P2Y receptor signaling regulates phenotype and IFN-alpha secretion of human plasmacytoid dendritic cells.
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 P2Y(6), P2Y(4), and P2Y(14), 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.
Shin
Amanda
A
Department of Internal Medicine, University of Munich, Munich, Germany.
Toy
Tracey
T
Rothenfusser
Simon
S
Robson
Neil
N
Vorac
Julia
J
Dauer
Marc
M
Stuplich
Moritz
M
Endres
Stefan
S
Cebon
Jonathan
J
Maraskovsky
Eugene
E
Schnurr
Max
M
D000255:Adenosine Triphosphate / Q000494:pharmacology; D015415:Biomarkers; D020013:Calcium Signaling / Q000187:drug effects; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism*; D008024:Ligands; D010641:Phenotype; D011493:Protein Kinase C / Q000378:metabolism; D058910:Purinergic P2 Receptor Agonists; D012333:RNA, Messenger / Q000235:genetics; D018048:Receptors, Purinergic P2 / Q000235:genetics / Q000378:metabolism*
D015415:Biomarkers; D016898:Interferon-alpha; D008024:Ligands; D058910:Purinergic P2 Receptor Agonists; D012333:RNA, Messenger; D018048:Receptors, Purinergic P2; D000255:Adenosine Triphosphate; D011493:Protein Kinase C