Extracellular adenosine 5'-triphosphate induces a loss of CD23 from human dendritic cells via activation of P2X7 receptors.
Dendritic cells (DC) express a number of P2X receptors including the P2X7/P2Z receptor whose activation by extracellular adenosine 5'-triphosphate (ATP) induces the influx of calcium, DC maturation, cytokine release and apoptosis. In B lymphocytes ATP induces the rapid shedding of CD23 and CD62 ligand by activating a membrane metalloprotease. In this study, we examined the expression and early effects of P2X7 receptor activation on monocyte-derived DC, generated from individuals either wild-type or homozygous for a loss-of-function single nucleotide polymorphism at position 1513 of the P2X7 gene. Labeling with an anti-human P2X7 receptor mAb demonstrated that DC express the P2X7 receptor at a lower level than macrophages. Short-term incubations (5 min) of DC with ATP induced an influx of ethidium+ (314 Da) into wild-type DC, but not into DC homozygous for the loss-of-function polymorphism. In contrast to results with ethidium+, ATP did not induce the influx of the viability dye propidium2+ (415 Da) into DC in short-term incubations. Addition of ATP also induced a rapid loss of CD23 from the surface of wild-type DC (t(1/2 )< 120 s), and this loss was inhibited by oxidized ATP and KN-62 which are known P2X7 receptor antagonists. Moreover, ATP-induced shedding of CD23 was slower from DC homozygous for the loss-of-function polymorphism than from wild-type DC. The data show that monocyte-derived DC express the P2X7 receptor whose activation opens a cation-selective channel, and which leads to rapid and near complete shedding of CD23. Both of these functions of the P2X7 receptor are impaired on DC from subjects who are homozygous for the loss-of-function 1513 polymorphism.
Sluyter
Ronald
R
Department of Medicine, University of Sydney, Level 5 South Block, Nepean Hospital, Penrith, NSW 2750, Australia. rons@med.usyd.edu.au
Wiley
James S
JS
D000255:Adenosine Triphosphate / Q000378:metabolism* / Q000494:pharmacology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D006801:Humans; D011419:Propidium / Q000378:metabolism; D017455:Receptors, IgE / Q000378:metabolism*; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D058486:Receptors, Purinergic P2X7; D013997:Time Factors
C546468:P2RX7 protein, human; D017455:Receptors, IgE; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D011419:Propidium; D000255:Adenosine Triphosphate