Choi E S, Hokom M M, Chen J L, Skrine J, Faust J, Nichol J, Hunt P
Amgen Inc., Amgen Center, Thousand Oaks, California 91320, USA.
Br J Haematol. 1996 Nov;95(2):227-33. doi: 10.1046/j.1365-2141.1996.d01-1920.x.
Thrombopoietin (TPO), the ligand for the c-Mpl cytokine receptor, is a recently identified cytokine with potent effects on platelet production. The receptor-binding portion of c-Mpl ligand is encompassed in another molecule known as megakaryocyte growth and development factor, or MGDF. Although it is clear that the administration of TPO or MGDF to animals dramatically increases the platelet count, the specific stage(s) of thrombopoiesis during which these molecules are principally active have not been unambiguously determined. Pharmacology studies administering MGDF at doses ranging from 0.1 to 630 micrograms/kg/d to mice revealed a biphasic response in platelet production. Administration of the drug at concentrations from 6 to 60 micrograms/kg/d resulted in platelet counts 5-fold above normal. However, doses > 60 micrograms/kg/d resulted in less-than-optimal platelet production. This phenomenon was investigated in vitro. Using an established culture system for the generation of human megakaryocytes and platelets, MGDF was shown to be optimally and equivalently active in the generation of mature megakaryocytes at concentrations from 10 to 1000 ng/ml. However, the cytokine was not required for proplatelet formation and in fact was inhibitory to that process in a dose-dependent manner. When MGDF was added to human megakaryocytes at concentrations of 200 ng/ml or greater, proplatelet formation was inhibited to 30% of control values. MGDF-mediated inhibition was specific, since the addition of the truncated form of the c-Mpl receptor reversed the inhibition in a dose-dependent manner. Other recombinant factors, interleukin-6, interleukin-11 and erythropoietin had no significant positive or negative effects in this human proplatelet assay. Together, these data suggest that although TPO and MGDF promote the full spectrum of megakaryocyte growth and development, they are not necessary for proplatelet formation, and may in part regulate platelet shedding by their absence.
血小板生成素（TPO）是c-Mpl细胞因子受体的配体，是一种最近发现的对血小板生成有强大作用的细胞因子。c-Mpl配体的受体结合部分包含在另一种称为巨核细胞生长和发育因子（MGDF）的分子中。尽管向动物体内注射TPO或MGDF会显著增加血小板计数，但这些分子主要发挥作用的血小板生成的具体阶段尚未明确确定。对小鼠进行的药理学研究表明，以0.1至630微克/千克/天的剂量给予MGDF会使血小板生成呈现双相反应。以6至60微克/千克/天的浓度给药会使血小板计数比正常水平高出5倍。然而，剂量大于60微克/千克/天会导致血小板生成不理想。对此现象进行了体外研究。使用一种成熟的用于生成人类巨核细胞和血小板的培养系统，结果显示MGDF在10至1000纳克/毫升的浓度下对成熟巨核细胞的生成具有最佳且等效的活性。然而，细胞因子对于前血小板形成并非必需，实际上它以剂量依赖的方式抑制该过程。当以200纳克/毫升或更高的浓度将MGDF添加到人类巨核细胞中时，前血小板形成被抑制至对照值的30%。MGDF介导的抑制作用具有特异性，因为添加c-Mpl受体的截短形式可剂量依赖性地逆转这种抑制作用。在这种人类前血小板检测中，其他重组因子，如白细胞介素-6、白细胞介素-11和促红细胞生成素没有显著的正向或负向作用。总之，这些数据表明，尽管TPO和MGDF促进了巨核细胞生长和发育的全过程，但它们对于前血小板形成并非必需，并且可能在一定程度上通过其缺失来调节血小板的释放。
