Extracellular adenine nucleotides modulate cytokine production by human monocyte-derived dendritic cells: dual effect on IL-12 and stimulation of IL-10

Abstract

To clarify the functional consequences of adenine nucleotides action on human monocyte‐derived dendritic cells (DC), we have systematically compared the effects of adenosine 5′‐O‐(3‐thiotriphosphate) (ATPγS), an ATP analog active on the P2Y11 receptor, on the responses to three DC stimuli, TNF‐α, LPS, sCD40L, tested at various concentrations, using two different IL‐12 assays. We observed that ATPγS potentiated the IL‐12p40 release induced by TNF‐α, but also by lipopolysaccharides (LPS) and soluble CD40 ligand (sCD40L). This potentiation was observed as long as the IL‐12p40 concentration under agonist stimulation remained below a threshold value close to 10 ng/ml; inhibition was observed above this value. The combinations ATPγS‐TNF‐α and ATPγS‐sCD40L were unable to induce detectable bioactive IL‐12p70 production and at concentrations of LPS that induced a significant stimulation of IL‐12p70, the effect of ATPγS was purely inhibitory. Our results also show that ATPγS synergized with LPS and sCD40L, but not TNF‐α, to stimulate IL‐10 production. In conclusion, we have clarified the discrepancies in the literature concerningthe action of adenine nucleotides on DC and our study supports the concept that, like prostaglandin E2 and other agents increasing cyclic AMP, they favor either a Th2 response or tolerance.

Cyclic AMP Modulates the Functional Plasticity of Immature Dendritic Cells by Inhibiting Src-like Kinases through Protein Kinase A-mediated Signaling

“…Our findings corroborate previous observations on the ability of cAMP-elevating agents to induce maturation of human monocyte-derived DCs and to favor the phenotypical changes associated with the typical terminal differentiation status induced by LPS (17)(18)(19). In this context, we also confirmed the data of la Sala et al (17) on the inability of cAMP to affect the cell surface level of MHC II molecules.…”

“…The ability of cAMPelevating agents to trigger the differentiation program of human monocyte-derived DCs has been documented by several authors (17)(18)(19)(20). Here we investigated the effects of high intracellular levels of cAMP on the LPS-generated signaling.…”

“…Contrasting evidence has been obtained as to whether cAMP-elevating agents are added onto the DCs (17)(18)(19). Synergistic effects have been observed on the TNF-mediated signaling and at low doses of LPS (below 10 ng/ml).…”

“…Intracellular cAMP is an important physiological mediator of the inflammation process, and it also plays a central role in the regulation of the immune response. Physiological and pharmacological agents that increase cAMP levels, such as prostaglandin E 2 (PGE 2 ) (10 -13), histamine (14,15), ␤ 2 -adrenergic receptor agonists (16), extracellular ATP (17)(18)(19), and bacterial toxins (20), are able to interfere with the differentiation process of DCs via the G protein-adenylyl cyclase pathway. These agents display different effects on the maturation process of iDCs and share the capability of blocking the release of pro-inflammatory cytokines, including IL-12 and TNF-␣, as well as stimulating IL-10 secretion by cAMP-dependent or -independent mechanisms (10 -20).…”

Modulation of murine dendritic cell function by adenine nucleotides and adenosine: Involvement of the A2B receptor

“…Indeed, ATP up-regulates CD83 (a maturation maker) and co-stimulatory molecules such as CD80 and CD86 [7][8][9]. It also reduces the LPS-induced production of IL-12p70 [7,10] and favours the expression of IL-10, thrombospondin-1 (TSP-1) and indoleamine 2,3-dioxygenase (IDO) [11]. In addition, adenine nucleotides affect the production of chemokines (CCL22, CCL5), chemokine receptors (CCR7, CCR5) and the migration of DC [12,13].…”