Schleuning M, Brumme V, Wilmanns W
Medizinische Klinik III, Universitätsklinikum Grosshadern, München, Germany.
Naunyn Schmiedebergs Arch Pharmacol. 1994 Jul;350(1):100-3. doi: 10.1007/BF00180018.
Earlier studies from our laboratory have demonstrated that phenothiazine derivatives are capable of inhibiting mitogen-induced activation of human T-cells and thymocytes. Similar to cyclosporin A, phenothiazine derivatives exert these inhibitory effects by decreasing the accumulation of lymphokine-specific mRNA. However, proliferation of T-cell blasts and of unfractionated human thymocytes can also be induced by interleukin 2. Since activation of T-cells via the interleukin 2 receptor seems to be resistant to the action of cyclosporin A, the present study was designed to investigate whether lymphokine-induced activation could be inhibited by phenothiazine derivatives. The effects of the phenothiazine derivatives chlorpromazine and/or fluphenazine have been studied and compared to the action of cyclosporin A and FK506 in human thymocytes, human T-cell blasts and in the human T-cell line H33-HJ JA1, which is an interleukin 2 producing cell line derived from Jurkat cells. As evidenced by the incorporation of [3H]-thymidine, cyclosporin A (1 microgram/ml) and FK506 (100 ng/ml) have no or only marginal inhibitory capacity on interleukin 2-induced proliferation in all T-cell systems tested. By contrast, phenothiazine derivatives (fluphenazine > chlorpromazine) exert a dose-dependent inhibition of the activation of these cells in pharmacologically relevant micromolar concentrations. Similar results were obtained by measuring the production of interferon-gamma in the supernatants of interleukin 2-induced human thymocytes. Our results suggest that the use of phenothiazines might be helpful in immunosuppressive regimens.
我们实验室早期的研究表明，吩噻嗪衍生物能够抑制丝裂原诱导的人T细胞和胸腺细胞的活化。与环孢素A类似，吩噻嗪衍生物通过减少淋巴因子特异性mRNA的积累发挥这些抑制作用。然而，白细胞介素2也可诱导T细胞母细胞和未分级的人胸腺细胞增殖。由于通过白细胞介素2受体激活T细胞似乎对环孢素A的作用具有抗性，因此本研究旨在调查吩噻嗪衍生物是否能够抑制淋巴因子诱导的活化。已研究了吩噻嗪衍生物氯丙嗪和/或氟奋乃静的作用，并将其与环孢素A和FK506在人胸腺细胞、人T细胞母细胞以及人T细胞系H33-HJ JA1中的作用进行了比较，H33-HJ JA1是一种源自Jurkat细胞的白细胞介素2产生细胞系。如[3H]-胸腺嘧啶核苷掺入所示，环孢素A（1微克/毫升）和FK506（100纳克/毫升）对所有测试的T细胞系统中白细胞介素2诱导的增殖没有或只有微弱的抑制能力。相比之下，吩噻嗪衍生物（氟奋乃静>氯丙嗪）在药理学相关的微摩尔浓度下对这些细胞的活化具有剂量依赖性抑制作用。通过测量白细胞介素2诱导的人胸腺细胞上清液中干扰素-γ的产生也获得了类似结果。我们的结果表明，使用吩噻嗪类药物可能有助于免疫抑制方案。
