Department of Obstetrics and Gynecology, University of Toyama, Toyama-shi, Toyama, Japan.
J Reprod Immunol. 2010 Jan;84(1):75-85. doi: 10.1016/j.jri.2009.09.005. Epub 2009 Dec 6.
Chorioamnionitis (CAM) is a major cause of preterm delivery. Inflammatory cytokines and chemokines play important roles in the pathogenesis of preterm delivery. Interleukin (IL)-17 is a key cytokine which induces inflammation and is critical to host defense. In this study, we examined the role of IL-17 in the pathogenesis of preterm delivery. The levels of cytokines including IL-17, IL-8 and tumor necrosis factor (TNF) alpha were measured by ELISA in amniotic fluid from 154 cases of preterm labor. Flow cytometry and immunohistochemical staining were performed to determine the distribution of IL-17-producing cells. IL-8 secretion was evaluated in primary cultured human amniotic mesenchymal (HAM) cells and human amniotic epithelial (HAE) cells stimulated with IL-17, TNFalpha or IL-1beta. We also studied the signaling pathway of IL-17 and TNFalpha in HAM cells. Levels of inflammatory cytokines in amniotic fluid were higher in preterm delivery cases than in term delivery cases. Furthermore, IL-8, IL-17 and TNFalpha levels were significantly higher in the preterm cases with CAM stage II or III than those without CAM. Flow cytometry and immunohistochemical staining revealed that CD3(+)CD4(+) T cells were the main source of IL-17 in the chorioamniotic membrane. Interestingly, TNFalpha-induced IL-8 secretion was enhanced by IL-17 in a dose-dependent manner in HAM cells. The IKK inhibitor BMS-345541 and mitogen-activated protein kinase (MAPK) inhibitors p38, JNK and p42/44 (ERK1/2 pathway) reduced IL-8 secretion by IL-17-stimulated and TNFalpha-stimulated HAM cells. These results indicate that IL-17, produced by T cells, promotes inflammation at the fetomaternal interface in preterm delivery.
绒毛膜羊膜炎（CAM）是早产的主要原因。炎症细胞因子和趋化因子在早产的发病机制中起着重要作用。白细胞介素（IL）-17 是一种关键的细胞因子，可诱导炎症，对宿主防御至关重要。在这项研究中，我们研究了 IL-17 在早产发病机制中的作用。通过 ELISA 测定了 154 例早产患者羊水样本中包括白细胞介素-17（IL-17）、白细胞介素-8（IL-8）和肿瘤坏死因子（TNF）α在内的细胞因子的水平。采用流式细胞术和免疫组织化学染色来确定 IL-17 产生细胞的分布。通过 IL-17、TNFα 或白细胞介素-1β刺激原代培养的人羊膜间充质（HAM）细胞和人羊膜上皮（HAE）细胞，评估 IL-8 的分泌。我们还研究了 HAM 细胞中 IL-17 和 TNFα 的信号通路。早产患者羊水中的炎症细胞因子水平高于足月分娩患者。此外，伴有 CAM Ⅱ期或Ⅲ期的早产患者的 IL-8、IL-17 和 TNFα 水平明显高于无 CAM 的患者。流式细胞术和免疫组织化学染色显示，在绒毛膜羊膜膜中，CD3(+)CD4(+)T 细胞是 IL-17 的主要来源。有趣的是，TNFα 诱导的 IL-8 分泌在 HAM 细胞中呈剂量依赖性地被 IL-17 增强。IKK 抑制剂 BMS-345541 和丝裂原活化蛋白激酶（MAPK）抑制剂 p38、JNK 和 p42/44（ERK1/2 通路）降低了由 IL-17 刺激和 TNFα 刺激的 HAM 细胞的 IL-8 分泌。这些结果表明，T 细胞产生的 IL-17 可促进早产时胎儿母体界面的炎症反应。
