic characterization and bidirectional regulation by Th1 and Th2 cytokines
Purinergic P2X 7 receptors have been shown in the lung, but little is known concerning P2X 7 function in pulmonary macrophages. In this study we characterized P2X 7 ‐dependent responses to extracellular ATP in resident and activated alveolar macrophages (AM) obtained by bronchoalveolar lavage of rat...
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Veröffentlicht in: | Drug development research 2003-05, Vol.59 (1), p.118-127 |
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Sprache: | eng |
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Zusammenfassung: | Purinergic P2X
7
receptors have been shown in the lung, but little is known concerning P2X
7
function in pulmonary macrophages. In this study we characterized P2X
7
‐dependent responses to extracellular ATP in resident and activated alveolar macrophages (AM) obtained by bronchoalveolar lavage of rats. Incubation of AM with high concentrations of ATP (5mM) or 3′‐O‐(4‐benzoyl)benzoyl‐ATP (B
z
ATP) (0.5mM), a P2X
7
agonist, induced: 1) rapid pore formation, 2) apoptosis, and 3) enhanced release of IL‐1α, IL‐1β, and IL‐6, but not TNF‐α following priming with lipopolysaccharide (LPS). Furthermore, higher expression of P2X
7
receptor in AM was associated with increased formation of Type 2 multinucleated giant cells (Type 2 MGC) in response to GMCSF. Immunopharmacological analysis also showed that P2X
7
‐dependent pore formation in AM was significantly increased by LPS (1 µg/ml) and the T helper 1 (Th1) cytokines, interferon‐γ (100U/ml), and, to a lesser extent, TNF‐α (>20 ng/ml). In contrast, the T helper 2 (Th2) cytokines IL‐4 (1pg/ml) as well as IL‐10 (1ng/ml) significantly inhibited these P2X
7
receptor functions. Transforming growth factor‐β (TGF‐β), a known deactivator of macrophages, had no significant effect. Our results demonstrate that AM exhibit all the characteristics of a functional P2X
7
receptor which upon appropriate stimulation activates the proinflammatory IL‐1→IL‐6 cytokine cascade and the formation of MGC, a hallmark of granulomatous reactions. Moreover, Th1 and Th2 cytokines reciprocally regulate P2X
7
function, suggesting a role for P2X
7
in pulmonary diseases associated with chronic inflammatory responses. Drug Dev. Res. 59:118–127, 2003. © 2003 Wiley‐Liss, Inc. |
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ISSN: | 0272-4391 1098-2299 |
DOI: | 10.1002/ddr.10209 |