阿奇霉素抑制细菌超抗原刺激的人外周血单个核细胞增殖、白细胞介素产生和丝裂原活化蛋白激酶。
Azithromycin suppresses proliferation, interleukin production and mitogen-activated protein kinases in human peripheral-blood mononuclear cells stimulated with bacterial superantigen.
机构信息
Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
出版信息
J Pharm Pharmacol. 2011 Oct;63(10):1320-6. doi: 10.1111/j.2042-7158.2011.01343.x. Epub 2011 Aug 19.
OBJECTIVES
Macrolide antibiotics are used for the treatment of immunological disorders such as psoriasis. However, few studies have investigated the immunoregulatory efficacy of macrolides in bacterial superantigen-stimulated immune cells.
METHODS
The suppressive efficacies of azithromycin, clarithromycin, roxithromycin and prednisolone were evaluated in vitro against the concanavalin A- or toxic shock syndrome toxin 1 (TSST-1)-induced proliferation of peripheral-blood mononuclear cells (PBMCs) obtained from nine healthy subjects. The concentrations of six cytokines in a PBMC-culture medium were measured using bead-array procedures followed by flow cytometry. Cellular c-jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) activity were measured using cell-based ELISA procedures.
KEY FINDINGS
Azithromycin, clarithromycin and roxithromycin inhibited the proliferation of both the concanavalin A- and superantigen-stimulated PBMCs dose-dependently. The effect of azithromycin was the strongest, with IC50 values of less than 5 µg/ml. Furthermore, the suppressive efficacy of prednisolone against concanavalin A- or TSST-1-stimulated PBMCs was significantly promoted in combination with 5 µg/ml azithromycin (P < 0.002). The concentrations of TNF-α, interleukin (IL)-2, -4, -5 and -10 in the supernatant of concanavalin A- or TSST-1-stimulated PBMCs cultured for 72 h decreased by 65-98% in the presence of 5 µg/ml azithromycin. The stimulation of PBMCs with concanavalin A or TSST-1 increased cellular JNK and ERK activity, and 5 µg/ml azithromycin significantly attenuated the increased activity of JNK in the TSST-1-stimulated cells and ERK in the concanavalin A- and TSST-1-stimulated PBMCs, respectively (P < 0.05).
CONCLUSIONS
Azithromycin suppresses mitogen- or superantigen-induced proliferation of PBMCs by possibly inhibiting both cellular JNK and ERK activity.
目的
大环内酯类抗生素用于治疗免疫性疾病，如银屑病。然而，很少有研究调查大环内酯类药物在细菌超抗原刺激免疫细胞中的免疫调节作用。
方法
评估阿奇霉素、克拉霉素、罗红霉素和强的松龙在体外对来自 9 名健康受试者外周血单个核细胞（PBMC）的刀豆球蛋白 A 或毒性休克综合征毒素 1（TSST-1）诱导的增殖的抑制作用。采用珠阵列程序和流式细胞术测量 PBMC 培养物中六种细胞因子的浓度。采用基于细胞的 ELISA 程序测量细胞 c-jun N 末端激酶（JNK）和细胞外信号调节激酶（ERK）的活性。
主要发现
阿奇霉素、克拉霉素和罗红霉素均能剂量依赖性地抑制刀豆球蛋白 A 和超抗原刺激的 PBMC 的增殖。阿奇霉素的作用最强，IC50 值低于 5 µg/ml。此外，5 µg/ml 阿奇霉素与强的松龙联合使用可显著促进强的松龙对刀豆球蛋白 A 或 TSST-1 刺激的 PBMC 的抑制作用（P < 0.002）。在 5 µg/ml 阿奇霉素存在的情况下，刀豆球蛋白 A 或 TSST-1 刺激的 PBMC 培养 72 小时后，上清液中 TNF-α、白细胞介素（IL）-2、-4、-5 和 -10 的浓度降低 65-98%。刀豆球蛋白 A 或 TSST-1 刺激 PBMC 可增加细胞 JNK 和 ERK 活性，5 µg/ml 阿奇霉素可显著减弱 TSST-1 刺激细胞 JNK 活性和刀豆球蛋白 A 和 TSST-1 刺激 PBMC 中 ERK 活性的增加（P < 0.05）。
结论
阿奇霉素可能通过抑制细胞 JNK 和 ERK 活性来抑制有丝分裂原或超抗原诱导的 PBMC 增殖。
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