Extracellular ATP and TNF-α Synergize in the Activation and Maturation of Human Dendritic Cells

Abstract

Extracellular ATP mediates numerous biological activities by interacting with plasma membrane P2 purinergic receptors. Recently, P2 receptors have been described on dendritic cells (DC), but their functional role remains unclear. Proposed functions include improved Ag presentation, cytokine production, chemotaxis, and induction of apoptosis. We investigated the effects of ATP and of other P2 receptor agonists on endocytosis, phenotype, IL-12 secretion, and T cell stimulatory capacity of human monocyte-derived DC. We found 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 allogeneic 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-α synergized in the activation of DC. Stimulated with a combination of ATP and TNF-α, DC expressed the maturation marker CD83, secreted large amounts of IL-12, and were potent stimulators of T cells. In the presence of the P2 receptor antagonist suramin, the effects of ATP were completely abolished. Our results suggest that extracellular ATP may play an important immunomodulatory role by activating DC and by skewing the immune reaction toward a Th1 response through the induction of IL-12 secretion.

Human Heat Shock Protein 70 Enhances Tumor Antigen Presentation through Complex Formation and Intracellular Antigen Delivery without Innate Immune Signaling

“…Nucleotides are known to activate a variety of immune cells (67)(68)(69)(70). We observed that ADP induced calcium signals in GM-CSF/IL-4 differentiated myeloid DCs, but not in T cells or the B cell lines (Fig.…”

Purinergic signaling in inflammatory cells: P2 receptor expression, functional effects, and modulation of inflammatory responses

“…The involvement of the purinergic system in DC functionality was equally confirmed by assessing the maturation status based on the levels of DC surface markers. The implication of P2 receptors in DC maturation was already suggested by Schnurr et al in showing that activation and maturation of DCs was blocked by suramin [133]. Later studies showed that in combination with TNF-α, ATP increased the expression of the DC surface markers CD80, CD83, and CD86 confirming a maturation-promoting effect [123].…”

A Vicious Cycle Involving Release of Heat Shock Protein 60 from Injured Cells and Activation of Toll-Like Receptor 4 Mediates Neurodegeneration in the CNS

“…Several molecules have been identified, which, when released from injured or dying eukaryotic cells, activate innate immunity. These endogenous activators of innate immunity are evolutionarily conserved proteins or nucleotides with the common feature of being "foreign" to the extracellular environment in a normal tissue (Basu et al, 2000;Sauter et al, 2000;Schnurr et al, 2000;Termeer et al, 2000;Somersan et al, 2001). The novelty of our data in this context is that such endogenous activators may also play a role in CNS injury.…”