Girndt M, Sester U, Kaul H, Hünger F, Köhler H
Medical Clinic IV, Nephrology, University Homburg, Homburg/Saar, Germany.
Transplantation. 1998 Aug 15;66(3):370-5. doi: 10.1097/00007890-199808150-00015.
Glucocorticoids act as immunosuppressive drugs mainly via their effects on antigen-presenting cells. They are known to influence production of cytokines as well as expression of cell surface molecules. B7 molecules belong to the most important costimulatory signals for T-cell activation during transplant rejection. They are expressed on antigen-presenting cells and up-regulated during the immune response. We studied the influence of glucocorticoids on the regulation of these accessory signals.
Human monocytes were purified from peripheral blood of healthy volunteers by centrifugal counterflow elutriation. Activation-dependent transcription and expression of B7-1 (CD80) and B7-2 (CD86) were detected by reverse transcription-polymerase chain reaction and flow cytometry in the absence or presence of glucocorticoids.
The expression pattern of B7-1 and B7-2 on monocytes depends on the type of stimulation. Activation by interferon-gamma induces both B7-1 and B7-2, whereas cAMP exclusively up-regulates B7-2. Glucocorticoids selectively inhibit the expression of B7-1 while leaving B7-2 unaffected. The effect occurs at concentrations that are reached during therapeutical application of the substances in humans. It is mediated via the cytoplasmic glucocorticoid receptor, as it can be abrogated by the glucocorticoid receptor antagonist RU38486. Inhibition of B7-1 occurs at the transcriptional level. Up-regulation of the molecule can similarly be inhibited by hydrocortisone, prednisolone, and dexamethasone at equipotent doses.
Inhibition of the up-regulation of B7-1 by glucocorticoids is a previously unknown mechanism of action of these substances and may relevantly contribute to their effects as immunosuppressive drugs.
糖皮质激素主要通过其对抗抗原呈递细胞的作用发挥免疫抑制药物的功效。已知它们会影响细胞因子的产生以及细胞表面分子的表达。B7分子是移植排斥反应期间T细胞活化最重要的共刺激信号之一。它们在抗原呈递细胞上表达，并在免疫反应过程中上调。我们研究了糖皮质激素对这些辅助信号调节的影响。
通过离心逆流淘析从健康志愿者的外周血中纯化人单核细胞。在不存在或存在糖皮质激素的情况下，通过逆转录 - 聚合酶链反应和流式细胞术检测B7-1（CD80）和B7-2（CD86）的激活依赖性转录和表达。
单核细胞上B7-1和B7-2的表达模式取决于刺激类型。γ干扰素激活可诱导B7-1和B7-2，而cAMP仅上调B7-2。糖皮质激素选择性抑制B7-1的表达，而对B7-2无影响。这种作用发生在人体治疗应用这些物质时所达到的浓度。它是通过细胞质糖皮质激素受体介导的，因为它可以被糖皮质激素受体拮抗剂RU38486消除。B7-1的抑制发生在转录水平。同等剂量的氢化可的松、泼尼松龙和地塞米松同样可以抑制该分子的上调。
糖皮质激素对B7-1上调的抑制是这些物质以前未知的作用机制，可能与其作为免疫抑制药物的作用密切相关。
