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Activation of Human Alveolar Macrophages via P2 Receptors: Coupling to Intracellular Ca²⁺ Increases and Cytokine Secretion¹

Daniel Myrtek^2,*, Tobias Müller^2,*, Verena Geyer^2,*, Natalie Derr^*, Davide Ferrari, Gernot Zissel^*, Thorsten Dürk^*, Stephan Sorichter^*, Werner Luttmann, Michael Kuepper, Johannes Norgauer, Francesco Di Virgilio, J. Christian Virchow, Jr and Marco Idzko^3,*

^* University Hospital Freiburg, Department of Pneumology, Freiburg, Germany; University Hospital Rostock, Department of Pneumology, Rostock, Germany; University of Ferrara, Department of Experimental and Diagnostic Medicine, Section of General Pathology, and Interdisciplinary Center for the Study of Inflammation, Ferrara, Italy; and University Hospital Jena, Department of Dermatology, Jena, Germany

Alveolar macrophages play a crucial role in the pathogenesis of inflammatory airway diseases. By the generation and release of different inflammatory mediators they contribute to both recruitment of different leukocytes into the lung and to airway remodeling. A potent stimulus for the release of inflammatory cytokines is ATP, which mediates its cellular effects through the interaction with different membrane receptors, belonging to the P2X and P2Y families. The aim of this study was to characterize the biological properties of purinoceptors in human alveolar macrophages obtained from bronchoalveolar lavages in the context of inflammatory airway diseases. The present study is the first showing that human alveolar macrophages express mRNA for different P2 subtypes, namely P2X₁, P2X₄, P2X₅, P2X₇, P2Y₁, P2Y₂, P2Y₄, P2Y₆, P2Y₁₁, P2Y₁₃, and P2Y₁₄. We also showed that extracellular ATP induced Ca²⁺ transients and increased IL-1β secretion via P2X receptors. Furthermore, extracellular nucleotides inhibited production of IL-12p40 and TNF-, whereas IL-6 secretion was up-regulated. In summary, our data further support the hypothesis that purinoceptors are involved in the pathogenesis of inflammatory lung diseases.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a grant from the DFG (Deutsche Forschungsgesellschaft).

² D.M., T.M., and V.G. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Marco Idzko, University Hospital Freiburg, Department of Pneumology, Killianstrasse 5, 79106 Freiburg, Germany. E-mail address: marco.idzko{at}uniklinik-freiburg.de

⁴ Abbreviations used in this paper: UDP-glc, UDP-glucose; BAL, bronchoalveolar lavage; BzATP, 2'3'-(4-benzoyl) benzoyl ATP.