Kim Mee Rhan, Manoukian Raffi, Yeh Richard, Silbiger Scott M, Danilenko Dimitry M, Scully Sheila, Sun Jilin, DeRose Margaret L, Stolina Marina, Chang David, Van Gwyneth Y, Clarkin Kristie, Nguyen Hung Q, Yu Yan Bin, Jing Shuqian, Senaldi Giorgio, Elliott Gary, Medlock Eugene S
Departments of Functional Genomics, Pathology, Inflammation, Clinical Immunology, and Protein Science, Amgen Inc, Thousand Oaks, California 91302, USA.
Blood. 2002 Oct 1;100(7):2330-40. doi: 10.1182/blood-2002-01-0012.
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 (hIL-17E). 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. Splenomegaly and lymphoadenopathy were predominant and included marked eosinophil infiltrates and lymphoid hyperplasia. 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 (Ig) 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-17Rh1 (IL-17BR/Evi27), 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.
我们已经鉴定并克隆了一种与白细胞介素-17（IL-17）家族细胞因子具有同源性的新型人类细胞因子，我们将其命名为人类IL-17E（hIL-17E）。随着几种IL-17家族成员的鉴定，了解这些分子在体内的功能至关重要。我们使用载脂蛋白E（ApoE）肝脏启动子生成了过表达hIL-17E的转基因小鼠。这些小鼠外周血出现变化，特别是总白细胞增加了3倍，其中嗜酸性粒细胞、淋巴细胞和中性粒细胞均增加。脾肿大和淋巴结病很明显，包括明显的嗜酸性粒细胞浸润和淋巴样增生。转基因小鼠血液和淋巴结中的CCR3(+)嗜酸性粒细胞分别增加了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呈现未成熟外观。转基因小鼠外周血中的CD19(+) B细胞增加了2至5倍，脾脏中增加了2倍，淋巴结中增加了10倍，而CD4(+) T淋巴细胞在血液和脾脏中均增加了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的血清水平较高。与B淋巴细胞增加一致，血清免疫球蛋白（Ig）M、IgG和IgE显著升高。用钥孔戚血蓝蛋白（KLH）对转基因小鼠进行抗原攻击导致抗KLH IgG减少，同时抗KLH IgA和IgE增加。转基因组织的原位杂交显示，与IL-17E结合的受体IL-17Rh1（IL-17BR/Evi27）上调。综上所述,这些数据表明IL-17E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-17E过表达导致循环嗜酸性粒细胞、IL-4、IL-5、嗜酸性粒细胞趋化因子和IgE水平升高，这一事实表明IL-17E可能是一种促进Th2型免疫反应的促炎细胞因子。
