T-helper cell type 2 (Th2) memory T cell-potentiating cytokine IL-25 has the potential to promote angiogenesis in asthma
T-helper cell type 2 (Th2) memory T cell-potentiating cytokine IL-25 has the potential to promote angiogenesis in asthma
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DOI：
10.1073/pnas.1014241108
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发表时间：
2011-01-25
影响因子：
11.1
通讯作者：
Ying, Sun
中科院分区：
文献类型：
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作者：
Corrigan, Chris J.;Wang, Wei;Ying, Sun
IL-25（IL-17 E）是一种辅助性T细胞2型（Th 2）细胞因子，最好描述为Th 2记忆反应的增强剂。其受体IL-25 R在气道结构细胞上表达的报道表明IL-25在重塑中具有更广泛的作用。我们假设IL-25刺激哮喘支气管粘膜局部血管生成。免疫组化法检测哮喘患者和对照组支气管活检组织中IL-25（+）、IL-25 R（+）和CD 31（+）（内皮）细胞。使用体外测定法检查IL-25对血管生成的作用。采用实时荧光定量PCR检测培养的人血管内皮细胞（HUVEC）中IL-25 R和VEGF mRNA的表达，采用细胞增殖试剂盒（WST-8）检测IL-25对HUVEC增殖的影响。免疫组化结果显示，哮喘患者支气管黏膜IL-25（+）、IL-25 R（+）及CD 31（+）/IL-25 R（+）细胞均显著高于对照组（P < 0.003）。哮喘患者IL-25阳性细胞数与1 s用力呼气量呈负相关（r = -0.639，P = 0.01）。在体外，HUVEC组成型表达IL-25 R，其被TNF-α进一步上调。IL-25和TNF-α也增加VEGF和VEGF受体的表达。IL-25在体外以浓度依赖性方式增加HUVEC增殖和微血管结构的数量、长度和面积。VEGF阻断剂、PI 3 K特异性抑制剂LY 294002和MAPK/ERK 1/2（MEK 1/2）特异性抑制剂U 0126均显著减弱IL-25诱导的血管生成，并且抑制剂还降低IL-25诱导的增殖和VEGF表达。我们的研究结果表明，IL-25在哮喘中升高，并有助于血管生成，至少部分通过增加内皮细胞VEGF/VEGF受体表达通过PI 3 K/Akt和Erk/MAPK途径。
IL-25 (IL-17E) is a T-helper cell type 2 (Th2) cytokine best described as a potentiator of Th2 memory responses. Reports of expression of its receptor, IL-25R, on airways structural cells suggest a wider role for IL-25 in remodeling. We hypothesized that IL-25 stimulates local angiogenesis in the asthmatic bronchial mucosa. Immunoreactive IL-25(+), IL-25R(+), and CD31(+) (endothelial) cells in sections of bronchial biopsies from asthmatics and controls were detected by immunohistochemistry. The effect of IL-25 on angiogenesis was examined using an in vitro assay. Real-time PCR was used to detect expression of IL-25R and VEGF mRNA in cultured human vascular endothelial cells (HUVEC), and a cell proliferation kit (WST-8) was used to measure the effect of IL-25 on HUVEC proliferation. Immunostaining showed that IL-25(+), IL-25R(+), and CD31(+)/IL-25R(+) cells were significantly elevated in the bronchial mucosa of asthmatics compared with controls (P < 0.003). In asthmatics, the numbers of IL-25(+) cells correlated inversely with the forced expiratory volume in 1 s (r = -0.639; P = 0.01). In vitro, HUVEC constitutively expressed IL-25R, which was up-regulated further by TNF-alpha. IL-25 and TNF-alpha also increased expression of VEGF and VEGF receptors. IL-25 increased HUVEC proliferation and the number, length, and area of microvessel structures in a concentration-dependent manner in vitro. VEGF blockade, the PI3K-specific inhibitor LY294002, and the MAPK/ERK1/2 (MEK1/2)-specific inhibitor U0126 all markedly attenuated IL-25-induced angiogenesis, and the inhibitors also reduced IL-25-induced proliferation and VEGF expression. Our findings suggest that IL-25 is elevated in asthma and contributes to angiogenesis, at least partly by increasing endothelial cell VEGF/VEGF receptor expression through PI3K/Akt and Erk/MAPK pathways.