Jovinge S, Ares M P, Kallin B, Nilsson J
Department of Medicine, Karolinska Hospital, King Gustaf Vth Research Institute, Stockholm, Sweden.
Arterioscler Thromb Vasc Biol. 1996 Dec;16(12):1573-9. doi: 10.1161/01.atv.16.12.1573.
The uptake of oxidatively modified low density lipoprotein (Ox-LDL) by intimal macrophages is believed to play a key role in the development of atherosclerosis. The present study demonstrates that Ox-LDL in low concentrations activates monocyte/macrophage release of factors that stimulate smooth muscle cell growth, whereas higher concentrations are inhibitory. Exposure of monocytes/macrophages to 8 micrograms/mL Ox-LDL increased expression of tumor necrosis factor-alpha (TNF-alpha) mRNA but had no effect on interleukin-1 beta, platelet-derived growth factor B and heparin-binding epidermal growth factor-like mitogen mRNA levels. Ox-LDL also stimulated monocyte/macrophage release of TNF-alpha in a dose-dependent manner, with maximal effect at an LDL concentration of 8 micrograms/mL. Addition of TNF-alpha-blocking antibodies to conditioned medium from monocytes/ macrophages already exposed to Ox-LDL reduced mitogenic activity by 44.7 +/- 8.4% (P < .005). Stimulation of TNF-alpha release by Ox-LDL was associated with activation of transcription factor AP-1, whereas the activity of transcription factor nuclear factor-kB remained unchanged. These findings suggest that enhanced secretion of TNF-alpha by macrophages exposed to Ox-LDL may be involved in the formation of atherosclerotic lesions.
内膜巨噬细胞对氧化修饰的低密度脂蛋白（Ox-LDL）的摄取被认为在动脉粥样硬化的发展中起关键作用。本研究表明，低浓度的Ox-LDL可激活单核细胞/巨噬细胞释放刺激平滑肌细胞生长的因子，而高浓度则具有抑制作用。单核细胞/巨噬细胞暴露于8微克/毫升的Ox-LDL会增加肿瘤坏死因子-α（TNF-α）mRNA的表达，但对白细胞介素-1β、血小板衍生生长因子B和肝素结合表皮生长因子样丝裂原mRNA水平没有影响。Ox-LDL还以剂量依赖的方式刺激单核细胞/巨噬细胞释放TNF-α，在LDL浓度为8微克/毫升时效果最佳。向已经暴露于Ox-LDL的单核细胞/巨噬细胞的条件培养基中添加TNF-α阻断抗体可使促有丝分裂活性降低44.7±8.4%（P<.005）。Ox-LDL刺激TNF-α释放与转录因子AP-1的激活有关，而转录因子核因子-κB的活性保持不变。这些发现表明，暴露于Ox-LDL的巨噬细胞增强分泌TNF-α可能参与动脉粥样硬化病变的形成。
