Schwarzmeier J D, Hilgarth M, Nguyen S T, Shehata M, Gruber G, Spittler A, Willheim M, Boltz-Nitulescu G, Höcker P, Berger R
Department of Hematology, Clinic of Internal Medicine I, Ludwig-Boltzmann Institute for Cytokine Research, Vienna, Austria.
Cancer Res. 1996 Oct 15;56(20):4679-85.
The course of hairy cell leukemia (HCL) is characterized by progressive pancytopenia. The pathogenesis of this phenomenon is still not fully understood. To study if the decrease in hematopoiesis in HCL is accompanied by abnormal concentrations of growth factors, we investigated the production of granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, interleukin 3 (IL-3), interleukin 6 (IL-6), and tumor necrosis factor alpha by peripheral blood mononuclear cells (PBMCs) of eight patients with HCL. The results point to a severe deficiency of production of all cytokines tested as compared to healthy donors. However, enrichment of autologous monocytes by counterflow centrifugation resulted in a marked increase of the levels of granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, IL-6, and tumor necrosis factor alpha. The most pronounced effects were seen with IL-6. Reverse transcription-PCR analysis indicated that pokeweed mitogen, IFN-alpha, and poly(I:C) are capable of inducing the expression of IL-6-specific mRNA in HCL cells. These findings are substantiated on the protein level by immunofluorescence analysis. Incubation of PBMCs with IFN-alpha resulted in a significant increase of intracellular IL-6 in HCL but not in healthy donors. This increase was also seen in hairy cells positive for CD19 and CDllc. Furthermore, IFN-alpha induced the secretion of IL-6 from PBMCs of HCL patients but not healthy donors. In conclusion, our studies with PBMCs from patients with HCL revealed an inadequate supply of hematopoietic growth factors that might, in part, be due to the monocytopenia characteristic for this disease. The findings also indicate that IFN-alpha is capable of inducing the production of IL-6 in the patients' PBMCs as well as in their hairy cells. These data from our in vitro studies support the clinical observation that treatment with IFN-alpha leads to reconstitution of hematopoiesis.
毛细胞白血病（HCL）的病程以进行性全血细胞减少为特征。这一现象的发病机制仍未完全明确。为研究HCL中造血功能的降低是否伴随着生长因子浓度异常，我们检测了8例HCL患者外周血单个核细胞（PBMC）中粒细胞集落刺激因子、粒细胞巨噬细胞集落刺激因子、白细胞介素3（IL-3）、白细胞介素6（IL-6）和肿瘤坏死因子α的产生情况。结果显示，与健康供者相比，所有检测的细胞因子产生均严重不足。然而，通过逆流离心法富集自体单核细胞后，粒细胞集落刺激因子、粒细胞巨噬细胞集落刺激因子、IL-6和肿瘤坏死因子α的水平显著升高。其中IL-6的效应最为明显。逆转录聚合酶链反应分析表明，商陆有丝分裂原、干扰素α（IFN-α）和聚肌苷酸胞苷酸（poly(I:C)）能够诱导HCL细胞中IL-6特异性mRNA的表达。免疫荧光分析在蛋白质水平证实了这些发现。用IFN-α孵育PBMC后，HCL患者细胞内IL-6显著增加，而健康供者细胞内未见增加。CD19和CD11c阳性的毛细胞中也出现了这种增加。此外，IFN-α可诱导HCL患者PBMC分泌IL-6，而健康供者PBMC则无此现象。总之，我们对HCL患者PBMC的研究表明，造血生长因子供应不足，这可能部分归因于该疾病的单核细胞减少特征。研究结果还表明，IFN-α能够诱导患者PBMC及其毛细胞产生IL-6。我们体外研究的这些数据支持了IFN-α治疗可导致造血功能重建的临床观察结果。
