ATP is released by monocytes stimulated with pathogen-sensing receptor ligands and induces IL-1β and IL-18 secretion in an autocrine way

被引:381
作者
Piccini, Alessandra [1 ]
Carta, Sonia [1 ]
Tassi, Sara [1 ]
Lasiglie, Denise [2 ,3 ]
Fossati, Gianluca [4 ]
Rubartelli, Anna [1 ]
机构
[1] Natl Inst Canc Res, Cell Biol Unit, I-16132 Genoa, Italy
[2] Univ Genoa, Inst Giannina Gaslini, Div Pediat 2, I-16147 Genoa, Italy
[3] Univ Genoa, Dept Pediat, I-16147 Genoa, Italy
[4] Italfarmaco SpA, Res Ctr, I-20126 Milan, Italy
关键词
inflammation; nonclassical secretion; pathogen-associated molecular patterns; processing;
D O I
10.1073/pnas.0709684105
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
IL-1 beta and IL-18 are crucial mediators of inflammation, and a defective control of their release may cause serious diseases. Yet, the mechanisms regulating IL-1 beta 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-1 beta 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 (MA, or treatment with apyrase, prevent IL-1 beta and IL-18 maturation and secretion triggered by the different stimuli. At variance, blocking P2X(7)R activity has no effects on IL-1 beta 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-1 beta and IL-18 secretion.
引用
收藏
页码:8067 / 8072
页数:6
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