Mutual augmentation of the induction of the histamine-forming enzyme, histidine decarboxylase, between alendronate and immuno-stimulants (IL-1, TNF, and LPS), and its prevention by clodronate
Mutual augmentation of the induction of the histamine-forming enzyme, histidine decarboxylase, between alendronate and immuno-stimulants (IL-1, TNF, and LPS), and its prevention by clodronate
复制标题
DOI：
10.1016/j.taap.2005.09.005
复制
发表时间：
2006-05-15
影响因子：
3.8
通讯作者：
Endo, Yasuo
中科院分区：
文献类型：
--
作者：
Deng, Xue;Yu, Zhiqian;Endo, Yasuo
含氮双膦酸盐（N-BPs）是一种强效的抗骨吸收药物，但具有炎症副作用，而组胺不仅是一种炎症介质，而且是一种免疫调节剂。在鼠模型中，单次腹膜内注射N-BP可诱导各种炎症反应，包括在免疫应答中重要的组织（如肝、肺、脾和骨髓）中诱导组胺形成酶组氨酸脱羧酶（HDC）。脂多糖（LPS）和促炎细胞因子IL-1和TNF也能够诱导HDC。我们以前报道过，在小鼠中，（i）N-BP的炎症作用依赖于IL-1，（ii）N-BP预处理增强LPS刺激的IL-1产生和HDC诱导，（iii）氯膦酸盐（非N-BP）与N-BP共同给药抑制后者的炎症作用（包括HDC诱导）。在这里，我们增加了新的发现，（a）阿仑膦酸钠预处理（典型的N-BP）增强IL-1和TNF诱导的HDC升高，（B）LPS预处理增强阿仑膦酸盐诱导的HDC升高，（c）氯膦酸盐与阿仑膦酸盐的共同给药消除了这些增强，（d）阿仑膦酸盐在IL-1缺陷小鼠中不诱导HDC，即使它们用LPS预处理，和（e）阿仑膦酸盐在所有测试的组织中增加IL-1 β，但在血清中不增加。这些结果表明：（1）阿仑膦酸钠与免疫增强剂之间存在相互促进作用（2）组织IL-10在阿仑膦酸钠刺激的HDC诱导中是重要的，和（3）氯膦酸盐的联合使用可能具有降低阿仑膦酸钠的炎症作用的潜力（我们以前发现氯膦酸盐不抑制阿仑膦酸盐的抗骨吸收活性）。(c)2005年爱思唯尔公司All rights reserved.
Nitrogen-containing bisphosphonates (N-BPs), powerful anti-bone-resorptive drugs, have inflammatory side effects, while histamine is not only an inflammatory mediator, but also an immuno-modifier. In murine models, a single intraperitoneal injection of an N-BP induces various inflammatory reactions, including the induction of the histamine-forming enzyme histidine decarboxylase (HDC) in tissues important in immune responses (such as liver, lungs, spleen, and bone marrow). Lipopolysaccharide (LPS) and the proinflammatory cytokines IL-1 and TNF are also capable of inducing HDC. We reported previously that in mice, (i) the inflammatory actions of N-BPs depend on IL-1, (ii) N-BP pretreatment augments both LPS-stimulated IL-1 production and HDC induction, and (iii) the co-administration of clodronate (a non-N-BP) with an N-BP inhibits the latter's inflammatory actions (including HDC induction). Here, we add the new findings that (a) pretreatment with alendronate (a typical N-BP) augments both IL-1- and TNF-induced HDC elevations, (b) LPS pretreatment augments the alendronate-induced HDC elevation, (c) co-administration of clodronate with alendronate abolishes these augmentations, (d) alendronate does not induce HDC in IL-1-deficient mice even if they are pretreated with LPS, and (e) alendronate increases IL-1 p in all tissues tested, but not in the serum. These results suggest that (1) there are mutual augmentations between alendronate and immuno-stimulants (IL-1, TNF, and LPS) in HDC induction, (2) tissue IL-10 is important in alendronate-stimulated HDC induction, and (3) combination use of clodronate may have the potential to reduce the inflammatory effects of alendronate (we previously found that clodronate, conveniently, does not inhibit the anti-bone-resorptive activity of alendronate). (c) 2005 Elsevier Inc. All rights reserved.