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Purinergic P2Y₂ Receptors Induce Increased MCP-1/CCL2 Synthesis and Release from Rat Alveolar and Peritoneal Macrophages¹

Department of Biomedical Science, University of Sheffield, Addison Building Western Bank, Sheffield, United Kingdom

Macrophages play a key role in inflammation by synthesis and release of proinflammatory cytokines and chemokines. Extracellular nucleotides released at sites of tissue damage may be an early danger signal for immune cells, and ATP-gated P2X₇ receptors are well known to mediate the rapid release of proinflammatory IL-18 and IL-1. However, there is little direct evidence for the involvement of other purine receptor subtypes in the release of other cytokines or chemokines. We initially used protein arrays to address whether extracellular ATP can release cytokines and/or chemokines from rat NR8383 alveolar macrophage, which lack the P2X₇ receptor. ATPS increased the release of the proinflammatory chemokine, MCP-1 (MCP-1/CCL2). Pharmacological profiling identified the receptor responsible as the P2Y₂ receptor. Brief activation (10 min) of P2Y₂ receptors increased MCP-1 mRNA levels within 30 min and increased its release at 60 min. Similar results were obtained from rat peritoneal macrophages. We investigated likely downstream signaling cascades that may be involved, specifically the canonical G_q-mediated phospholipase C (PLC) and subsequent MAP kinase pathways, and G_i/G_o-mediated signaling. We could find no evidence for these pathways being involved in the P2Y₂R-induced increase in mRNA levels although inhibition of PLC blocked the UTP-induced increased release of MCP-1. Thus, the PLC-activated pathway can account for the increased release of MCP-1, but a novel signaling pathway may be involved in the increase in MCP-1 mRNA by activation of P2Y₂ receptors in alveolar and peritoneal macrophage.

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 the Wellcome Trust.

² Address correspondence and reprint requests to Dr. Annmarie Surprenant, Faculty of Life Science, Michael Smith Building, University of Manchester, Manchester, U.K. E-mail address: a.surprenant{at}manchester.ac.uk

³ Abbreviations used in this paper: PLC, phospholipase C; BzATP, 2'(3')-O-(4-Benzoylbenzoyl)adenosine 5'-triphosphate; MIP-1, macrophage inflammatory protein-1; RI, relative index; PPADS, 4-[[4-Formyl-5-hydroxy-6-methyl-3-[(phosphonooxy)methyl]-2-pyridinyl]azo]-1,3-benzenedisulfonic acid.