Glyburide inhibits the Cryopyrin/Nalp3 inflammasome.
Glyburide inhibits the Cryopyrin/Nalp3 inflammasome.
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DOI：
10.1083/jcb.200903124
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发表时间：
2009-10-05
期刊：
影响因子：
--
通讯作者：
Dixit VM
中科院分区：
文献类型：
--
作者：
Lamkanfi M;Mueller JL;Vitari AC;Misaghi S;Fedorova A;Deshayes K;Lee WP;Hoffman HM;Dixit VM
格列本脲是一种常用于治疗2型糖尿病的磺酰脲类药物，通过阻止Cyropyrin活化来关闭IL-1β分泌。炎性小体激活半胱天冬酶-1以加工和分泌细胞因子白细胞介素-1 β（IL-1β）和IL-18。Cryopyrin/NALP 3/NLRP 3是由微生物配体、微生物相关分子模式（DAMP）和晶体触发的炎性小体的重要组分。不适当的Cryopyrin活性已被牵连在痛风性关节炎，阿尔茨海默氏症和矽肺的发病机制。因此，Nalp 3炎性体的抑制剂提供了相当大的治疗前景。在这项研究中，我们表明，2型糖尿病药物格列本脲防止激活的Cryopyrin炎性小体。格列本脲的环己基脲基团与三磷酸腺苷（ATP）敏感性K+（KATP）通道结合，用于胰岛素分泌，对炎性小体抑制作用显著。缺乏KATP亚基或ATP结合盒转运蛋白的巨噬细胞也能正常激活Cryopyrin炎性小体。格列本脲类似物抑制ATP诱导的表达家族性寒冷相关自身炎症综合征相关Cryopyrin突变的人单核细胞分泌IL-1β，但不抑制低血糖诱导的IL-1β分泌，因此表明抑制作用发生在Cryopyrin的上游。与Cryopyrin在内毒素血症中的作用同时，格列本脲显著延迟了脂多糖诱导的小鼠致死性。因此，格列本脲是第一个被鉴定的防止Cryopyrin活化和微生物配体、DAMP和晶体诱导的IL-1β分泌的化合物。
Glyburide, a sulfonylurea drug commonly used to treat type 2 diabetes, shuts down IL-1β secretion by preventing Cyropyrin activation. Inflammasomes activate caspase-1 for processing and secretion of the cytokines interleukin-1β (IL-1β) and IL-18. Cryopyrin/NALP3/NLRP3 is an essential component of inflammasomes triggered by microbial ligands, danger-associated molecular patterns (DAMPs), and crystals. Inappropriate Cryopyrin activity has been incriminated in the pathogenesis of gouty arthritis, Alzheimer's, and silicosis. Therefore, inhibitors of the Nalp3 inflammasome offer considerable therapeutic promise. In this study, we show that the type 2 diabetes drug glyburide prevented activation of the Cryopyrin inflammasome. Glyburide's cyclohexylurea group, which binds to adenosine triphosphatase (ATP)–sensitive K+ (KATP) channels for insulin secretion, is dispensable for inflammasome inhibition. Macrophages lacking KATP subunits or ATP-binding cassette transporters also activate the Cryopyrin inflammasome normally. Glyburide analogues inhibit ATP- but not hypothermia-induced IL-1β secretion from human monocytes expressing familial cold-associated autoinflammatory syndrome–associated Cryopyrin mutations, thus suggesting that inhibition occurs upstream of Cryopyrin. Concurrent with the role of Cryopyrin in endotoxemia, glyburide significantly delays lipopolysaccharide-induced lethality in mice. Therefore, glyburide is the first identified compound to prevent Cryopyrin activation and microbial ligand-, DAMP-, and crystal-induced IL-1β secretion.
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DOI：
10.1073/pnas.0611496104
发表时间：
2007-05-08
影响因子：
11.1
作者：
Duncan, Joseph A.;Bergstralht, Daniel T.;Ting, Jenny Pan-Yun
通讯作者：
Ting, Jenny Pan-Yun
影响因子：
4.4
作者：
Lamkanfi, Mohamed;Amer, Amal;Nunez, Gabriel
通讯作者：
Nunez, Gabriel
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
56.9
作者：
Dostert, Catherine;Petrilli, Virginie;Tschopp, Jurg
通讯作者：
Tschopp, Jurg
影响因子：
4.8
作者：
Pelegrin, Pablo;Surprenant, Annmarie
通讯作者：
Surprenant, Annmarie