Wickenhauser C, Thiele J, Lorenzen J, Schmitz B, Frimpong S, Schramm K, Neumann I, Zankovich R, Fischer R
Institute of Pathology, University of Cologne, Germany.
Leukemia. 1999 Mar;13(3):327-34. doi: 10.1038/sj.leu.2401314.
Polycythemia rubra vera (PV) represents a clonal hematological disorder defined by an abnormal expansion of erythroid precursors and megakaryopoiesis, in particular. Ample evidence has been provided that the IL-6/1L-6R complex may be responsible for the proliferation of normal and neoplastic megakaryocytes in vitro and this fact lead us to the hypothesis, that defects in the regulation of IL-6 synthesis take part in the pathogenesis of PV. The study was carried out to determine the IL-6 serum levels and the megakaryocytic IL-6 production in patients with PV and to compare these data with the situation in hematologically healthy donors as well as in patients suffering from spurious polycythemia--smokers polyglobuly (PG). For this purpose, IL-6 serum levels were measured by ELISA and the megakaryocytic production studied by immunohistochemistry, reverse hemolytic plaque assay (RHPA) together with reverse transcription/polymerase chain reaction (RT-PCR) in highly enriched megakaryocyte preparations. In additional experiments, the influence of IL-3 stimulation and the expression of IL-6R were tested. Serum levels of IL-6 did not differ between the three groups under study. In contrast, immunohistochemistry revealed a raised proportion of megakaryocytes expressing IL-6 in PV as compared to normal donors and patients suffering from PG. The percentage of megakaryocytes actively secreting this cytokine as detected by the RHPA was 20 times greater than in both the other groups. This phenomenon was further substantiated by the fact that IL-6 mRNA could only be shown in PV megakaryocyte preparations. The regulation of IL-6 secretion appears to be abnormal in PV. Whereas in the normal and in the PG group IL-3 stimulation exerts a marked increase in megakaryocytic IL-6 secretion, PV megakaryocytes responded with a paradoxical down-regulation of IL-6 synthesis combined with the loss of IL-6R. Our data describe for the first time an abnormally raised IL-6 production by PV megakaryocytes and point towards fundamental regulatory alterations of the IL-6 synthesis in this disease.
真性红细胞增多症（PV）是一种克隆性血液系统疾病，其特征尤其在于红系前体细胞和巨核细胞生成的异常扩增。有充分证据表明，IL-6/IL-6R复合物可能在体外负责正常和肿瘤性巨核细胞的增殖，这一事实使我们提出假说，即IL-6合成调节缺陷参与了PV的发病机制。本研究旨在测定PV患者的血清IL-6水平和巨核细胞IL-6生成，并将这些数据与血液学健康供者以及患有假性红细胞增多症（吸烟者红细胞增多症，PG）患者的情况进行比较。为此，通过ELISA测定血清IL-6水平，并在高度富集的巨核细胞制剂中通过免疫组织化学、反向溶血空斑试验（RHPA）以及逆转录/聚合酶链反应（RT-PCR）研究巨核细胞生成。在额外的实验中，测试了IL-3刺激的影响和IL-6R的表达。所研究的三组之间血清IL-6水平没有差异。相比之下，免疫组织化学显示，与正常供者和PG患者相比，PV患者中表达IL-6的巨核细胞比例升高。通过RHPA检测到的活跃分泌这种细胞因子的巨核细胞百分比比其他两组高20倍。IL-6 mRNA仅在PV巨核细胞制剂中检测到这一事实进一步证实了这一现象。PV中IL-6分泌的调节似乎异常。在正常组和PG组中，IL-3刺激可使巨核细胞IL-6分泌显著增加，而PV巨核细胞的反应是IL-6合成反常下调并伴有IL-6R的丧失。我们的数据首次描述了PV巨核细胞IL-6生成异常升高，并指出了该疾病中IL-6合成的基本调节改变。
