Transgenic overexpression of human IL-17E results in eosinophilia, B-lymphocyte hyperplasia, and altered antibody production
Transgenic overexpression of human IL-17E results in eosinophilia, B-lymphocyte hyperplasia, and altered antibody production
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DOI：
10.1182/blood-2002-01-0012
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发表时间：
2002-10-01
期刊：
影响因子：
20.3
通讯作者：
Medlock, ES
中科院分区：
文献类型：
--
作者：
Kim, MR;Manoukian, R;Medlock, ES
我们已经鉴定并克隆了一种与白细胞介素-17（IL-17）家族的细胞因子具有同源性的新型人细胞因子，我们将其称为人IL-17 E（hIL-17 E）。随着几个IL-17家族成员的鉴定，了解这些分子的体内功能至关重要。我们使用载脂蛋白E（ApoE）肝启动子产生过表达hIL-17 E的转基因小鼠。这些小鼠显示外周血变化，特别是总白细胞增加3倍，包括嗜酸性粒细胞、淋巴细胞和中性粒细胞增加。脾肿大和淋巴结肿大占优势，包括明显的嗜酸性粒细胞浸润和淋巴样增生。CCR 3（+）嗜酸性粒细胞在转基因小鼠的血液和淋巴结中分别增加了50倍和300倍。骨髓和脾脏中的嗜酸性粒细胞也分别增加了8至18倍。在骨髓中，大多数嗜酸性粒细胞具有不成熟的外观。转基因小鼠外周血中CD 19（+）B细胞增加2至5倍，脾脏中增加2倍，淋巴结中增加10倍，而血液和脾脏中CD 4（+）T淋巴细胞增加2倍。观察到细胞因子IL-2、IL-4、IL-5、粒细胞集落刺激因子、嗜酸性粒细胞趋化因子和干扰素γ的高血清水平。与B淋巴细胞增加一致，血清免疫球蛋白（1g）M、IgG和IgE显著升高。用匙孔血蓝蛋白（KLH）抗原攻击转基因小鼠，导致抗KLH IgG降低，同时抗KLH伊加和IgE升高。转基因组织的原位杂交显示，IL-11 7 Rh 1（IL-17 BR/Ev 127），一种结合IL-17 E的受体，被上调。综上所述，这些数据证实IL-17 E调节造血和免疫功能，刺激嗜酸性粒细胞和B淋巴细胞的发育。hIL-17 E过表达导致高水平的循环嗜酸性粒细胞、IL-4、IL-5、嗜酸细胞活化趋化因子和IgE的事实表明IL-17 E可能是有利于Th 2型免疫应答的促炎细胞因子。(C)2002年，美国血液学会。
We have Identified and cloned a novel human cytokine with homology to cytokines of the Interleukin-17 (IL-17) family, which we have termed human IL-17E (hIL17E). With the identification of several IL-17 family members, it is critical to understand the in vivo function of these molecules. We have generated transgenic mice overexpressing hIL-17E using an apolipoprotein E (ApoE) hepatic promoter. These mice displayed changes In the peripheral blood, particularly, a 3-fold Increase in total leukocytes consisting of increases In eosinophils, lymphocytes, and neutrophils. Splenomegally and lymphoadenopathy were predominant and Included marked eosinophil Infiltrates and lymphoid hyperplasla. CCR3(+) eosinophils Increased In the blood and lymph nodes of the transgenic mice by 50- and 300-fold, respectively. Eosinophils also increased 8- to 18-fold In the bone marrow and spleen, respectively. In the bone marrow, most of the eosinophils had an Immature appearance. CD19(+) B cells Increased 2- to 5-fold In the peripheral blood, 2-fold In the spleen, and 10-fold In the lymph nodes of transgenic mice, whereas CD4(+) T lymphocytes Increased 2-fold In both blood and spleen. High serum levels of the cytokines IL-2, IL-4, IL-5, granulocyte colony-stimulating factor, eotaxin, and Interferon gamma were observed. Consistent with B-lymphocyte increases, serum immunoglobulin (1g) M, IgG, and IgE were significantly elevated. Antigenic challenge of the transgenic mice with keyhole limpet hemocyanin (KLH) resulted in a decrease In anti-KLH IgG accompanied by increases of anti-KLH IgA and IgE. In situ hybridization of transgenic tissues revealed that IL-11 7Rh1 (IL-17BR/Ev127), a receptor that binds IL-17E, Is up-regulated. Taken together, these data Indicate that IL-17E regulates hematopoietic and Immune functions, stimulating the development of eosinophils and B lymphocytes. The fact that hIL-17E overexpression results In high levels of circulating eosinophils, IL-4, IL-5, eotaxin, and IgE suggests that IL-17E may be a proinflammatory cytokine favoring Th2-type Immune responses. (C) 2002 by The American Society of Hematology.