Anti-inflammatory effects of α-galactosylceramide analogs in activated microglia: involvement of the p38 MAPK signaling pathway.
Anti-inflammatory effects of α-galactosylceramide analogs in activated microglia: involvement of the p38 MAPK signaling pathway.
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DOI：
10.1371/journal.pone.0087030
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Kim HS
中科院分区：
文献类型：
--
作者：
Jeong YH;Kim Y;Song H;Chung YS;Park SB;Kim HS
小胶质细胞活化在神经退行性疾病的发生和发展中起着关键作用。因此，控制小胶质细胞活化的抗炎剂可以作为神经退行性疾病的潜在治疗剂。在这里，我们设计并合成了α-半乳糖神经酰胺（α-GalCer）类似物，以在活化的小胶质细胞中发挥抗炎作用。我们对25种α-GalCer类似物进行了生物学评价，并观察到它们对LPS刺激的BV 2小胶质细胞中NO释放和TNF-α产生的抑制作用存在有趣的初步构效关系。在鉴定4d和4 e为命中化合物后，我们进一步使用RT-PCR分析研究其抗炎作用的潜在机制。我们证实4d和4 e在mRNA水平调节iNOS、考克斯-2、IL-1β和IL-6的表达，在转录后水平调节TNF-α的表达。此外，4d和4 e均抑制LPS诱导的NF-κB和AP-1的DNA结合活性以及p38 MAPK的磷酸化，而不影响其他MAP激酶。当我们检测p38 MAPK特异性抑制剂SB 203580对小胶质细胞活化的抗炎作用时，我们观察到与4d和4 e相同的抑制模式，不仅对NO和TNF-α的产生，而且对NF-κB和AP-1的DNA结合活性。这些结果提示p38 MAPK通过调节NF-κB和AP-1活性在4d和4 e的抗炎作用中发挥重要作用。
Microglial activation plays a pivotal role in the development and progression of neurodegenerative diseases. Thus, anti-inflammatory agents that control microglial activation can serve as potential therapeutic agents for neurodegenerative diseases. Here, we designed and synthesized α-galactosylceramide (α-GalCer) analogs to exert anti-inflammatory effects in activated microglia. We performed biological evaluations of 25 α-GalCer analogs and observed an interesting preliminary structure-activity relationship in their inhibitory influence on NO release and TNF-α production in LPS-stimulated BV2 microglial cells. After identification of 4d and 4e as hit compounds, we further investigated the underlying mechanism of their anti-inflammatory effects using RT-PCR analysis. We confirmed that 4d and 4e regulate the expression of iNOS, COX-2, IL-1β, and IL-6 at the mRNA level and the expression of TNF-α at the post-transcriptional level. In addition, both 4d and 4e inhibited LPS-induced DNA binding activities of NF-κB and AP-1 and phosphorylation of p38 MAPK without affecting other MAP kinases. When we examined the anti-inflammatory effect of a p38 MAPK-specific inhibitor, SB203580, on microglial activation, we observed an identical inhibitory pattern as that of 4d and 4e, not only on NO and TNF-α production but also on the DNA binding activities of NF-κB and AP-1. Taken together, these results suggest that p38 MAPK plays an important role in the anti-inflammatory effects of 4d and 4e via the modulation of NF-κB and AP-1 activities.
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影响因子：
15
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