Ricin Toxin Activates the NALP3 Inflammasome.
Ricin Toxin Activates the NALP3 Inflammasome.
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DOI：
10.3390/toxins2061500
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发表时间：
2010-06-01
期刊：
影响因子：
4.2
通讯作者：
Magun B
中科院分区：
文献类型：
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作者：
Lindauer M;Wong J;Magun B
蓖麻毒素具有明显的核糖毒性作用，可抑制蛋白质合成和应激激活蛋白激酶（SAPKs）的磷酸化。蓖麻毒素的促炎作用被认为是由于c-Jun N-末端激酶（JNK）和p38 MAPK的激活导致编码促炎转录物的基因上调而引起的。我们以前报道过巨噬细胞和白细胞介素-1 β（IL-1β）信号传导是小鼠宿主对输送到肺部的蓖麻毒素的免疫应答所必需的。在这里，我们报告了蓖麻毒素介导的IL-1β从骨髓源性巨噬细胞中的释放依赖于NALP 3炎性体，NALP 3炎性体是一种支架复合物，介导caspase-1将pro-IL-1 β裂解为活性IL-1β。IL-1β从巨噬细胞的释放受到活性氧（ROS）清除剂N-乙酰半胱氨酸（NAC）和高细胞外K+的抑制，这是已知抑制NALP 3/cryopyrin/CIAS 1炎性小体形成的两种试剂。通过使用p38 MAPK和JNK的抑制剂，我们证明了通过抑制SAPK磷酸化，蓖麻毒素介导的IL-1β的释放被增强，而不是被抑制。相反，蛋白酶体抑制剂硼替佐米和MG-132完全抑制蓖麻毒素诱导的巨噬细胞释放IL-1β。这些数据表明，蓖麻毒素介导的翻译抑制本身，通过促进不稳定蛋白的消失，通常抑制炎性小体的形成，可能构成了蓖麻毒素的IL-1依赖性炎症信号转导的机制。
Ricin exhibits well characterized ribotoxic actions that lead to the inhibition of protein synthesis and the phosphorylation of stress activated protein kinases (SAPKs). Proinflammatory effects of ricin are thought to be caused by upregulation of genes encoding proinflammatory transcripts as a result of the activation of c-Jun N-terminal kinase (JNK) and p38 MAPK. We reported previously that macrophages and interleukin-1β (IL-1β) signaling are required for murine host immune responses to ricin delivered to the lungs. Here we report that ricin-mediated IL-1β release from bone-marrow derived macrophages is dependent on the NALP3 inflammasome, a scaffolding complex that mediates pro-IL-1β cleavage to active IL-1β by caspase-1. Release of IL-1β from macrophages was suppressed by the reactive oxygen species (ROS) scavenger N-acetyl cysteine (NAC) and high extracellular K+, which are two agents known to inhibit NALP3/cryopyrin/CIAS1 inflammasome formation. By employing inhibitors of p38 MAPK and JNK, we demonstrated that ricin-mediated release of IL-1β was enhanced, rather than suppressed, by inhibition of SAPK phosphorylation. In contrast, proteasomal inhibitors bortezomib and MG-132 completely suppressed ricin-induced IL-1β release from macrophages. These data suggest that ricin-mediated translational inhibition itself, by fostering the disappearance of labile protein(s) that normally suppress inflammasome formation, may constitute the mechanism underlying IL-1-dependent inflammatory signaling by ricin.
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影响因子：
12.4
作者：
Petrilli, V.;Papin, S.;Tschopp, J.
通讯作者：
Tschopp, J.
影响因子：
16
作者：
Martinon, F;Burns, K;Tschopp, J
通讯作者：
Tschopp, J
DOI：
10.1046/j.1365-2613.1997.300363.x
发表时间：
1997-08-01
影响因子：
3
作者：
Brown, RFR;White, DE
通讯作者：
White, DE
影响因子：
4.4
作者：
Lindauer, Meghan L.;Wong, John;Magun, Bruce E.
通讯作者：
Magun, Bruce E.
影响因子：
30.5
作者：
通讯作者：
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