Interleukin-25 promotes basic fibroblast growth factor expression by human endothelial cells through interaction with IL-17RB, but not IL-17RA
Interleukin-25 promotes basic fibroblast growth factor expression by human endothelial cells through interaction with IL-17RB, but not IL-17RA
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DOI：
10.1111/j.1365-2222.2012.04062.x
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发表时间：
2012-11-01
影响因子：
6.1
通讯作者：
Ying, S.
中科院分区：
文献类型：
--
作者：
Wang, W.;Fan, Y. Q.;Ying, S.
背景 与其他 IL-17 家族成员不同，Th2 衍生细胞因子 IL-25 (IL-17E) 诱导（促进）Th2 反应。 IL-25 的两种受体（IL-17RA、IL-17RB）之一或两者在炎症细胞和组织结构细胞上表达，表明除了促进 Th2 型炎症外，IL-25 还可能作用于 Th2 型炎症部位的结构细胞（例如哮喘支气管粘膜），促进重塑变化。 目的 我们之前的研究表明，哮喘气道中 IL-25 和 IL-17RB 免疫反应性表达升高，且共定位后者转化为内皮细胞。因此，我们推测IL-25通过该受体作用于内皮细胞，诱导关键的血管生成和重塑细胞因子碱性成纤维细胞生长因子（bFGF）的产生。方法采用聚合酶链式反应（PCR）免疫细胞化学/免疫组化和ELISA检测人血管内皮细胞（HUVEC）表达IL-17RB、IL-17RA和bFGF以及IL-25和bFGF的免疫反应性。在哮喘支气管活检中。使用受体阻断抗体、PCR 和体外血管生成测定来研究 IL-25 是否作用于 IL-17RB 或 IL-17RA 来诱导 bFGF 表达和血管生成。 PCR方法还用于研究IL-25介导的bFGF表达所涉及的信号通路。结果HUVEC持续表达IL-17RB、IL-17RA和bFGF。 IL-25 进一步增加后者的产生，但在阻断 IL-17RB（而非 IL-17RA 受体）后减弱。内源性 VEGF 和 bFGF 的中和完全消除了 IL-25 诱导的血管生成，阻断 IL-17RB 也可抑制血管生成，但阻断 IL-17RA 则不会。 PI3K 特异性抑制剂 LY294002 也完全减弱 IL-25 诱导的 bFGF 表达。哮喘支气管粘膜中 IL-25 和 bFGF 的免疫反应性升高，并且各自的表达彼此相关。结论和临床相关性我们的数据支持这样的假设：IL-25 通过 PI3K 信号通路作用于内皮细胞 IL-17RB 受体，从而导致哮喘气道中 bFGF 升高。针对这些途径可能有利于气道重塑的治疗。
Background Unlike other IL-17 family members, the Th2-derived cytokine IL-25 (IL-17E) induces (promotes) Th2 responses. One or both of the two receptors for IL-25 (IL-17RA, IL-17RB) is expressed on inflammatory cells and tissue structural cells, suggesting that in addition to promoting Th2-type inflammation IL-25 may also act on structural cells at sites of Th2-type inflammation such as in the asthmatic bronchial mucosa to promote remodelling changes.Objective Our previous studies showed elevated expression of IL-25 and IL-17RB immunoreactivity in asthmatic airways with co-localization of the latter to endothelial cells. We therefore hypothesized that IL-25 acts on endothelial cells through this receptor to induce production of the key angiogenic and remodelling cytokine basic fibroblast growth factor (bFGF).Methods Polymerase chain reaction (PCR) immunocytochemistry/immunohistochemistry and ELISA were employed to detect expression of IL-17RB, IL-17RA and bFGF by human vascular endothelial cells (HUVEC) and immunoreactivity for IL-25 and bFGF in asthmatic bronchial biopsies. Receptor-blocking antibodies, PCR and an in vitro angiogenesis assay were used to investigate whether IL-25 acts on IL-17RB or IL-17RA to induce bFGF expression and angiogenesis. PCR was also employed to investigate the signalling pathways involved in IL-25-mediated bFGF expression.Results HUVEC constitutively expressed IL-17RB, IL-17RA and bFGF. Production of the latter was further increased by IL-25, but attenuated after blockade of the IL-17RB, but not the IL-17RA receptor. Neutralization of endogenous VEGF and bFGF completely abrogated IL-25-induced angiogenesis which was also inhibited by blocking IL-17RB, but not IL-17RA. The PI3K-specific inhibitor LY294002 also completely attenuated IL-25-induced bFGF expression. Immunoreactivity for IL-25 and bFGF was elevated in the asthmatic bronchial mucosa and the expression of each correlated with the other.Conclusions and Clinical Relevance Our data support the hypothesis that IL-25 contributes to elevated bFGF in asthmatic airways by acting on the endothelial cell IL-17RB receptor through PI3K-signalling pathways. Targeting the pathways might benefit therapy of airways remodelling.