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,
*
Institute of Interdisciplinary Research, Institut de Biologie et de Médecine Moléculaires, Université Libre de Bruxelles, Gosselies, Belgium; and
Institute of Interdisciplinary Research, School of Medicine and
Departement of Medical Chemistry, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
Recently, it has been shown that ATP and TNF-
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- 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.
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