The bisphosphonate acute phase response:: rapid and copious production of proinflammatory cytokines by peripheral blood γδ T cells in response to aminobisphosphonates is inhibited by statins
The bisphosphonate acute phase response:: rapid and copious production of proinflammatory cytokines by peripheral blood γδ T cells in response to aminobisphosphonates is inhibited by statins
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DOI：
10.1111/j.1365-2249.2005.02665.x
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发表时间：
2005-01-01
影响因子：
4.6
通讯作者：
Sewell, AK
中科院分区：
文献类型：
--
作者：
Hewitt, RE;Lissina, A;Sewell, AK
双膦酸类药物是一类新型药物，已在全球范围内注册用于各种临床应用。已知双膦酸盐，特别是氨基双膦酸盐(NBPS)有许多副作用，包括体温上升和伴随的类似于典型急性时相反应的流感样症状。这种反应的机制已经部分阐明，似乎与肿瘤坏死因子(TNF)α和白介素6(IL)6的释放有关，尽管释放这些细胞因子的效应细胞和作用机制仍然是个谜。在这里，我们表明，NBP诱导的急性时相反应不同于典型的急性时相反应，因为CD14(+)细胞，如单核细胞和巨噬细胞，不是产生细胞因子的主要细胞。我们发现，通过抑制甲氧丙戊酸途径，NBPS可诱导外周血Gammadelta T细胞快速而大量地产生TNFα和IL6。预先使用他汀类药物可以抑制3-羟基-3-甲基戊二酰辅酶A(HMG CoA)还原酶，阻断NBP诱导的Gammadelta T细胞产生这些促炎细胞因子，并可能提供一种避免相关急性时相反应的方法。此外，我们的发现为HMG辅酶A还原酶抑制剂的抗炎作用提供了进一步的机制。
The bisphosphonates are a novel class of drug that have been registered for various clinical applications worldwide. Bisphosphonates, and in particular the aminobisphosphonates (nBPs), are known to have a number of side-effects including a rise in body temperature and accompanying flu-like symptoms that resemble a typical acute phase response. The mechanism for this response has been partially elucidated and appears to be associated with the release of tumour necrosis factor (TNF)alpha and interleukin (IL)6, although the effector cells that release these cytokines and the mechanism of action remain enigmatic. Here, we show that the nBP-induced acute phase response differs from the typical acute phase response in that CD14(+) cells such as monocytes and macrophages are not the primary cytokine producing cells. We show that by inhibiting the mevalonate pathway, nBPs induce rapid and copious production of TNFalpha and IL6 by peripheral blood gammadelta T cells. Prior treatment with statins, which inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, blocks nBP-induced production of these proinflammatory cytokines by gammadelta T cells and may offer a means of avoiding the associated acute phase response. In addition, our findings provide a further mechanism for the anti-inflammatory effects attributed to inhibitors of HMG CoA reductase.