Inhibition of NF-kappa B activity by thalidomide through suppression of IkappaB kinase activity.
Inhibition of NF-kappa B activity by thalidomide through suppression of IkappaB kinase activity.
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发表时间：
2001
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通讯作者：
J. A. Keifer;D. Guttridge;B. P. Ashburner;A. Baldwin
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作者：
J. A. Keifer;D. Guttridge;B. P. Ashburner;A. Baldwin
镇静和抗恶心药物沙利度胺，导致人类出生缺陷，已被证明具有抗炎和抗癌特性。沙利度胺的抗炎作用与抑制细胞因子表达和抑制血管生成的抗癌作用有关。目前尚不清楚沙利度胺的致畸特性是否以任何方式与该药物的有益的抗疾病特性有关。转录因子NF-κ B已被证明是炎症基因如肿瘤坏死因子-α和白细胞介素-8的关键调节因子。NF-κ B的抑制与动物模型中的炎症减少有关，例如类风湿性关节炎。我们发现沙利度胺可以通过抑制IkappaB激酶的活性来阻断NF-κ B的激活。与观察到的NF-kappaB抑制一致，沙利度胺阻断了细胞因子诱导的NF-kappaB调节基因（例如编码白细胞介素-8、TRAF 1和c-IAP 2的基因）的表达。这些数据表明，沙利度胺的治疗潜力可能是基于其通过抑制IkappaB激酶活性来阻断NF-κ B活化的能力。
The sedative and anti-nausea drug thalidomide, which causes birth defects in humans, has been shown to have both anti-inflammatory and anti-oncogenic properties. The anti-inflammatory effect of thalidomide is associated with suppression of cytokine expression and the anti-oncogenic effect with inhibition of angiogenesis. It is presently unclear whether the teratogenic properties of thalidomide are connected in any way to the beneficial, anti-disease characteristics of this drug. The transcription factor NF-kappaB has been shown to be a key regulator of inflammatory genes such as tumor necrosis factor-alpha and interleukin-8. Inhibition of NF-kappaB is associated with reduced inflammation in animal models, such as those for rheumatoid arthritis. We show here that thalidomide can block NF-kappaB activation through a mechanism that involves the inhibition of activity of the IkappaB kinase. Consistent with the observed inhibition of NF-kappaB, thalidomide blocked the cytokine-induced expression of NF-kappaB-regulated genes such as those encoding interleukin-8, TRAF1, and c-IAP2. These data indicate that the therapeutic potential for thalidomide may be based on its ability to block NF-kappaB activation through suppression of IkappaB kinase activity.