Potentiation of caspase-1 activation by the P2X7 receptor is dependent on TLR signals and requires NF-κB-driven protein synthesis
Potentiation of caspase-1 activation by the P2X7 receptor is dependent on TLR signals and requires NF-κB-driven protein synthesis
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DOI：
10.4049/jimmunol.175.11.7611
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发表时间：
2005-12-01
影响因子：
4.4
通讯作者：
Dubyak, GR
中科院分区：
文献类型：
--
作者：
Kahlenberg, JM;Lundberg, KC;Dubyak, GR
促炎细胞因子IL-1 β和IL-18在被半胱天冬酶-1切割之前是无活性的。P2 X7受体（P2 X7 R），一种ATP门控离子通道的刺激，触发caspase-1的快速激活。在这项研究中，我们证明，原代和Bac 1小鼠巨噬细胞TLR激动剂的预处理所需的caspase-1激活P2 X7 R，但它不是必需的受体本身的激活。通过尼日利亚菌素（一种K+/H+离子载体）激活半胱天冬酶-1类似地需要LPS引发。LPS的这种引发依赖于蛋白质合成，因为环己酰胺阻断了LPS引发巨噬细胞通过P2 X7 R活化半胱天冬酶-1的能力。在LPS刺激阻断LPS通过P2 X7 R增强半胱天冬酶-1活化的能力之前，用蛋白酶体抑制剂MG 132或I κ B激酶抑制剂Bay 11-7085预处理细胞，NF-κ B可能介导这种蛋白质合成。因此，巨噬细胞中的半胱天冬酶-1调节需要炎性刺激，其通过TLR发出信号以上调响应于K+释放刺激（例如ATP）激活半胱天冬酶-1加工机制所需的基因产物。
The proinflammatory cytokines IL-1 beta and IL-18 are inactive until cleaved by the enzyme caspase-1. Stimulation of the P2X7 receptor (P2X7R), an ATP-gated ion channel, triggers rapid activation of caspase-1. In this study we demonstrate that pretreatment of primary and Bac1 murine macrophages with TLR agonists is required for caspase-1 activation by P2X7R but it is not required for activation of the receptor itself. Caspase-1 activation by nigericin, a K+/H+ ionophore, similarly requires LPS priming. This priming by LPS is dependent on protein synthesis, given that cyclohexamide blocks the ability of LPS to prime macrophages for activation of caspase-1 by the P2X7R. This protein synthesis is likely mediated by NF-kappa B as pretreatment of cells with the proteasome inhibitor MG132, or the I kappa B kinase inhibitor Bay 11-7085 before LPS stimulation blocks the ability of LPS to potentiate the activation of caspase-1 by the P2X7R. Thus, caspase-1 regulation in macrophages requires inflammatory stimuli that signal through the TLRs to up-regulate gene products required for activation of the caspase-1 processing machinery in response to K+-releasing stimuli such as ATP.