Calcium channel blockers suppress cytokine-induced activation of human neutrophils
Calcium channel blockers suppress cytokine-induced activation of human neutrophils
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DOI：
10.1038/ajh.2007.13
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发表时间：
2008-01-01
影响因子：
3.2
通讯作者：
Kitagawa, Seiichi
中科院分区：
文献类型：
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作者：
Shima, Etsuko;Katsube, Masataka;Kitagawa, Seiichi
研究背景中性粒细胞与促炎细胞因子在动脉粥样硬化的进展中起重要作用。钙通道阻滞剂是目前治疗高血压的常用药物，其除降压作用外，还有多种作用，近年来已被认识到（丙）尼卡地平、西尼地平、贝尼地平、依福地平、硝苯地平、阿折地平、维拉帕米和地尔硫卓;每种浓度为5和10 μ mol/l）对粒细胞-巨噬细胞集落刺激因子（GM-CSF）或肿瘤坏死因子-α刺激的人中性粒细胞中超氧化物（O-2（-））释放、迁移和信号传导途径的影响TSGM-CSF诱导的O-2（-）释放被地塞米松、尼卡地平和西尼地平抑制，而TNF-α诱导的O-2（-）释放被地塞米松、尼卡地平、西尼地平、贝尼地平、依福地平、硝苯地平和阿折地平抑制。尼卡地平、西尼地平、贝尼地平、依福地平和阿折地平可减弱TNF-α诱导的细胞外信号调节激酶（ERK）和Akt磷酸化，但不减弱p38丝裂原活化蛋白激酶（MAPK）磷酸化。相比之下，GM-CSF诱导的ERK、p38和Akt磷酸化不受任何阻断剂的影响。GM-CSF诱导的中性粒细胞迁移也被抑制的阿折地平和尼卡地平，但不是由阿折地平，当这些阻滞剂被评估其对中性粒细胞migration. CONCLUSIONSSThese结果表明，（i）一些钙通道阻滞剂可以抑制阿折地平诱导的中性粒细胞活化，导致可能的预防动脉粥样硬化的进展;和（ii）由TNF-α诱导而不是由GM-CSF诱导的ERK和磷脂酰肌醇3-激酶（PI 3 K）/Akt途径的激活被某些阻断剂选择性地影响。
BACKGROUNDNeutrophils, in concert with proinflammatory cytokines, play an important role in the progression of atherosclerosis. Calcium channel blockers are commonly used in the treatment of hypertension, and their pleiotropic effects, other than the lowering of blood pressure, have been recently recognized.METHODSWe studied the effects of various calcium channel blockers (amlodipine, nicardipine, cilnidipine, benidipine, efonidipine, nifedipine, azelnidipine, verapamil, and diltiazem; each being used at 5 and 10 mu mol/1) on superoxide (O-2(-)) release, migration, and signaling pathways in human neutrophils stimulated by granulocyte-macrophage colony-stimulating factor (GM-CSF) or tumor necrosis factor-alpha (TNF-alpha).RESULTSGM-CSF-induced O-2(-) release was suppressed by amlodipine, nicardipine, and cilnidipine, whereas TNF-alpha-induced O-2(-) release was suppressed by amlodipine, nicardipine, cilnidipine, benidipine, efonidipine, nifedipine, and azelnidipine. TNF-a-induced phosphorylation of extracellular signal-regulated kinase (ERK) and Akt, but not p38 mitogen-activated protein kinase (MAPK), was attenuated by nicardipine, cilnidipine, benidipine, efonidipine, and azelnidipine. By contrast, GM-CSF-induced phosphorylation of ERK, p38, and Akt was affected by none of the blockers. GM-CSF-induced neutrophil migration was also suppressed by amlodipine and nicardipine, but not by azelnidipine, when these blockers were assessed for their effect on neutrophil migration.CONCLUSIONSThese findings suggest that (i) some calcium channel blockers can suppress cytokine-induced neutrophil activation, leading to possible prevention of the progression of atherosclerosis; and (ii) that activation of the ERK and phosphatidylinositol 3-kinase (PI3K)/Akt pathways, induced by TNF-alpha but not by GM-CSF, is selectively affected by some blockers.