Extracellular ATP and TNF-alpha synergize in the activation and maturationof human dendritic cells

Extracellular ATP mediates numerous biological activities by interacting wi th plasma membrane P2 purinergic receptors. Recently, P2 receptors have bee n described on dendritic cells (DC), but their functional role remains uncl ear. Proposed functions include improved Ag presentation, cytokine producti on, chemotaxis, and induction of apoptosis. We investigated the effects of ATP and of other P2 receptor agonists on endocytosis, phenotype, IL-12 secr etion, and T cell stimulatory capacity of human monocyte-derived DC. We fou nd that in the presence of extracellular ATP, DC transiently increase their endocytotic activity, Subsequently, DC up-regulate CD86, CD54, and MHC-II; ; secrete IL-12; and exhibit an improved stimulatory capacity for allogenei c T cells. These effects were more pronounced when chemically modified ATP derivatives with agonistic activity on P2 receptors, which are resistent to degradation by ectonucleotidases, were applied. Furthermore, ATP and TNF-a lpha synergized in the activation of DC. Stimulated with a combination of A TP and TNF-cu, DC expressed the maturation marker CD83, secreted large amou nts of IL-12, and were potent stimulators of T cells. In the presence of th e P2 receptor antagonist suramin, the effects of ATP were completely abolis hed. Our results suggest that extracellular ATP may play an important immun omodulatory role by activating DC and by skewing the immune reaction toward a Th1 response through the induction of IL-12 secretion.