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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

机译:双膦酸盐急性期反应:他汀类药物可抑制外周血γδT细胞对氨基双膦酸盐的反应而迅速大量产生促炎细胞因子

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摘要

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)α 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 TNFα and IL6 by peripheral blood γδ 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 γδ 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.
机译:双膦酸盐是一类新颖的药物,已在全球范围内用于各种临床应用。已知双膦酸酯,尤其是氨基双膦酸酯(nBP)具有许多副作用,包括体温升高和伴随的类似于典型急性期反应的流感样​​症状。尽管已经释放了这些细胞因子的效应细胞和作用机制仍然神秘,但是已经部分阐明了这种反应的机制,并且似乎与肿瘤坏死因子(TNF)α和白介素(IL)6的释放有关。在这里,我们显示nBP诱导的急性期反应不同于典型的急性期反应,因为CD14 +细胞(例如单核细胞和巨噬细胞)不是主要的细胞因子产生细胞。我们表明,通过抑制甲羟戊酸途径,nBPs诱导外周血γδT细胞快速大量产生TNFα和IL6。用抑制3-羟基-3-甲基戊二酰辅酶A(HMG CoA)还原酶的他汀类药物进行的先前治疗,可阻断γδT细胞对nBP诱导的这些促炎性细胞因子的产生,并可提供避免相关急性期反应的手段。此外,我们的发现为HMG CoA还原酶抑制剂的抗炎作用提供了进一步的机制。

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