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首页> 外文期刊>Life sciences >Terbinafine stimulates the pro-inflammatory responses in human monocytic THP-1 cells through an ERK signaling pathway.
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Terbinafine stimulates the pro-inflammatory responses in human monocytic THP-1 cells through an ERK signaling pathway.

机译：特比萘芬通过ERK信号通路刺激人单核THP-1细胞中的促炎反应。

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AIMS: Oral antifungal terbinafine has been reported to cause liver injury with inflammatory responses in a small percentage of patients. However the underlying mechanism remains unknown. To examine the inflammatory reactions, we investigated whether terbinafine and other antifungal drugs increase the release of pro-inflammatory cytokines using human monocytic cells. MAIN METHODS: Dose- and time-dependent changes in the mRNA expression levels and the release of interleukin (IL)-8 and tumor necrosis factor (TNF)alpha from human monocytic THP-1 and HL-60 cells with antifungal drugs were measured. Effects of terbinafine on the phosphorylation of extracellular signal-regulated kinase (ERK)1/2, p38 mitogen-activated protein (MAP) kinase and c-Jun N-terminal kinase (JNK)1/2 were investigated. KEY FINDINGS: The release of IL-8 and TNFalpha from THP-1 and HL-60 cells was significantly increased by treatment with terbinafine but not by fluconazole, suggesting that terbinafine can stimulate monocytes and increase the pro-inflammatory cytokine release. Terbinafine also significantly increased the phosphorylation of ERK1/2 and p38 MAP kinase in THP-1 cells. Pretreatment with a MAP kinase/ERK kinase (MEK)1/2 inhibitor U0126 significantly suppressed the increase of IL-8 and TNFalpha levels by terbinafine treatment in THP-1 cells, but p38 MAPK inhibitor SB203580 did not. These results suggested that an ERK1/2 pathway plays an important role in the release of IL-8 and TNFalpha in THP-1 cells treated with terbinafine. SIGNIFICANCE: The release of inflammatory mediators by terbinafine might be one of the mechanisms underlying immune-mediated liver injury. This in vitro method may be useful to predict adverse inflammatory reactions that lead to drug-induced liver injury.
机译：目的：口服抗真菌特比萘芬在少数患者中据报道可引起肝损伤并伴有炎症反应。但是，其潜在机制仍然未知。为了检查炎症反应，我们调查了特比萘芬和其他抗真菌药物是否使用人单核细胞增加促炎细胞因子的释放。主要方法：测量了人类单核细胞THP-1和HL-60细胞中抗真菌药物的mRNA表达水平的剂量和时间依赖性变化以及白介素（IL）-8和肿瘤坏死因子（TNF）α的释放。研究了特比萘芬对细胞外信号调节激酶（ERK）1/2，p38丝裂原活化蛋白（MAP）激酶和c-Jun N端激酶（JNK）1/2磷酸化的影响。主要发现：特比萘芬治疗可显着增加THP-1和HL-60细胞IL-8和TNFα的释放，而氟康唑则不能，这表明特比萘芬可刺激单核细胞并增加促炎性细胞因子的释放。特比萘芬还显着增加THP-1细胞中ERK1 / 2和p38 MAP激酶的磷酸化。在特比萘芬治疗中，使用MAP激酶/ ERK激酶（MEK）1/2抑制剂U0126进行预处理可以显着抑制IL-8和TNFalpha的水平升高，而p38 MAPK抑制剂SB203580则不能。这些结果表明，在用特比萘芬处理的THP-1细胞中，ERK1 / 2途径在IL-8和TNFα的释放中起重要作用。意义：特比萘芬释放炎性介质可能是免疫介导的肝损伤的机制之一。这种体外方法可能有助于预测导致药物诱导的肝损伤的不良炎症反应。

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