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,2
* Department of Experimental and Diagnostic Medicine, Section of General Pathology, and
Center of Biotechnology, University of Ferrara, Ferrara, Italy;
Laboratory of Immunology, Istituto Dermopatico dell’Immacolata, IRCCS, Rome, Italy; and
§ Departments of Pneumology and
¶ Dermatology, University of Freiburg, Freiburg, Germany
1Correspondence: Department of Experimental and Diagnostic Medicine, Section of General Pathology, University of Ferrara, via L. Borsari 46, I-44100 Ferrara, Italy. E-mail: dfr{at}dns.unife.it
We investigated the expression of purinoceptors in human dendritic
cells, providing functional, pharmacological, and biochemical evidence
that immature and mature cells express P2Y and P2X subtypes, coupled to
increase in the intracellular Ca2+, membrane
depolarization, and secretion of inflammatory cytokines. The
ATP-activated Ca2+ change was biphasic, with a fast release
from intracellular stores and a delayed influx across the plasma
membrane. A prolonged exposure to ATP was toxic to dendritic cells that
swelled, lost typical dendrites, became phase lucent, detached from the
substrate, and eventually died. These changes were highly suggestive of
expression of the cytotoxic receptor P2X7, as confirmed by
ability of dendritic cells to become permeant to membrane impermeant
dyes such as Lucifer yellow or ethidium bromide. The P2X7
receptor ligand 2',3'-(4-benzoylbenzoyl)-ATP was a better agonist then
ATP for Ca2+ increase and plasma membrane depolarization.
Oxidized ATP, a covalent blocker of P2X receptors, and the selective
P2X7 antagonist KN-62 inhibited both permeabilization and
Ca2+ changes induced by ATP. The following purinoceptors
were expressed by immature and mature dendritic cells:
P2Y1, P2Y2, P2Y5, P2Y11
and P2X1, P2X4, P2X7. Finally,
stimulation of LPS-matured cells with ATP triggered release of IL-1ß
and TNF-
. Purinoceptors may provide a new avenue to modulation of
dendritic cells function.—Ferrari, D., La Sala, A., Chiozzi, P.,
Morelli, A., Falzoni, S., Girolomoni, G., Idzko, M.,
Dichmann, S., Norgauer, J., Di Virgilio, F. The P2
purinergic receptors of human dendritic cells: identification and
coupling to cytokine release.
Key Words: extracellular nucleotides • nucleotide receptors • IL-1ß • TNF- • inflammation
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