The study on thrombopoietic activity of interleukin 6

我们已经初步表明，几种细胞因子可以作为Meg-CSF（早期因子）或巨核细胞成熟因子（晚期因子）调节体外巨核细胞生成。白细胞介素-3 （IL-3）、促红细胞生成素（Epo）和粒细胞巨噬细胞集落刺激因子（GM-CSF）刺激巨核细胞集落生长；IL-3、GM-CSF、Epo、巨噬细胞(M)-CSF和IL-6在液体培养系统中促进巨核细胞的成熟，而粒细胞(G)-CSF和IL-lb在体外对巨核细胞的生成没有刺激作用。为了确定这些细胞因子是否在体内刺激血小板生成，在小鼠体内给药（例如，5天）。虽然GM-CSF、G-CSF和M-CSF对血小板计数没有影响，但IL6和IL-lb诱导血小板水平显著增加，并伴有骨髓巨核细胞大小的增加。促红细胞生成素引起血小板计数轻微但短暂的增加。IL-6对巨核细胞生成和血小板生成的影响被认为是直接的，因为IL-6受体在巨核细胞上被证实（使用高度纯化的大鼠巨核细胞）。由于IL-lb在体外对巨核细胞生成没有影响，IL-lb在体内对血小板生成的影响可能是通过IL-6介导的，通过检测注射IL-lb的小鼠血清中几种细胞因子的水平。对小鼠长期给予IL-6的研究表明，只要给予IL-6，这种作用就会持续存在。IL-6的刺激作用也在灵长类动物中得到证实。由于该细胞因子在小鼠和灵长类动物中所研究剂量的副作用最小且可逆，因此IL-6可能是血小板减少症患者的血小板生成刺激因子。

We have initially shown that several cytokines modulate in vitro megakaryocytopoiesis, either as Meg-CSF (early factor) or as megakaryocyte maturation factor (late factor). Interleukin-3 (IL-3), erythropoietin (Epo), and granulocytemacrophage colony-stimulating factor (GM-CSF) stimulated megakaryocyte colony growth ; IL-3, GM-CSF, Epo, macrophage (M)-CSF and IL-6 promoted maturation of megakaryocytes in liquid culture system whereas granulocyte (G)-CSF and IL-lb did not have a stimulatory effect on megakaryocytopoiesis in vitro. To determine if some of these cytokines stimulate thrombocytopoiesis in vivo, in vivo administrations (i. p., 5 days) of each cytokine were performed in mouse. Although GM-CSF, G-CSF and M-CSF did not influence on platelet count, IL6 and IL-lb induced a marked increase in platelet levels associated with an increment in marrow megakaryocyte size. Epo elicited a mild, but transient increase in platelet counts. The effect of IL-6 on megakaryocytopoiesis and thrombocytopoiesis was considered direct, because IL-6 receptors were demonstrated on megakaryocytes (using highly purified rat megakaryocytes). As IL-lb had no effects on megakaryocytopoiesis in vitro, the in vivo effect of IL-lb on thrombocytopoiesis was possibly mediated via IL-6 by determinations of serum levels for several cytokines in the mice injected with IL-lb. The long-term administration of IL-6 to mice revealed that the effect persists as long as IL-6 are administrated. The stimulatory effect of IL-6 was also confirmed in primates. Since side effects of this cytokine were minimum and reversible in mice and primates in the doses studied, IL-6 is probably useful as a thrombopoiesis-stimulatory factor in patients with thrombocytopenia.