Bisphosphonates distributed to bone exert toxic effects specifically towards osteoclasts. On the other hand, intravenous administration of a nitrogen‐containing bisphosphonate (N‐BP) such as zoledronate induces acute‐phase reactions (APRs), including influenza‐like fever 1 day later, indicating an interaction with immunocompetent cells circulating blood. Although it has been reported that activation of γδ T cells is pivotal to induce an APR following treatment with zoledronate, downstream events, including the production of inflammatory cytokines after activation of γδ T cells, remain obscure. We investigated the effects of zoledronate on inflammatory cytokine expression in human peripheral blood mononuclear cells (PBMCs) in vitro. While zoledronate induced mRNA expressions of tumour necrosis factor‐α (TNF‐α), interleukin (IL)‐1β, IL‐6 and interferon‐γ (IFN‐γ) in PBMC, depletion of γδ T cells abolished that zoledronate‐induced expression of those cytokines, indicating the necessity of γδ T cells for expression induction by zoledronate. However, which types of cells were responsible for the production of those cytokines in blood remained unclear. As it is generally accepted that monocytes and macrophages are primary sources of inflammatory cytokines, CD14⁺ cells from PBMC were exposed to zoledronate in the presence of PBMC, which resulted in induced expression of mRNAs for IL‐1β, IL‐6 and IFN‐γ, but not for TNF‐α. These results indicate that CD14⁺ cells are responsible, at least in part, for the production of IL‐1β, IL‐6 and IFN‐γ in blood exposed to zoledronate. This suggests that CD14⁺ cells play an essential role in the occurrence of APRs following N‐BP administration.

中文翻译：

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唑来膦酸盐促进γδT细胞存在下外周单核细胞中人CD14阳性单核细胞中炎性细胞因子的表达

分布在骨骼中的双膦酸盐对破骨细胞具有特异性毒性作用。另一方面，静脉注射唑来膦酸盐等含氮双膦酸盐 (N-BP) 会诱导急性期反应 (APR)，包括 1 天后的流感样发热，表明与循环血液中的免疫活性细胞相互作用。尽管据报道，γδ T 细胞的激活是唑来膦酸盐治疗后诱导 APR 的关键，但下游事件，包括 γδ T 细胞激活后炎性细胞因子的产生，仍然不清楚。我们在体外研究了唑来膦酸盐对人外周血单个核细胞 (PBMC) 中炎性细胞因子表达的影响。而唑来膦酸盐诱导肿瘤坏死因子-α（TNF-α）、白细胞介素（IL）-1β、PBMC 中的 IL-6 和干扰素-γ (IFN-γ)，γδ T 细胞的消耗消除了唑来膦酸盐诱导的这些细胞因子的表达，表明 γδ T 细胞对唑来膦酸盐诱导表达的必要性。然而，哪些类型的细胞负责在血液中产生这些细胞因子仍不清楚。众所周知，单核细胞和巨噬细胞是炎性细胞因子的主要来源，CD14^{来自 PBMC 的+}细胞在 PBMC 存在下暴露于唑来膦酸盐，这导致诱导表达 IL-1β、IL-6 和 IFN-γ 的 mRNA，但不诱导 TNF-α 的表达。这些结果表明，CD14 ⁺细胞至少部分负责在暴露于唑来膦酸盐的血液中产生 IL-1β、IL-6 和 IFN-γ。这表明 CD14 ⁺细胞在 N-BP 给药后 APR 的发生中起重要作用。