Legrue S J, Sheu T L, Carson D D, Laidlaw J L, Sanduja S K
Department of Immunology, University of Texas M.D. Anderson Hospital and Tumor Institute, Houston 77030.
Lymphokine Res. 1988 Spring;7(1):21-9.
We investigated possible mechanisms by which the cyclic depsipeptide didemnin B (DB) inhibits lymphocyte proliferation. DB inhibited the proliferation of Con-A stimulated murine splenocytes, the interleukin-2 (IL-2) dependent proliferation of the CTLL-2 cell line, and the interleukin 4 (IL 4) dependent growth of both CTLL-2 and D10.G.4.1 cell lines at approximately equimolar concentrations (SD50 = 3 to 10 X 10(-9)M). Inhibition of CTLL-2 growth by 10(-8)M DB was partially reversible, and significantly blocked the incorporation of [3H]-thymidine even when added 24 hr after initial IL 2 stimulation. Concentrations of DB (10(-8)M) that completely blocked mitogen-driven spleen cell blastogenesis only partially inhibited the synthesis and secretion of IL-2. Although DB blocked the growth of T lymphocyte clones in response to both recombinant human IL 2 and recombinant murine IL 4, the suppression was not due to an uncoupling of lymphokinetic signaling but was closely correlated with an inhibition of protein and RNA synthesis. Addition of DB to an in vitro translation system did not inhibit protein synthesis. Thus, we conclude that DB functions as an antiproliferative, and not as a specifically immunosuppressive, compound.
我们研究了环缩肽didemnin B（DB）抑制淋巴细胞增殖的可能机制。DB在大约等摩尔浓度（SD50 = 3至10×10⁻⁹M）下，抑制刀豆蛋白A刺激的小鼠脾细胞增殖、CTLL-2细胞系依赖白细胞介素-2（IL-2）的增殖以及CTLL-2和D10.G.4.1细胞系依赖白细胞介素4（IL-4）的生长。10⁻⁸M DB对CTLL-2生长的抑制作用部分可逆，即使在初始IL-2刺激24小时后添加，也能显著阻断[³H] - 胸腺嘧啶核苷的掺入。完全阻断有丝分裂原驱动的脾细胞母细胞形成的DB浓度（10⁻⁸M）仅部分抑制IL-2的合成和分泌。尽管DB阻断了T淋巴细胞克隆对重组人IL-2和重组小鼠IL-4的生长反应，但这种抑制并非由于淋巴动力学信号解偶联，而是与蛋白质和RNA合成的抑制密切相关。将DB添加到体外翻译系统中不会抑制蛋白质合成。因此，我们得出结论，DB作为一种抗增殖化合物发挥作用，而不是作为一种特异性免疫抑制化合物。
