oxLDL antibody inhibits MCP-1 release in monocytes/macrophages by regulating Ca(2+) /K(+) channel flow.
oxLDL antibody inhibits MCP-1 release in monocytes/macrophages by regulating Ca(2+) /K(+) channel flow.
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DOI：
10.1111/jcmm.13033
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发表时间：
2017-05
影响因子：
5.3
通讯作者：
Zhao M
中科院分区：
文献类型：
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作者：
Su J;Zhou H;Liu X;Nilsson J;Fredrikson GN;Zhao M
oxLDL肽疫苗及其抗体过继转移在动脉粥样硬化动物模型中显示出显著的预防或治疗作用。这背后的分子机制尚不清楚。在这里，我们报告oxLDL通过TLR-4（Toll样受体4）和ERK MAPK途径诱导单核细胞/巨噬细胞中MCP-1释放，并且具有钙/钾通道依赖性。使用针对CD 36、TLR-4、SR-AI和LOX-1的阻断抗体，发现仅TLR-4抗体具有抑制作用，并且发现ERK MAPK特异性抑制剂（PD 98059）与其他MAPK组成员（p38和JNK MAPK）的抑制剂相比对oxLDL诱导的MCP-1释放具有显著的抑制作用。细胞因子和趋化因子的释放需要细胞外钙离子的内流和钾离子外流的不平衡。电压依赖性钙通道（VDCC）抑制剂硝苯地平和ATP调节钾通道（K+ ATP）抑制剂格列本脲可抑制oxLDL诱导的MCP-1释放。钾流出和内流平衡维持巨噬细胞开放钙通道的负电位，我们的结果表明，oxLDL实际上诱导了钾内流通道-内向整流通道（Kir）的关闭，从而导致钙通道的开放。ERK MAPK抑制剂PD 98059抑制oxLDL诱导的Ca 2 +/Kir通道改变。其单克隆抗体通过FcγRIIB（CD 32）干扰oxLDL诱导的MCP-1释放。使用针对FcγRI（CD 64）、FcγRIIB（CD 32）和FcγRIII（CD 16）的阻断抗体，发现仅CD 32阻断抗体可逆转oxLDL抗体对oxLDL诱导的MCP-1释放的抑制作用。有趣的是，oxLDL抗体特异性抑制oxLDL诱导的ERK MAPK激活和随后的Ca 2 +/Kir通道改变，以及MCP-1释放。因此，我们发现了oxLDL抗体抑制oxLDL诱导的ERK MAPK通路和随后的MCP-1释放的分子机制。
oxLDL peptide vaccine and its antibody adoptive transferring have shown a significantly preventive or therapeutic effect in atherosclerotic animal model. The molecular mechanism behind this is obscure. Here, we report that oxLDL induces MCP‐1 release in monocytes/macrophages through their TLR‐4 (Toll‐like receptor 4) and ERK MAPK pathway and is calcium/potassium channel‐dependent. Using blocking antibodies against CD36, TLR‐4, SR‐AI and LOX‐1, only TLR‐4 antibody was found to have an inhibitory effect and ERK MAPK‐specific inhibitor (PD98059) was found to have a dramatic inhibitory effect compared to inhibitors of other MAPK group members (p38 and JNK MAPKs) on oxLDL‐induced MCP‐1 release. The release of cytokines and chemokines needs influx of extracellular calcium and imbalance of efflux of potassium. Nifedipine, a voltage‐dependent calcium channel (VDCC) inhibitor, and glyburide, an ATP‐regulated potassium channel (K+ ATP) inhibitor, inhibit oxLDL‐induced MCP‐1 release. Potassium efflux and influx counterbalance maintains the negative potential of macrophages to open calcium channels, and our results suggest that oxLDL actually induces the closing of potassium influx channel – inward rectifier channel (Kir) and ensuing the opening of calcium channel. ERK MAPK inhibitor PD98059 inhibits oxLDL‐induced Ca2+/Kir channel alterations. The interfering of oxLDL‐induced MCP‐1 release by its monoclonal antibody is through its FcγRIIB (CD32). Using blocking antibodies against FcγRI (CD64), FcγRIIB (CD32) and FcγRIII (CD16), only CD32 blocking antibody was found to reverse the inhibitory effect of oxLDL antibody on oxLDL‐induced MCP‐1 release. Interestingly, oxLDL antibody specifically inhibits oxLDL‐induced ERK MAPK activation and ensuing Ca2+/Kir channel alterations, and MCP‐1 release. Thus, we found a molecular mechanism of oxLDL antibody on inhibition of oxLDL‐induced ERK MAPK pathway and consequent MCP‐1 release.