HEMATOPOIETIC AND LUNG ABNORMALITIES IN MICE WITH A NULL MUTATION OF THE COMMON BETA-SUBUNIT OF THE RECEPTORS FOR GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR AND INTERLEUKIN-3 AND INTERLEUKIN-5
HEMATOPOIETIC AND LUNG ABNORMALITIES IN MICE WITH A NULL MUTATION OF THE COMMON BETA-SUBUNIT OF THE RECEPTORS FOR GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR AND INTERLEUKIN-3 AND INTERLEUKIN-5
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DOI：
10.1073/pnas.92.21.9565
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发表时间：
1995-10-10
影响因子：
11.1
通讯作者：
BEGLEY, CG
中科院分区：
文献类型：
--
作者：
ROBB, L;DRINKWATER, CC;BEGLEY, CG
利用基因打靶技术，建立了编码粒细胞-巨噬细胞集落刺激因子(GM-CSF)、白介素3(IL-3；多粒细胞集落刺激因子)和白介素5(IL-5)受体复合体(β(C)(-/-)小鼠)共同β亚单位(β(C))基因零突变的小鼠。在β(C)(-/-)小鼠骨髓细胞克隆培养中，β(C)(-/-)小鼠骨髓细胞中GM-CSF的高亲和力结合被取消，而杂合子动物(β(C)(+/-)小鼠)的细胞显示出中等数量的高亲和力受体，IL-3的结合不受影响，证实了β(C)(-/-)小鼠外周血和骨髓中的嗜酸性粒细胞数量减少，而其他血液学参数正常。即使高浓度的GM-CSF和IL-5也不能刺激集落形成，但细胞对IL-3和其他生长因子的刺激表现出正常的定量反应，β(C)(-/-)小鼠发育正常并存活到年轻成人，尽管它们出现了肺支气管血管周围淋巴组织浸润物和类似肺泡蛋白沉积症的区域。β(C)(-/-)和野生型窝产仔在GM-CSF的系统清除和分布方面没有明显差异，这些数据证实了β(C)通常限制GM-CSF的高亲和力结合，并表明GM-CSF的系统清除不是通过这种高亲和力受体复合体介导的。
Gene targeting was used to create mice with a null mutation of the gene encoding the common beta subunit (beta(C)) of the granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin 3 (IL-3; multi-CSF), and interleukin 5 (IL-5) receptor complexes (beta(C)(-/-) mice). High-affinity binding of GM-CSF was abolished in beta(C)(-/-) bone marrow cells, while cells from heterozygous animals (beta(C)(+/-) mice) showed an intermediate number of high-affinity receptors, Binding of IL-3 was unaffected, confirming that the IL-3-specific beta chain remained intact, Eosinophil numbers in peripheral blood and bone marrow of beta(C)(-/-) animals were reduced, while other hematological parameters were normal, In clonal cultures of beta(C)(-/-) bone marrow cells, even high concentrations of GM-CSF and IL-5 failed to stimulate colony formation, but the cells exhibited normal quantitative responsiveness to stimulation by IL-3 and other growth factors, beta(C)(-/-) mice exhibited normal development and survived to young adult life, although they developed pulmonary peribronchovascular lymphoid infiltrates and areas resembling alveolar proteinosis. There was no detectable difference in the systemic clearance and distribution of GM-CSF between beta(C)(-/-) and wild-type littermates, The data establish that beta(C) is normally limiting for high-affinity binding of GM-CSF and demonstrate that systemic clearance of GM-CSF is not mediated via such high-affinity receptor complexes.