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Published online before print July 7, 2004

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(Journal of Leukocyte Biology. 2004;76:796-803.)
© 2004 by Society for Leukocyte Biology

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

Frédéric Marteau^*,1, 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

¹Correspondence: Institute of Interdisciplinary Research, IRIBHM, Building C5-110, 808, route de Lennik, 1070 Brussels, Belgium. E-mail: fmarteau{at}ulb.ac.be

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 P2Y₁₁ 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 ADPßS 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. ADPßS 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, ADPßS inhibited the release of IL-12p40, IL-12p70, and TNF- stimulated by LPS (1–100 ng/ml). The inhibitory effect of ADPßS 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 ADPßS 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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