The P2Y11 receptor mediates the ATP-induced maturation of human monocyte-derived dendritic cells.
Recently, it has been shown that ATP and TNF-alpha synergize in the activation and maturation of human dendritic cells (DC); the effect of ATP was reproduced by hydrolysis-resistant derivatives of ATP and was blocked by suramin, suggesting the involvement of a P2 receptor, but the particular subtype involved was not identified. In this report we confirm that ATP and various derivatives synergize with TNF-alpha and LPS to induce the maturation of human monocyte-derived DC, as revealed by up-regulation of the CD83 marker and the secretion of IL-12. The rank order of potency of various analogs (AR-C67085 > adenosine 5'-O-(3-thiotriphosphate) = 2'- and 3'-O-(4-benzoyl-benzoyl) ATP > ATP > 2-methylthio-ATP) was close to that of the recombinant human P2Y11 receptor. Furthermore, these compounds activated cAMP production in DC, in a xanthine-insensitive way, consistent with the involvement of the P2Y11 receptor, which among P2Y subtypes has the unique feature of being dually coupled to phospholipase C and adenylyl cyclase activation. The involvement of the P2Y11/cAMP/protein kinase A signaling pathway in the nucleotide-induced maturation of DC is supported by the inhibitory effect of H89, a protein kinase A inhibitor. Taken together, our results demonstrate that ATP activates DC through stimulation of the P2Y11 receptor and subsequent increase in intracellular cAMP.
Wilkin
F
F
Institute of Interdisciplinary Research, Institut de Biologie et de Médecine Moléculaires, Université Libre de Bruxelles, Gosselies, Belgium. fwilkin@hotmail.com
Duhant
X
X
Bruyns
C
C
Suarez-Huerta
N
N
Boeynaems
J M
JM
Robaye
B
B
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology*; D015703:Antigens, CD; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D003713:Dendritic Cells / Q000166:cytology* / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D004306:Dose-Response Relationship, Immunologic; D004357:Drug Synergism; D006801:Humans; D007136:Immunoglobulins / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D018048:Receptors, Purinergic P2 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology; D013873:Thionucleotides / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014530:Uridine Diphosphate / Q000494:pharmacology; D014544:Uridine Triphosphate / Q000494:pharmacology; D000097802:CD83 Antigen
D000255:Adenosine Triphosphate; D015703:Antigens, CD; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D007136:Immunoglobulins; D018664:Interleukin-12; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D018048:Receptors, Purinergic P2; D013873:Thionucleotides; D014409:Tumor Necrosis Factor-alpha; D014530:Uridine Diphosphate; D014544:Uridine Triphosphate; D000097802:CD83 Antigen; C109734:P2RY11 protein, human; C008501:2-methylthio-ATP