Foreign body-type multinucleated giant cell formation is potently induced by α-tocopherol and prevented by the diacylglycerol kinase inhibitor R59022
Foreign body-type multinucleated giant cell formation is potently induced by α-tocopherol and prevented by the diacylglycerol kinase inhibitor R59022
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DOI：
10.1016/s0002-9440(10)63474-8
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发表时间：
2003-09-01
影响因子：
6
通讯作者：
Anderson, JM
中科院分区：
文献类型：
--
作者：
McNally, AK;Anderson, JM
多核异物巨细胞（FBGC）是通过单核细胞衍生的巨噬细胞融合在植入的生物医学器械上形成的，据信介导了生物材料表面的氧化损伤。我们的人巨噬细胞培养和白细胞介素（IL）-4诱导的FBGC形成的体外系统的开发，以研究巨噬细胞融合机制和FBGC的生理意义上植入的生物材料和在其他网站的慢性炎症。在这里，我们证明了抗氧化剂维生素E（90% α-生育酚）适度诱导巨噬细胞融合，并增加IL-4诱导的FBGC形成。此外，纯化的α-生育酚，而不是β-、γ-或δ-生育酚，最显著地诱导巨噬细胞融合，导致低于正常血浆浓度的汇合FBGC的培养物。这在类似的抗氧化剂普罗布考或Trolox中没有观察到，表明α-生育酚对FBGC形成的影响与其抗氧化活性无关。与报道的α-生育酚激活二酰基甘油激酶一致，二酰基甘油激酶抑制剂R59022完全消除FBGC形成。R59022对IL-4诱导的FBGC形成的抑制被α-生育酚逆转，表明FBGC形成涉及二酰基甘油激酶活化。这项研究表明，在慢性炎症部位的巨噬细胞融合/ FBGC形成机制中，二酰基甘油激酶发挥了新的作用，并揭示了多效性亲脂性化合物α-生育酚是一种高效的巨噬细胞融合因子。
Multinucleated foreign body giant cells (FBGCs) form by monocyte-derived macrophage fusion on implanted biomedical devices and are believed to mediate oxidative damage to biomaterial surfaces. Our in vitro system of human macrophage culture and interleukin (IL)-4-induced FBGC formation was developed to study the macrophage fusion mechanism and the physiological significance of FBGCs on implanted biomaterials and at other sites of chronic inflammation. Here, we demonstrate that the antioxidant vitamin E (90% alpha-tocopherol) moderately induces macrophage fusion and increases IL-4-induced FBGC formation. Moreover, purified a-tocopherol, but not beta-, gamma-, or delta-tocopherol, most remarkably induces macrophage fusion, leading to cultures of confluent FBGCs below normal plasma concentrations. This is not observed with the similar antioxidants; probucol or Trolox, suggesting that the a-tocopherol effects on FBGC formation are independent of its antioxidant activity. Consistent with the reported activation of diacylglycerol kinase by a-tocopherol, the diacylglycerol kinase inhibitor R59022 completely abrogates FBGC formation. R59022 inhibition of IL-4-induced FBGC formation is reversed by alpha-tocopherol, suggesting that FBGC formation involves diacylglycerol kinase activation. This study suggests a novel role for diacylglycerol kinase in the mechanism of macrophage fusion/ FBGC formation at sites of chronic inflammation and reveals that the pleiotropic lipophilic compound, alpha-tocopherol, is a highly potent macrophage fusion factor.