Contrasting effects of alendronate and clodronate on RAW 264 macrophages:: the role of a bisphosphonate metabolite
Contrasting effects of alendronate and clodronate on RAW 264 macrophages:: the role of a bisphosphonate metabolite
复制标题
DOI：
10.1016/s0928-0987(98)00065-7
复制
发表时间：
1999-05-01
影响因子：
4.6
通讯作者：
Mönkkönen, J
中科院分区：
文献类型：
--
作者：
Makkonen, N;Salminen, A;Mönkkönen, J
氯膦酸盐(二氯亚甲基双膦酸盐)是一种含卤素的双膦酸盐，可抑制原始264巨噬细胞释放细胞因子，并在类风湿关节炎中具有抗炎作用，而含氨基的双膦酸盐如阿伦磷酸(4-氨基-1-羟基丁叉双膦酸盐)具有促炎性质，可引起急性时相反应。这些药理作用的基础尚不清楚。最近，研究表明，氯屈膦酸盐在体外可被某些细胞株代谢成一种三磷酸腺苷的类似物，而氨基双膦酸类则不能。因此，我们研究了氯屈磷酸钠是否也可以被未加工的264巨噬细胞代谢，以及代谢产物(AppCCl(2)p)在细胞内的积累是否可以解释氯屈磷酸钠的抗炎特性。比较了阿伦磷酸钠和AppCCl(2)p对RAW 264细胞释放细胞因子(IL-1β、IL-6和TNFα)的影响，并研究了双膦酸盐和AppCCl(2)p对转录因子核因子-kappaB和AP-1 DNA结合活性的影响。在凝胶迁移率改变分析中，用阿伦磷酸钠预处理RAW 264巨噬细胞可增加内毒素刺激的IL-1β的释放，并增加核因子-kappa B与DNA的结合。在没有内毒素诱导的情况下，阿伦磷酸钠不影响细胞因子的释放或核因子-kappaB的结合。氯屈磷酸钠可被RAW 264细胞代谢成AppCCl(2)p。与氯屈磷酸钠一样，AppCCl(2)p也能抑制脂多糖诱导的巨噬细胞释放细胞因子和NO。氯屈膦酸盐及其代谢物也可抑制内毒素刺激的核因子-kappaB与DNA的结合。综上所述，这些结果表明，氯磷酸盐的代谢物可能与氯磷酸盐的抗炎特性有关，不同的双膦酸盐对细胞因子释放的不同影响可能部分是通过改变核因子-kappa B的DNA结合活性来实现的。
Clodronate (dichloromerhylidene-bisphosphonate), a halogen-containing bisphosphonate, can inhibit the release of cytokines from RAW 264 macrophages and has anti-inflammatory properties in rheumatoid arthritis, whilst amino-containing bisphosphonates such as alendronate (4-amino-1-hydroxybutylidene-bisphosphonate), have pro-inflammatory properties and can cause an acute phase response. The basis for these pharmacological properties is unclear. Recently, it was demonstrated that clodronate is metabolised by certain cell lines in vitro to an analogue of ATP, whereas amino-bisphosphonates are not. We therefore investigated whether clodronate can also be metabolised by RAW 264 macrophages and whether intracellular accumulation of the metabolite (AppCCl(2)p) could account for the anti-inflammatory properties of clodronate. The effect of alendronate and AppCCl(2)p on the release of cytokines (IL-1 beta, IL-6, and TNF alpha) from RAW 264 cells was compared, and the effect of the bisphosphonates and AppCCl(2)p on the DNA binding activities of transcription factors, NF-kappa B and AP-1, was investigated. Pretreatment of RAW 264 macrophages with alendronate augmented the LPS-stimulated release of IL-1 beta and increased the binding of NF-kappa B to DNA in an electrophoretic mobility shift assay. Without LPS-induction, alendronate did not affect cytokine release or NF-kappa B binding. Clodronate was metabolised by RAW 264 cells to AppCCl(2)p. Like clodronate, AppCCl(2)p inhibited the LPS-induced release of cytokines and NO from RAW 264 macrophages. Both clodronate and its metabolite also inhibited the LPS-stimulated binding of NF-kappa B to DNA. in conclusion, these results suggest that the metabolite of clodronate may be responsible for the anti-inflammatory properties of clodronate, and that the contrasting effects of different bisphosphonates on the release of cytokines could be mediated partly through changes in the DNA binding activity of NF-kappa B. (C) 1999 Elsevier Science B.V. All rights reserved.