Thiol-reactive metal compounds inhibit NF-κB activation by blocking IκB kinase
Thiol-reactive metal compounds inhibit NF-κB activation by blocking IκB kinase
复制标题
DOI：
10.4049/jimmunol.164.11.5981
复制
发表时间：
2000-06-01
影响因子：
4.4
通讯作者：
Jue, DM
中科院分区：
文献类型：
--
作者：
Jeon, KI;Jeong, JY;Jue, DM
金化合物用于治疗类风湿性关节炎。 NF-kappa B 是一种转录因子，与许多炎症基因的表达有关。 NF-kappa B 通过信号诱导的磷酸化和随后抑制性 I kappa B（与 NF-kappa B 分离的抑制蛋白）蛋白的降解而被激活，并且先前已鉴定出多亚基 I kappa B 激酶 (IKK)。我们测试了各种金化合物对 LPS 刺激的 RAW 264.7 小鼠巨噬细胞中 NF-kappa B 和 IKK 激活的影响，亲脂性金化合物金诺芬抑制 LPS 诱导的核 kappa B 结合活性增加、I kappa B 蛋白降解和 IKK 激活。金诺芬还阻断 TNF 和 PMA/离子霉素诱导的 IKK 激活，表明金诺芬作用的靶标在这些不同的信号通路中是常见的。添加亲水性金化合物（例如金硫苹果酸盐、金硫葡萄糖和 AuCl3）可抑制体外 IKK 活性。其他硫醇反应性金属离子（例如锌和铜）也在体外抑制 IKK 活性，并在 LPS 刺激的巨噬细胞中抑制 IKK 的诱导。体外 IKK 活性需要还原剂的存在，并通过添加硫醇基反应剂来阻断。 IKK 复合物的两个催化亚基 IKK α 和 IKK β 均被这些硫醇修饰剂抑制，表明这些亚基中存在半胱氨酸硫氢基，这对于酶活性至关重要。金化合物在治疗类风湿性关节炎中的抗炎活性可能取决于金对该硫醇基团的修饰。
Gold compounds are used in the treatment of rheumatoid arthritis. NF-kappa B is a transcription factor implicated in the expression of many inflammatory genes. NF-kappa B is activated by signal-induced phosphorylation and subsequent degradation of inhibitory I kappa B (inhibitory protein that dissociates from NF-kappa B) proteins, and a multisubunit I kappa B kinase (IKK) has been identified previously. We tested the effect of various gold compounds on the activation of NF-kappa B and IKK in LPS-stimulated RAW 264.7 mouse macrophages, A lipophilic gold compound, auranofin, suppressed the LPS-induced increase of nuclear kappa B-binding activity, degradation of I kappa B proteins, and IKK activation. Auranofin also blocked IKK activation induced by TNF and PMA/ionomycin, suggesting that the target of auranofin action is common among these diverse signal pathways. In vitro IKK activity was suppressed by addition of hydrophilic gold compounds, such as aurothiomalate, aurothioglucose, and AuCl3. Other thiol-reactive metal ions such as zinc and copper also inhibited IKK activity in vitro, and induction of IKK in LPS-stimulated macrophages. In vitro IKK activity required the presence of reducing agent and was blocked by addition of thiol group-reactive agents. Two catalytic subunits of IKK complex, IKK alpha and IKK beta, were both inhibited by these thiol-modifying agents, suggesting the presence of a cysteine sulfhydryl group in these subunits, which is critical for enzyme activity. The antiinflammatory activity of gold compounds in the treatment of rheumatoid arthritis may depend on modification of this thiol group by gold.