Pattern of interleukin-1β secretion in response to lipopolysaccharide and ATP before and after interleukin-1 blockade in patients with CIAS1 mutations
Pattern of interleukin-1β secretion in response to lipopolysaccharide and ATP before and after interleukin-1 blockade in patients with CIAS1 mutations
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DOI：
10.1002/art.22842
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发表时间：
2007-09-01
影响因子：
--
通讯作者：
Rubartelli, Anna
中科院分区：
文献类型：
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作者：
Gattorno, Marco;Tassi, Sara;Rubartelli, Anna
客观的。研究慢性婴儿神经、皮肤、关节 (CINCA) 综合征和 Muckle-Wells 综合征 (MWS) 患者中白细胞介素 1 β (IL-1 β) 的合成、加工和分泌，以及 IL-1 阻断的临床和生物学效应，以了解 CIAS1 基因突变与 IL-1 β 分泌过多之间的分子机制，以及对 IL-1 受体拮抗剂的潜在反应(IL-1Ra)。方法。六名 CINCA 综合征或 MWS 患者接受 IL-1Ra 治疗并进行纵向随访。从患者和 24 名健康供体获得的单核细胞用脂多糖 (LPS) 激活 3 小时，并通过蛋白质印迹法测定细胞内和分泌的 IL-1 β 水平。暴露于外源 ATP 之前和之后的酶联免疫吸附测定。结果。 CIAS1 突变患者的单核细胞中 LPS 诱导的 IL-1 β 分泌显着增加。然而，与健康受试者不同，IL-1β的分泌不是由外源ATP诱导的。 IL-1Ra 治疗带来了显着的临床改善，同时患者细胞在体外对 LPS 诱导的 IL-1 β 分泌进行了早期且强烈的下调。结论。我们的结果表明，在健康个体中观察到的 ATP 刺激对 IL-1 β 释放的要求在携带 CIAS1 突变的患者中被绕过。这表明冷热蛋白是 ATP 的直接目标，并且突变使蛋白质不再需要 ATP 激活。此外，IL-1Ra治疗引起的显着改善至少部分归因于首次注射拮抗剂后IL-1β分泌的强烈减少。这些发现可能对其他以 IL-1 β 增加为特征的慢性炎症有影响。
Objective. To examine the synthesis, processing, and secretion of interleukin-1 beta (IL-1 beta), as well as the clinical and biologic effects of IL-1 blockade, in patients with chronic infantile neurologic, cutaneous, articular (CINCA) syndrome and Muckle-Wells syndrome (MWS), in an effort to understand the molecular mechanisms linking mutations of the CIAS1 gene and IL-1 beta hypersecretion, and the underlying response to IL-1 receptor antagonist (IL-1Ra).Methods. Six patients with CINCA syndrome or MWS were treated with IL-1Ra and followed up longitudinally. Monocytes obtained from the patients and from 24 healthy donors were activated with lipopolysaccharide (LPS) for 3 hours, and intracellular and secreted IL-1 beta levels were determined by Western blotting and. enzyme-linked immunosorbent assay before and after exposure to exogenous ATP.Results. LPS-induced IL-1 beta secretion was markedly increased in monocytes from patients with CIAS1 mutations. However, unlike in healthy subjects, secretion of IL-1 beta was not induced by exogenous ATP. Treatment with IL-1Ra resulted in a dramatic clinical improvement, which was paralleled by an early and strong down-regulation of LPS-induced IL-1 beta secretion by the patients' cells in vitro.Conclusion. Our results showed that the requirements of ATP stimulation for IL-1 beta release observed in healthy individuals are bypassed in patients bearing CIAS1 mutations. This indicates that cryopyrin is the direct target of ATP and that the mutations release the protein from the requirement of ATP for activation. In addition, the dramatic amelioration induced by IL-1Ra treatment is at least partly due to the strong decrease in IL-1 beta secretion that follows the first injections of the antagonist. These findings may have implications for other chronic inflammatory conditions characterized by increased IL-1 beta.