ATP is released by monocytes stimulated with pathogen-sensing receptor ligands and induces IL-1β and IL-18 secretion in an autocrine way
ATP is released by monocytes stimulated with pathogen-sensing receptor ligands and induces IL-1β and IL-18 secretion in an autocrine way
复制标题
DOI：
10.1073/pnas.0709684105
复制
发表时间：
2008-06-10
影响因子：
11.1
通讯作者：
Rubartelli, Anna
中科院分区：
文献类型：
--
作者：
Piccini, Alessandra;Carta, Sonia;Rubartelli, Anna
IL-1β和IL-18是炎症的重要介质，对它们的释放控制不当可能会导致严重的疾病。然而，调节IL-1β和IL-18分泌的机制部分尚不清楚。这两种细胞因子都是以非活性细胞质前体的形式产生的。对活性形式的处理是由caspase-1介导的，而caspase-1又被多蛋白复合炎症体激活。在这里，我们表明，在原代人类单核细胞中，作用于不同病原体感知受体的微生物组件和危险相关分子尿酸都有能力诱导IL-1β和IL-18的成熟和分泌，这一过程首先涉及细胞外内源性ATP的释放。ATP释放之后是对嘌呤能受体P2X的自分泌刺激(7)。事实上，P2X(7)受体(MA)的拮抗剂或apyrase治疗，可以阻止IL-1β和IL-18的成熟和由不同刺激触发的分泌。在不同的情况下，阻断P2X(7)R活性对携带突变的炎症体的单核细胞分泌IL-1β没有影响，单核细胞不需要外源ATP来激活。P2X(7)R参与之后是K+外流和磷脂酶A的激活(2)。这两个事件都是由所有刺激诱导的加工和分泌所必需的。因此，作用于不同病原体感受器的刺激集中在一条共同的途径上，其中ATP外化是导致炎症体激活和IL-1β和IL-18分泌的一系列事件的第一步。
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.