P2X7 receptor differentially couples to distinct release pathways for IL-1β in mouse macrophage
P2X7 receptor differentially couples to distinct release pathways for IL-1β in mouse macrophage
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DOI：
10.4049/jimmunol.180.11.7147
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发表时间：
2008-06-01
影响因子：
4.4
通讯作者：
Surprenant, Annmarie
中科院分区：
文献类型：
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作者：
Pelegrin, Pablo;Barroso-Gutierrez, Consuelo;Surprenant, Annmarie
促炎性IL-1细胞因子IL-1 α、IL-1 β和IL-18是对损伤和感染的急性免疫应答的关键介质。其细胞释放的机制尚不清楚。细胞外ATP激活嘌呤能P2 X（7）受体（P2 X（7）R）是LPS致敏的巨噬细胞快速释放IL-1 β的关键生理诱导剂。我们研究了三种巨噬细胞类型的ATP介导的IL-1细胞因子释放模式，试图为不同的释放机制提供直接证据。我们使用来自P2 X（7）R（-/-）小鼠的腹腔巨噬细胞，发现通过ATP释放IL-1 α、IL-18以及IL-1 β仅由P2 X（7）R激活引起，所有这些IL-1细胞因子的释放都涉及泛连接蛋白1（panx 1），并且IL-1 β的释放既有panx 1依赖性成分，也有非依赖性成分。我们比较了LPS引发的腹腔巨噬细胞、RAW 264.7巨噬细胞和J774A.1巨噬细胞的IL-1释放模式。我们发现RAW264.7巨噬细胞容易释放pro-IL-1 β，而不依赖于panx 1，但不释放成熟IL-1 β，因为它们不表达具有半胱天冬酶激活募集结构域的凋亡斑点样蛋白，因此没有半胱天冬酶-1炎性小体活性。我们描述了两种不同的释放途径：众所周知的caspase-1级联介导的IL-1 β的释放被caspase-1或panx 1的抑制选择性阻断，以及钙非依赖性，caspase-1/panx 1非依赖性的pro-IL-1 β的释放被甘氨酸选择性阻断。这些释放反应均与细胞损伤或细胞溶解效应无关。这首次直接证明了ATP诱导的pro-IL-1 β释放的独特信号传导机制。
The proinflammatory IL-1 cytokines IL-1 alpha, IL-1 beta, and IL-18 are key mediators of the acute immune response to injury and infection. Mechanisms underlying their cellular release remain unclear. Activation of purinergic P2X(7) receptors (P2X(7)R) by extracellular ATP is a key physiological inducer of rapid IL-1 beta release from LPS-primed macrophage. We investigated patterns of ATP-mediated release of IL-1 cytokines from three macrophage types in attempts to provide direct evidence for or against distinct release mechanisms. We used peritoneal macrophage from P2X(7)R(-/-) mice and found that release of IL-1 alpha, IL-18, as well as IL-1 beta, by ATP resulted exclusively from activation of P2X(7)R, release of all these IL-1 cytokines involved pannexin-1 (panx1), and that there was both a panx1-dependent and -independent component to IL-1 beta release. We compared IL-1-release patterns from LPS-primed peritoneal macrophage, RAW264.7 macrophage, and J774A.1 macrophage. We found RAW264.7 macrophage readily release pro-IL-1 beta independently of panx1 but do not release mature IL-1 beta because they do not express apoptotic speck-like protein with a caspase-activating recruiting domain and so have no caspase-1 inflammasome activity. We delineated two distinct release pathways: the well-known caspase-1 cascade mediating release of processed IL-1 beta that was selectively blocked by inhibition of caspase-1 or panx1, and a calcium-independent, caspase-1/panx1-independent release of pro-IL-1 beta that was selectively blocked by glycine. None of these release responses were associated with cell damage or cytolytic effects. This provides the first direct demonstration of a distinct signaling mechanism responsible for ATP-induced release of pro-IL-1 beta.