Published online before print July 7, 2004

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0104032

Received for publication January 21, 2004.
Revised May 18, 2004.
Accepted for publication June 7, 2004.

Article

Involvement of multiple P2Y receptors and signaling pathways in the action of adenine nucleotides diphosphates on human monocyte-derived dendritic cells

Frédéric Marteau ^*@, Didier Communi ^*, Jean-Marie Boeynaems ^*, and Nathalie Suarez-Gonzalez ^*

*Institute of Interdisciplinary Research, IRIBHM, and Departement of Medical Chemistry, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium

Abstract

Adenosine 5`-triphosphate (ATP), which is released from necrotic cells, induces a semimaturation state of dendritic cells (DC), characterized by the up-regulation of costimulatory molecules and the inhibition of proinflammatory cytokines. This action is mediated by cyclic adenosine monophosphate (cAMP) and involves the P2Y<sub>11</sub> receptor. As DC express the ecto-enzyme CD39, which converts ATP into adenosine 5`-diphosphate (ADP), the effects of adenine nucleotides diphosphates on molecular signaling {intracellular calcium ([Ca²⁺]_i), cAMP, extracellular signal-regulated kinase 1 (ERK1)}, costimulatory molecule expression (CD83), and cytokine production [interleukin (IL)-12, tumor necrosis factor (TNF-), IL-10] were investigated in human monocyte-derived DC. ADP, 2-methylthio-ADP, and ADPS had no effect on cAMP, increased [Ca²⁺]_i, and stimulated the phosphorylation of ERK1. The effect on ERK1 was inhibited by AR-C69931MX, a P2Y₁₂ and P2Y₁₃ antagonist. On the contrary the effect on [Ca²⁺]_i was neither inhibited by AR-C69931MX or by the P2Y₁ antagonist MRS-2179. Both effects were inhibited by pertussis toxin. ADPS alone was less potent for up-regulation of CD83 than ATPS and did not increase the CD83 expression by DC stimulated with lipopolysaccharide (LPS). Similar to ATPS, ADPS inhibited the release of IL-12p40, IL-12p70, and TNF- stimulated by LPS (1-100 ng/ml). The inhibitory effect of ADPS on IL-12 release was neither reversed by AR-C69931MX or by MRS-2179. The two nucleotides had opposite effects on IL-10 production: inhibition by ADPS and potentiation by ATPS. In conclusion, ATP can modulate the function of DC, directly via a cAMP increase mediated by the P2Y₁₁ receptor and indirectly via its degradation into ADP, which acts via G_i-coupled receptors coupled to ERK activation and calcium mobilization. These distinct mechanisms converge on the inhibition of inflammatory cytokine production, particularly IL-12, but have a differential effect on IL-10.

Key Words: IL-12 • IL-10 • ATP • ADP

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