ATP is released by monocytes stimulated with pathogen-sensing receptor ligands and induces IL-1beta and IL-18 secretion in an autocrine way.
IL-1beta and IL-18 are crucial mediators of inflammation, and a defective control of their release may cause serious diseases. Yet, the mechanisms regulating IL-1beta and IL-18 secretion are partially undefined. Both cytokines are produced as inactive cytoplasmic precursors. Processing to the active form is mediated by caspase-1, which is in turn activated by the multiprotein complex inflammasome. Here, we show that in primary human monocytes microbial components acting on different pathogen-sensing receptors and the danger-associated molecule uric acid are all competent to induce maturation and secretion of IL-1beta and IL-18 through a process that involves as a first event the extracellular release of endogenous ATP. ATP release is followed by autocrine stimulation of the purinergic receptors P2X(7). Indeed, antagonists of the P2X(7) receptor (P2X(7)R), or treatment with apyrase, prevent IL-1beta and IL-18 maturation and secretion triggered by the different stimuli. At variance, blocking P2X(7)R activity has no effects on IL-1beta secretion by monocytes carrying a mutated inflammasome that does not require exogenous ATP for activation. P2X(7)R engagement is followed by K+ efflux and activation of phospholipase A(2). Both events are required for processing and secretion induced by all of the stimuli. Thus, stimuli acting on different pathogen-sensing receptors converge on a common pathway where ATP externalization is the first step in the cascade of events leading to inflammasome activation and IL-1beta and IL-18 secretion.
Cell Biology Unit, National Cancer Research Institute, Largo Rosanna Benzi 10, 16132 Genoa, Italy. alessandra.piccini@istge.it
Alessandra
A
Piccini
Sonia
S
Carta
Sara
S
Tassi
Denise
D
Lasiglié
Gianluca
G
Fossati
Anna
A
Rubartelli
D000255:Adenosine Triphosphate / Q000378:metabolism*; D019898:Autocrine Communication / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D020382:Interleukin-18 / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D007700:Kinetics; D008024:Ligands; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D064801:Phospholipase A2 Inhibitors; D011188:Potassium / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051192:Receptors, Pattern Recognition / Q000378:metabolism*; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058486:Receptors, Purinergic P2X7; D051193:Toll-Like Receptors / Q000378:metabolism
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D020382:Interleukin-18; D053583:Interleukin-1beta; D008024:Ligands; C546468:P2RX7 protein, human; D064801:Phospholipase A2 Inhibitors; D051192:Receptors, Pattern Recognition; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D051193:Toll-Like Receptors; D000255:Adenosine Triphosphate; D011188:Potassium