IL-converting enzyme/caspase-I inhibitor VX-765 blocks the hypersensitive response to an inflammatory stimulus in monocytes from familial cold autoinflammatory syndrome patients
IL-converting enzyme/caspase-I inhibitor VX-765 blocks the hypersensitive response to an inflammatory stimulus in monocytes from familial cold autoinflammatory syndrome patients
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DOI：
10.4049/jimmunol.175.4.2630
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发表时间：
2005-08-15
影响因子：
4.4
通讯作者：
Hoffman, HM
中科院分区：
文献类型：
--
作者：
Stack, JH;Beaumont, K;Hoffman, HM
家族性寒冷性自身炎症综合征 (FCAS) 和相关的自身炎症性疾病、Muckle-Wells 综合征和新生儿发病的多系统炎症性疾病，其特征是编码冷热蛋白（一种参与 IL 转换酶/Caspase-1 激活的接头蛋白）的 CIAS1 基因突变。据推测，冷热蛋白突变会导致 caspase-1 依赖性促炎细胞因子、IL-1β 和 IL-18 的异常分泌。在这项研究中，我们检查了 FCAS 患者 PBMC 中的细胞因子分泌，发现 IL-1 β 和 IL-18 分泌对 LPS 刺激有明显的高反应性，但没有证据表明这些细胞因子的基础分泌增加，或基础或刺激的 pro-IL-1 β 水平发生变化。 VX-765 是一种口服活性 IL 转换酶/caspase-1 抑制剂，在来自 FCAS 和对照受试者的 LPS 刺激细胞中，以相同的效力阻断 IL-1 β 分泌。这些结果进一步将冷热蛋白突变与异常 caspase-1 激活联系起来，并支持 caspase-1 抑制剂（例如 VX-765）在自身炎症性疾病中的临床测试。
Familial cold autoinflammatory syndrome (FCAS) and the related autoinflammatory disorders, Muckle-Wells syndrome and neonatal onset multisystem inflammatory disease, are characterized by mutations in the CIAS1 gene that encodes cryopyrin, an adaptor protein involved in activation of IL-converting enzyme/caspase-1. Mutations in cryopyrin are hypothesized to result in abnormal secretion of caspase-1-dependent proinflammatory cytokines, IL-1 beta and IL-18. In this study, we examined cytokine secretion in PBMCs from FCAS patients and found a marked hyperresponsiveness of both IL-1 beta and IL-18 secretion to LPS stimulation, but no evidence of increased basal secretion of these cytokines, or alterations in basal or stimulated pro-IL-1 beta levels. VX-765, an orally active IL-converting enzyme/caspase-1 inhibitor, blocked IL-1 beta secretion with equal potency in LPS-stimulated cells from FCAS and control subjects. These results further link mutations in cryopyrin with abnormal caspase-1 activation, and support the clinical testing of caspase-1 inhibitors such as VX-765 in autoinflammatory disorders.