Effects of Zoledronate on Local and Systemic Production of IL-1β, IL-18, and TNF-α in Mice and Augmentation by Lipopolysaccharide
Effects of Zoledronate on Local and Systemic Production of IL-1β, IL-18, and TNF-α in Mice and Augmentation by Lipopolysaccharide
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DOI：
10.1248/bpb.b18-00923
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发表时间：
2019-06-01
影响因子：
2
通讯作者：
Endo, Yasuo
中科院分区：
文献类型：
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作者：
Funayama, Hiromi;Tashima, Itaru;Endo, Yasuo
含氮双膦酸盐（N-BPs）的抗骨吸收作用远强于非N-BPs。然而，反复施用N-BP会选择性地在颌骨中引起骨坏死。由于BP在发炎的骨骼中大量积累，因此从颌骨中积累的池中释放的任何N-BP都可能直接作用于周围软组织中的细胞并诱导炎症或坏死。在这里，我们研究了唑来膦酸盐（最有效的N-BP，颌骨坏死发生率最高）对小鼠炎症细胞因子的局部和全身作用。在耳廓内局部：（i）唑来膦酸盐诱导白细胞介素-1 β的长期积累（IL-1 β）和IL-18，但不是肿瘤坏死因子-α（ii）唑来膦酸盐和脂多糖（LPS，革兰氏阴性菌的细胞壁组分）相互增强IL-1 β、IL-18和TNF-α的产生，和（iii）奥昔膦酸盐（一种有毒的非N-BP）本身不仅产生IL-1 β和IL-18，而且产生TNF-α。在使用唑来膦酸盐和/或LPS腹腔注射的全身实验中，（i）唑来膦酸盐本身不增加血清中的上述细胞因子，和（ii）在用唑来膦酸盐预处理（3天前）的小鼠中，LPS诱导的血清IL-1 β和IL-18的增加大大增强，延迟轻微的TNF-α增加。这些结果与先前的结果一起表明：（a）IL-1 β前体和IL-18前体在暴露于N-BP的软组织中的细胞内积累，并且感染不仅可以增加它们的产生，而且可以增加它们成熟形式的释放，（B）IL-1 β和IL-18（可能与TNF-α一起）可能在N-BP诱导的炎症和/或坏死中起重要作用，和（c）BP细胞毒性作用的潜在机制在N-BP和非N-BP之间可能不同。
Bisphosphonates (BPs) containing nitrogen (N-BPs) exhibit far stronger anti-bone-resorptive effects than non-N-BPs. However, repeated administration of N-BPs causes osteonecrosis selectively in jawbones. As BPs accumulate in large amounts within inflamed bones, any N-BP released from the pool accumulated within jawbones might directly act on cells in the surrounding soft-tissues and induce inflammation or necrosis. Here, we examined the local and systemic effects of zoledronate (the most potent N-BP with the highest incidence of jawbone-necrosis) on inflammatory cytokines in mice. Locally within ear-pinnas: (i) zoledronate induced long-lasting accumulation of interleuikin-1 beta (IL-1 beta) and IL-18, but not tumor necrosis factor-alpha (TNF-alpha), (ii) zoledronate and lipopolysaccharide (LPS, a cell-wall component of Gram-negative bacteria) mutually augmented the productions of IL-1 beta, IL-18, and TNF-alpha, and (iii) oxidronate (a toxic non-N-BP) by itself produced not only IL-1 beta and IL-18, but also TNF-alpha. In systemic experiments using intraperitoneal injection of zoledronate and/or LPS, (i) zoledronate by itself increased none of the above cytokines in serum, and (ii) in mice pretreated (3 d before) with zoledronate, the LPS-induced increases in serum IL-1 beta and IL-18 were greatly augmented with a delayed slight TNF-alpha augmentation. These results, together with previous ones, suggest that (a) pro-IL-1 beta and pro-IL-18 accumulate within cells in soft-tissues exposed to N-BPs, and infection may augment not only their production, but also the release of their mature forms, (b) IL-1 beta and IL-18 (possibly together with TNF-alpha) may play important roles in N-BP-induced inflammation and/or necrosis, and (c) mechanisms underlying the cytotoxic effects of BPs may differ between N-BPs and non-N-BPs.