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

Shin, A. et al. (2008) P2Y receptor signaling regulates phenotype and IFN- secretion of human plasmacytoid dendritic cells. Blood, 111(6), pp. 3062-3069. (doi: 10.1182/blood-2007-02-071910)

Abstract

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-α 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-α 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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Robson, Dr Neil
• Authors: Shin, A., Toy, T., Rothenfusser, S., Robson, N.C., Vorac, J., Dauer, M., Stuplich, M., Endres, S., Cebon, J., Maraskovsky, E., and Schnurr, M.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Blood
• Publisher: American Society of Hematology
• ISSN: 0006-4971