Inhibition of nuclear factor-kappab activation in mouse macrophages and the RAW 264.7 cell line by a synthetic adenyl carbocyclic nucleoside.
Inhibition of nuclear factor-kappab activation in mouse macrophages and the RAW 264.7 cell line by a synthetic adenyl carbocyclic nucleoside.
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合成腺苷碳环核苷抑制小鼠巨噬细胞和 RAW 264.7 细胞系中核因子-kappab 的激活。
DOI：
10.1016/s0006-2952(00)00367-1
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发表时间：
2000
影响因子：
5.8
通讯作者：
Parmely,MJ
中科院分区：
文献类型：
--
作者：
Xia,D;Wang,F;Parmely,MJ
腺基碳环核苷对多种细胞有很强的抗炎作用。在这方面值得注意的是，它们能够抑制由细菌脂多糖激活的小鼠巨噬细胞产生肿瘤坏死因子-α(肿瘤坏死因子-α)。由于小鼠肿瘤坏死因子-α基因的转录激活高度依赖于κB增强子，本研究确定了合成的碳环核苷9-[(1S，3R)-顺式-环戊烷-3-醇]腺嘌呤(CPA)是否能抑制脂多糖诱导的核因子-κB(NF-κB)的激活。用脂多糖刺激小鼠腹膜巨噬细胞或RAW 264.7巨噬细胞样细胞，凝胶迁移率改变分析检测到四种不同的κB结合核蛋白复合体。经100μM CPA处理的细胞显示，核蛋白κB结合活性的测量和依赖于κB的转录激活减弱，表明核蛋白κB的激活水平显著降低。然而，核苷对脂多糖诱导的胞浆内核转录因子κB抑制物IκBα的降解和核转位的核转位κB p50、p65和c-Rel多肽均无影响。这些发现表明，某些腺基碳环核苷通过一种新的机制抑制NF-κB/REL复合体的激活，从而抑制它们的结合活性，而不阻止它们与IκBα的解离或它们的核转位。
Adenyl carbocyclic nucleosides have potent anti-inflammatory effects on a number of cell types. Notable in this regard is their ability to inhibit the production of tumor necrosis factor-α (TNF-α) by mouse macrophages that have been activated with bacterial lipopolysaccharide (LPS). Because the transcriptional activation of the mouse TNF-α gene is highly dependent on κB enhancers, the present study determined whether the synthetic carbocyclic nucleoside 9-[(1S,3R)-cis-cyclopentan-3-ol]adenine (cPA) inhibited LPS-induced nuclear factor-κB (NF-κB) activation in these cells. Stimulation of either mouse peritoneal macrophages or RAW 264.7 macrophage-like cells with LPS led to the appearance of four distinct κB-binding nucleoprotein complexes detected by gel mobility shift assays. Cells treated with 100 μM cPA showed significantly reduced levels of NF-κB activation as evidenced by measurements of nucleoprotein κB-binding activity and diminished κB-dependent transcriptional activation. However, both the LPS-induced degradation of the cytoplasmic NF-κB inhibitor IκBα and the nuclear translocation of the NF-κB p50, p65, and c-Rel peptides were unaffected by treatment of the cells with the nucleoside. These findings suggest that certain adenyl carbocyclic nucleosides inhibit the activation of NF-κB/Rel complexes by a novel mechanism that results in an inhibition of their DNA-binding activities, without blocking their dissociation from IκBα or their nuclear translocation.