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 Blood, 15 March 2008, Vol. 111, No. 6, pp. 3062-3069.
Prepublished online as a Blood First Edition Paper on November 9, 2007; DOI 10.1182/blood-2007-02-071910.

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IMMUNOBIOLOGY

P2Y receptor signaling regulates phenotype and IFN-{alpha} secretion of human plasmacytoid dendritic cells

Amanda Shin1, Tracey Toy2, Simon Rothenfusser3, Neil Robson2, Julia Vorac3, Marc Dauer1, Moritz Stuplich3, Stefan Endres3, Jonathan Cebon2, Eugene Maraskovsky4, and Max Schnurr1

1 Department of Internal Medicine, University of Munich, Munich, Germany; 2 Division of Clinical Pharmacology, University of Munich, Munich, Germany; 3 Ludwig Institute for Cancer Research, Melbourne Centre for Clinical Sciences, Austin Health, Heidelberg, Australia; and 4 CSL Limited, Parkville, Australia

Plasmacytoid dendritic cells (PDCs) play powerful regulatory roles in innate and adaptive immune responses and are a major source of type I interferon (IFN) following viral infection. During inflammation and mechanical stress, cells release nucleotides into the extracellular space where they act as signaling molecules via G protein–coupled P2Y receptors. We have previously reported on the regulation of myeloid dendritic cell (DC) function by nucleotides. Here, we report that human PDCs express several subtypes of P2Y receptors and mobilize intracellular calcium in response to nucleotide exposure. As a functional consequence, PDCs acquire a mature phenotype that is further enhanced in the context of CD40 ligation. Strikingly, nucleotides strongly inhibit IFN-{alpha} secretion induced by influenza virus or CpG-A. This effect is most pronounced for the uridine nucleotides UDP and UTP and the sugar nucleotide UDP-glucose, ligands of P2Y6, P2Y4, and P2Y14, respectively. Nucleotide-induced inhibition of IFN-{alpha} production is blocked by suramin, a P2Y receptor antagonist. Pharmacological data point toward a role of protein kinase C in the negative regulation of type I IFN. Manipulating PDC function with P2Y receptor agonists may offer novel therapeutic strategies for autoimmune diseases or cancer.


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