Inoue H, Kadoya T, Kabaya K, Tachibana K, Nishi N, Sato M, Ohsawa M, Mikayama T, Mori K J
Pharmaceutical Research Laboratory, Kirin Brewery Co., Ltd., Maebashi, Japan.
J Lab Clin Med. 1994 Oct;124(4):529-36.
Interleukin-6 (IL-6) is a novel cytokine with activities that can affect hematopoietic cells including those of the megakaryocytic lineage. We have examined the effects of monomethoxy polyethylene glycol-modified recombinant human interleukin-6 (Peg-IL-6) on thrombopoiesis in vivo. To compare the thrombopoietic activity between Peg-IL-6 and unmodified IL-6, each was administered subcutaneously to mice every 24 hours at various doses. A dose-response experiment showed that Peg-IL-6 and IL-6 increased platelet counts in a dose-dependent fashion at a plateau stimulation level of 0.5 micrograms/day and 10 micrograms/day, respectively. This dose of Peg-IL-6 and IL-6 induced the elevated platelet counts by approximately 140% to 160% and 50% to 60%, respectively. Peg-IL-6 treatment (0.5 micrograms/day) for x-ray (6.0 Gy) irradiated mice induced an increase in the rate of platelet recovery, and a higher dosage (5 micrograms/day) completely blocked the induction of thrombocytopenia in this model. In contrast, IL-6 (10 micrograms/day) could not protect the animals from platelet nadir but reduced the period of thrombocytopenia after x-ray irradiation. Furthermore, when administered to 5-fluorouracil-treated mice, 5 micrograms/day of Peg-IL-6 diminished the platelet nadir and increased platelet counts on individual days during the recovery phase. The potent thrombopoietic activity of Peg-IL-6 were due to prolongation of circulating IL-6 levels that were reverted from Peg-IL-6 in vivo. These findings indicate that reduction of total body clearance of IL-6 induces potent thrombopoiesis and that Peg-IL-6 may be a useful thrombopoietic agent.
白细胞介素-6（IL-6）是一种新型细胞因子，其活性可影响造血细胞，包括巨核细胞系的细胞。我们研究了单甲氧基聚乙二醇修饰的重组人白细胞介素-6（Peg-IL-6）对体内血小板生成的影响。为了比较Peg-IL-6和未修饰的IL-6之间的血小板生成活性，将它们分别以不同剂量每24小时皮下注射给小鼠。剂量反应实验表明，Peg-IL-6和IL-6分别在0.5微克/天和10微克/天的平台刺激水平下以剂量依赖性方式增加血小板计数。该剂量的Peg-IL-6和IL-6分别使血小板计数升高约140%至160%和50%至60%。对接受X射线（6.0 Gy）照射的小鼠进行Peg-IL-6治疗（0.5微克/天）可诱导血小板恢复率增加，更高剂量（5微克/天）在该模型中完全阻断了血小板减少症的诱导。相比之下，IL-6（10微克/天）不能保护动物免受血小板最低点的影响，但缩短了X射线照射后血小板减少的时间。此外，当给5-氟尿嘧啶治疗的小鼠给药时，5微克/天的Peg-IL-6减少了血小板最低点，并在恢复阶段的各个日子增加了血小板计数。Peg-IL-6的强大血小板生成活性归因于体内从Peg-IL-6转化而来的循环IL-6水平的延长。这些发现表明，IL-6全身清除率的降低可诱导强大的血小板生成，并且Peg-IL-6可能是一种有用的血小板生成剂。
