Transplantable myeloproliferative disease induced in mice by an interleukin 6 retrovirus.
Transplantable myeloproliferative disease induced in mice by an interleukin 6 retrovirus.
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DOI：
10.1084/jem.176.4.1149
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发表时间：
1992-10-01
期刊：
影响因子：
--
通讯作者：
Hawley TS
中科院分区：
文献类型：
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作者：
Hawley RG;Fong AZ;Burns BF;Hawley TS
接受致命辐射的小鼠移植了感染了带有小鼠 IL-6 基因的新型重组逆转录病毒（鼠干细胞病毒-白细胞介素 6 [MSCV-IL-6]）的骨髓细胞，在植入后 4 周内出现了致命的骨髓增殖性疾病。该综合征的血液学表现包括外周白细胞计数升高（高达 430 x 10(3) 细胞/mm3），以中性粒细胞、小细胞性贫血和血小板增多或血小板减少为主。小鼠的肺、肝和偶尔的淋巴结出现广泛的中性粒细胞浸润，加上脾脏骨髓生成增强（祖细胞数量增加 30-60 倍）导致脾肿大。尽管IL-6长期刺激中性粒细胞过量，但受影响小鼠的骨髓在重复连续移植过程中能够重新填充受致命辐射的宿主的造血组织（骨髓和脾脏）。在最长的记录病例中，单个 MSCV-IL-6 标记细胞的后代将骨髓增殖性疾病转移给两个二级、四个三级和两个四级受体（克隆总共持续了 72 周）。这些结果证明 IL-6 产生细胞具有相当长的增殖寿命，支持 IL-6 在维持造血前体细胞中的体内作用。 IL-6 产生失调也具有显着的全身影响。小鼠的肾脏系膜细胞增殖增加，肝脏频繁异常，血浆蛋白水平显着改变。与之前的研究不同，外源 IL-6 基因的组成型表达导致以大量浆细胞增多为特征的淋巴增殖性疾病，在观察期间 MSCV-IL-6 小鼠中出现了最小的浆细胞扩张。目前和之前的研究中观察到的疾病表型差异的可能解释是表达外源IL-6基因的不同细胞类型、使用MSCV-IL-6逆转录病毒递送系统实现的更高的IL-6持续循环水平和/或MSCV-IL-6小鼠在浆细胞增多症开始前过早死亡（移植后3-15周）。该动物模型对于进一步研究 IL-6 在正常和异常造血以及炎症反应中的功能应该是有用的。
Lethally irradiated mice transplanted with bone marrow cells infected with a novel recombinant retrovirus (murine stem cell virus-interleukin 6 [MSCV-IL-6]) bearing a mouse IL-6 gene developed a fatal myeloproliferative disease within 4 wk of engraftment. The hematologic manifestations of the syndrome included elevated peripheral leukocyte counts (up to 430 x 10(3) cells/mm3) with a predominance of neutrophilic granulocytes, microcytic anemia, and thrombocytosis or thrombocytopenia. The mice showed extensive neutrophil infiltration of the lungs, liver, and occasionally lymph nodes, plus splenomegaly resulting from enhanced splenic myelopoiesis (30-60-fold increase in progenitor numbers). Despite the chronic stimulation of neutrophil excess by IL-6, bone marrow from affected mice was capable of repopulating the hematopoietic tissues (bone marrow and spleen) of lethally irradiated hosts during repeated serial transplantation. In the longest documented case, the progeny of a single MSCV-IL-6-marked cell transferred the myeloproliferative disease to two secondary, four tertiary, and two quaternary recipients (the clone endured for a total of 72 wk). These results, demonstrating considerable proliferative longevity of the IL-6-producing cells, support an in vivo role of IL-6 in the maintenance of hematopoietic precursors. Dysregulated IL-6 production also had significant systemic effects. The mice displayed increased mesangial cell proliferation in the kidney, frequent liver abnormalities, and marked alterations in plasma protein levels. Unlike previous studies where constitutive expression of exogenous IL-6 genes resulted in lymphoproliferative disorders characterized by massive plasmacytosis, minimal plasma cell expansion occurred in the MSCV-IL-6 mice during the observation period. Potential explanations for the differences in disease phenotypes observed in the present and previous studies are different cell types expressing the exogenous IL-6 genes, higher sustained circulating levels of IL-6 achieved using the MSCV-IL- 6 retroviral delivery system, and/or the premature death (3-15 wk after transplantation) of the MSCV-IL-6 mice before the onset of plasmacytosis. This animal model should prove useful for further investigation of the function of IL-6 in normal and abnormal hematopoiesis and in inflammatory responses.