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

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 α (TNF‐α), IL‐10] were investigated in human monocyte‐derived DC. ADP, 2‐methylthio‐ADP, and ADPβS 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. ADPβS alone was less potent for up‐regulation of CD83 than ATPγS and did not increase the CD83 expression by DC stimulated with lipopolysaccharide (LPS). Similar to ATPγS, ADPβS inhibited the release of IL‐12p40, IL‐12p70, and TNF‐α stimulated by LPS (1–100 ng/ml). The inhibitory effect of ADPβS 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 ADPβS and potentiation by ATPγS. 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 Gi‐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.