Staphylococcus aureus-superantigen decreases FKIBP51 mRNA expression and cell-response to suppressive efficacy of a glucocorticoid in human peripheral blood mononuclear cells:: Possible implication of mitogen-activated protein kinase pathways
Staphylococcus aureus-superantigen decreases FKIBP51 mRNA expression and cell-response to suppressive efficacy of a glucocorticoid in human peripheral blood mononuclear cells:: Possible implication of mitogen-activated protein kinase pathways
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DOI：
10.1016/j.ejphar.2007.05.021
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发表时间：
2007-09-10
影响因子：
5
通讯作者：
Oka, Kitaro
中科院分区：
文献类型：
--
作者：
Fukushima, Hisayo;Hirano, Toshihiko;Oka, Kitaro
糖皮质激素通常用于治疗慢性炎症性疾病，但许多患者对糖皮质激素治疗不敏感。糖皮质激素药效学的这些个体差异的分子基础很少被考虑。在这里，我们重点关注金黄色葡萄球菌产生的超抗原，如中毒性休克综合征毒素-1 (TSST-1)，对人外周血单核细胞的糖皮质激素敏感性以及细胞对糖皮质激素产生 FK506 结合蛋白 (FKBP51) 转录本的反应的影响。通过细胞增殖试验评估外周血单核细胞对糖皮质激素的敏感性。通过实时逆转录聚合酶链反应（RT-PCR）测定FKBP51mRNA表达。我们还使用细胞计数珠阵列比较了刀豆球蛋白 A 和 TSST-1 刺激的外周血核细胞培养上清液中产生的各种细胞因子的浓度。通过基于细胞的 ELISA 分析用刀豆球蛋白 A 和 TSST-1 刺激的外周血单核细胞中丝裂原激活蛋白激酶 (MAPK) 磷酸化活性。泼尼松龙显着抑制伴刀豆球蛋白A诱导的外周血单核细胞增殖，但几乎不抑制TSST-1诱导的外周血单核细胞增殖。在刀豆球蛋白 A 刺激的外周血单核细胞中，泼尼松龙达到 50% (IC50) 值的免疫抑制剂浓度平均值 (S.D.) 为 52.6 (54.2) ng/ml，显着低于 TSST-1 刺激的外周血单核细胞，即 574.2 (817.0) ng/ml (P < 0.001）。 TSST-1刺激外周血单核细胞48小时减弱了泼尼松龙诱导的FKBP51mRNA表达，同时降低了对利雷尼松龙的抗增殖作用的敏感性。 TSST-1刺激的外周血单核细胞产生的白介素-2 (IL-2)浓度显着高于用刀豆球蛋白A刺激的外周血单核细胞(P < 0.0001)。伴刀豆球蛋白 A 和 TSST-1 均增强细胞外信号调节激酶 (ERK) 和 p38 的磷酸化，而外周血单核细胞中 c-jun 末端激酶 (JNK) 磷酸化水平仅因 TSST-1 刺激而增加。此外，发现 JNK 和丝裂原激活蛋白激酶 (MEK)/ERK 抑制剂可以恢复 TSST-1 导致的 FKBP5 I mRNA 减少。我们的数据表明，TSST-1 通过 JNK 激活和随后产生的 IL-2 降低外周血单核细胞中糖皮质激素的活性。因此，JNK可能是克服外周血单核细胞中TSST-1诱导的糖皮质激素不敏感的有吸引力的靶标。 (c) 2007 Elsevier B.V. 保留所有权利。
Glucocorticoids are commonly used for treatment of chronic inflammatory diseases, while a number of patients show insensitivity to glucocorticoid treatment. The molecular basis of these individual differences in glucocorticoid pharmacodynamics has little been taken into account. Here we focus on the implication of Staphylococcus aureus-producing superantigen, such as toxic shock syndrome toxin-1 (TSST-1), in the glucocorticoid sensitivity of human peripheral blood mononuclear cells and cell-response to glucocorticoid to produce a transcript for FK506-binding protein (FKBP51). Peripheral blood mononuclear cell-sensitivity to glucocorticoid was assessed by a cell proliferation test. FKBP51mRNA expressions were determined by real-time reverse transcription-polymerase chain reaction (RT-PCR). We also compared concentrations of various cytokines produced in culture supernatant between concanavalin A- and TSST-1-stimulated peripheral blood raononuclear cells using a cytometric beads array. Mitogen-activated protein kinase (MAPK) phosphorylation activity in peripheral blood mononuclear cells stimulated with concanavalin A and TSST-1 was analyzed by a cell-based ELISA. Prednisolone markedly inhibited concanavalin A-induced peripheral blood mononuclear cell proliferation, but they scarcely inhibited TSST-1-induced peripheral blood mononuclear cell proliferation. The mean (S.D.) of immunosuppressant concentrations that would give 50% (IC50) values for prednisolone in concanavalin A-stimulated peripheral blood mononuclear cells was 52.6 (54.2) ng/ml, which was significantly lower than that in TSST-1-stimulated peripheral blood mononuclear cells, i.e., 574.2 (817.0) ng/ml (P < 0.001). TSST-1-stimulated peripheral blood mononuclear cells for 48 h attenuated prednisolone-induced FKBP5lmRNA expressions concomitantly with decreased sensitivity to the anti -proliferative effects of rirednisolone. Concentrations of interleukin-2 (IL-2) produced from TSST-1-stimulated peripheral blood mononuclear cells were significantly higher than that from peripheral blood mononuclear cells stimulated with concanavalin A (P < 0.0001). Both concanavalin A and TSST-1 enhanced the phosphorylation of extracellular signal-regulated kinase (ERK) and p38, whereas the level of c-jun terminal kinase (JNK) phosphorylation was only increased by TSST-1-stimulation in peripheral blood mononuclear cells. Furthermore, the decreased FKBP5 I mRNA by TSST-1was found to be recovered by JNK and mitogen-activated protein kinase (MEK)/ERK inhibitors. Our data suggest that TSST-1 reduces activity of glucocorticoid in peripheral blood mononuclear cells by JNK activation and subsequent production of IL-2. Therefore, JNK might be zm attractive target for overcoming glucocorticoid insensitivity induced by TSST-1 in peripheral blood mononuclear cells. (c) 2007 Elsevier B.V. All rights reserved.