Extracellular adenine nucleotides modulate cytokine production by human monocyte-derived dendritic cells: dual effect on IL-12 and stimulation of IL-10.
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) (ATPgammaS), an ATP analog active on the P2Y(11) receptor, on the responses to three DC stimuli, TNF-alpha, LPS, sCD40L, tested at various concentrations, using two different IL-12 assays. We observed that ATPgammaS potentiated the IL-12p40 release induced by TNF-alpha, 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 ATPgammaS-TNF-alpha and ATPgammaS-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 ATPgammaS was purely inhibitory. Our results also show that ATPgammaS synergized with LPS and sCD40L, but not TNF-alpha, to stimulate IL-10 production. In conclusion, we have clarified the discrepancies in the literature concerning the action of adenine nucleotides on DC and our study supports the concept that, like prostaglandin E(2) and other agents increasing cyclic AMP, they favor either a Th2 response or tolerance.
Institute of Interdisciplinary Research, Institute of Biology and Molecular Medicine, Université Libre de Bruxelles, Gosselies, Belgium. fwilkin@hotmail.com
Françoise
F
Wilkin
Patrick
P
Stordeur
Michel
M
Goldman
Jean-Marie
JM
Boeynaems
Bernard
B
Robaye
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000328:Adult; D003994:Bucladesine / Q000494:pharmacology; D023201:CD40 Ligand / Q000494:pharmacology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects*; D019281:Dimerization; D015232:Dinoprostone / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000235:genetics; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000235:genetics; D053765:Interleukin-12 Subunit p35; D053762:Interleukin-12 Subunit p40; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000166:cytology; D021122:Protein Subunits / Q000096:biosynthesis* / Q000235:genetics; D018048:Receptors, Purinergic P2 / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
C508858:IL12A protein, human; D053765:Interleukin-12 Subunit p35; D053762:Interleukin-12 Subunit p40; D008070:Lipopolysaccharides; C109734:P2RY11 protein, human; D021122:Protein Subunits; D018048:Receptors, Purinergic P2; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D023201:CD40 Ligand; D018664:Interleukin-12; C022571:adenosine 5'-O-(3-thiotriphosphate); D003994:Bucladesine; D000255:Adenosine Triphosphate; D015232:Dinoprostone