A Heterodimeric Cytokine, Consisting of IL-17A and IL-17F, Promotes Migration and Capillary-Like Tube Formation of Human Vascular Endothelial Cells
A Heterodimeric Cytokine, Consisting of IL-17A and IL-17F, Promotes Migration and Capillary-Like Tube Formation of Human Vascular Endothelial Cells
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DOI：
10.1620/tjem.240.47
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发表时间：
2016-09-01
影响因子：
2.2
通讯作者：
Ohrui, Takashi
中科院分区：
文献类型：
--
作者：
Numasaki, Muneo;Tsukamoto, Hiroki;Ohrui, Takashi
白细胞介素（IL）-17家族由六种同型二聚体细胞因子IL-17 A、IL-17 B、IL-17 C、IL-17 D、IL-17 E/IL-25和IL-17 F组成，介导多种生物活性，包括调节趋化因子分泌和血管生成。在IL-17家族成员中，IL-17 A和IL-17 E/IL-25是血管生成刺激剂，而IL-17 B和IL-17 F是血管生成抑制剂。最近，IL-17 A/F异源二聚体，包括IL-17 A和IL-17 F亚基，被发现作为IL-17细胞因子家族的另一个成员。然而，迄今为止，IL-17 A/F是否具有影响血管生成相关的血管内皮功能的生物学作用尚不清楚。因此，在本研究中，我们研究了IL-17 A/F对血管内皮细胞生长、迁移和毛细血管样管形成的生物学效应。重组IL-17 A/F蛋白对人真皮微血管内皮细胞（HMVECs）的生长没有直接影响，然而，在改良的Boyden趋化细胞室中孵育4小时后，IL-17 A/F通过磷脂酰肌醇-3激酶（PI 3 K）信号通路在很宽的剂量范围内显著诱导HMVECs迁移。我们进一步研究了IL-17 A/F对毛细血管样管形成的生物学效应，使用人脐静脉内皮细胞（HUVEC）和人真皮成纤维细胞（HDF）的共培养系统，其模拟了体内微环境。在该共培养系统中，IL-17 A/F通过PI 3 K和细胞外信号调节激酶（ERK）信号通路以剂量依赖性方式显著促进毛细血管样内皮管形成。此外，IL-17 A/F上调血管生成生长因子如IL-8和生长相关癌基因（GRO）-α的分泌。这些发现鉴定了IL-17 A/F作为间接血管生成剂的新生物学功能。
The interleukin (IL)-17 family, consisting of six homodimeric cytokines IL-17A, IL-17B, IL-17C, IL-17D, IL-17E/IL-25, and IL-17F, mediates a variety of biological activities including regulation of chemokine secretion and angiogenesis. Among the IL-17 family members, IL-17A and IL-17E/IL-25 are angiogenesis stimulators, while IL-17B and IL-17F are angiogenesis inhibitors. Recently, IL-17A/F heterodimer, comprised of the IL-17A and IL-17F subunits, was found as another member of the IL-17 cytokine family. However, to date, it has been unknown whether IL-17A/F has biological actions to affect the angiogenesis-related vascular endothelial functions. Therefore, in this study, we investigated the biological effects of IL-17A/F on the growth, migration and capillary-like tube formation of vascular endothelial cells. Recombinant IL-17A/F protein had no direct effects on the growth of human dermal microvascular endothelial cells (HMVECs), whereas, after 4-hour incubation in a modified Boyden Chemotaxicell chamber, IL-17A/F significantly induced migration of HMVECs over a wide range of doses via the phosphatidylinositol-3 kinase (PI3K) signaling pathway. We further investigated the biological effect of IL-17A/F on capillary-like tube formation using a co-culture system of human umbilical vein endothelial cells (HUVECs) and human dermal fibroblasts (HDFs), which mimicked the in vivo microenvironment. In this co-culture system, IL-17A/F significantly promoted capillary-like endothelial tube formation in a dose dependent fashion via the PI3K and extracellular signal-regulated kinase (ERK) signaling pathways. Additionally, IL-17A/F up-regulated secretion of angiogenic growth factors such as IL-8 and growth-related oncogene(GRO)-alpha by HDFs. These findings identify a novel biological function for IL-17A/F as an indirect angiogenic agent.