Cilostazol is anti-inflammatory in BV2 microglial cells by inactivating nuclear factor-kappaB and inhibiting mitogen-activated protein kinases
Cilostazol is anti-inflammatory in BV2 microglial cells by inactivating nuclear factor-kappaB and inhibiting mitogen-activated protein kinases
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DOI：
10.1111/j.1476-5381.2009.00615.x
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发表时间：
2010-03-01
影响因子：
7.3
通讯作者：
Choi, Il-Whan
中科院分区：
文献类型：
--
作者：
Jung, Won-Kyo;Lee, Da-Young;Choi, Il-Whan
背景与目的：西洛他唑是3'-5'-环磷酸腺苷(cAMP)磷酸二酯酶的特异性抑制剂，广泛用于治疗周围血管疾病的缺血症状。尽管西洛他唑已被证明具有血管舒张特性以及抗血小板和抗炎作用，但其在小胶质细胞中的细胞机制尚不清楚。在本研究中，我们评估了西洛他唑对脂多糖（LPS）刺激的小鼠 BV2 小胶质细胞中促炎介质产生的抗炎作用。实验方法：我们检查了西洛他唑对 LPS 诱导的核因子-κB（NF-κ B）激活和丝裂原激活蛋白激酶（MAPK）磷酸化的影响。主要结果：西洛他唑抑制了一氧化氮 (NO)、前列腺素 E-2 (PGE(2)) 和促炎细胞因子、白介素-1 (IL-1)、肿瘤坏死因子-α 和单核细胞趋化蛋白-1 (MCP-1) 的浓度依赖性。西洛他唑的抑制作用不受腺苷酸环化酶抑制剂 SQ 22536 治疗的影响，表明西洛他唑的这些作用不依赖于 cAMP。西洛他唑显着抑制 NF-kappa B 的 DNA 结合和转录活性。此外，西洛他唑通过抑制细胞外信号调节激酶 1 和 2 (ERK1/2) 以及 c-Jun N 末端激酶 (JNK) 阻断 NF-kappa B 激活的上游信号传导，但不影响 p38 MAPK 的活性。结论和意义：我们的结果表明，抑制 NF-kappa B、ERK、JNK信号通路可能会抑制 LPS 诱导的 NO 和 PGE(2) 的产生。因此，西洛他唑可能通过抑制激活的小胶质细胞中促炎介质和细胞因子的产生而具有治疗神经退行性疾病的潜力。
Background and purpose:Cilostazol is a specific inhibitor of 3'-5'-cyclic adenosine monophosphate (cAMP) phosphodiesterase, which is widely used to treat ischemic symptoms of peripheral vascular disease. Although cilostazol has been shown to exhibit vasodilator properties as well as antiplatelet and anti-inflammatory effects, its cellular mechanism in microglia is unknown. In the present study, we assessed the anti-inflammatory effect of cilostazol on the production of pro-inflammatory mediators in lipopolysaccharide (LPS)-stimulated murine BV2 microglia.Experimental approach:We examined the effects of cilostazol on LPS-induced nuclear factor-kappaB (NF-kappa B) activation and phosphorylation of mitogen-activated protein kinases (MAPKs).Key results:Cilostazol suppressed production of nitric oxide (NO), prostaglandin E-2 (PGE(2)) and the proinflammatory cytokines, interleukin-1 (IL-1), tumour necrosis factor-alpha, and monocyte chemoattractant protein-1 (MCP-1), in a concentration-dependent manner. Inhibitory effects of cilostazol were not affected by treatment with an adenylate cyclase inhibitor, SQ 22536, indicating that these actions of cilostazol were cAMP-independent. Cilostazol significantly inhibited the DNA binding and transcriptional activity of NF-kappa B. Moreover, cilostazol blocked signalling upstream of NF-kappa B activation by inhibiting extracellular signal-regulated kinases 1 and 2 (ERK1/2) and c-Jun N-terminal kinase (JNK), but without affecting the activity of p38 MAPK.Conclusion and implications:Our results demonstrate that suppression of the NF-kappa B, ERK, JNK signalling pathways may inhibit LPS-induced NO and PGE(2) production. Therefore, cilostazol may have therapeutic potential for neurodegenerative diseases by inhibiting pro-inflammatory mediators and cytokine production in activated microglia.