Advanced glycation end products induce secretion of chemokines and apoptosis in human first trimester trophoblasts
Advanced glycation end products induce secretion of chemokines and apoptosis in human first trimester trophoblasts
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DOI：
10.1093/humrep/deh389
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发表时间：
2004-09-01
影响因子：
6.1
通讯作者：
Hiramatsu, Y
中科院分区：
文献类型：
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作者：
Konishi, H;Nakatsuka, M;Hiramatsu, Y
背景技术背景：我们研究了晚期糖基化终末产物（AGEs）对人类滋养层细胞的影响，已知AGEs在糖尿病、自身免疫性疾病或吸烟患者体内积累。方法：取孕6-10周早孕绒毛组织。用免疫印迹和免疫组化方法检测AGEs受体（AGEs）的表达和定位。用ELISA法测定培养液中巨噬细胞炎性蛋白（MIP）-1 α和MIP-1 β（活化调节的正常T细胞表达和分泌的RANTES）和人绒毛膜促性腺激素（hCG）。Hoechst 33258染色和原位缺口末端标记技术检测滋养细胞凋亡。结果：胎盘滋养层细胞中存在胎盘素。AGEs以时间和剂量依赖性方式显著刺激滋养细胞分泌MIP-1 α和MIP-1 β。AGEs可显著诱导细胞凋亡，减少hCG分泌。一氧化氮合酶（NOS）抑制剂或甲磺酸萘莫司他（一种合成丝氨酸蛋白酶抑制剂和转录因子NF-κ B激活抑制剂）可显著抑制AGEs引起的MIP-1 α和MIP-1 β分泌增加。这些药物还抑制AGEs对hCG分泌和滋养细胞凋亡的影响。结论：这些AGE介导的滋养细胞变化可能导致着床和胎盘形成的损害。NOS抑制剂或萘莫司他甲磺酸盐可能会改变这些影响。
BACKGROUND: We studied the effects of advanced glycation end products (AGEs), which are known to accumulate in patients with diabetes, autoimmune diseases, or that smoke, on human trophoblasts. METHODS: First trimester human chorionic villi of 6-10 week gestation were obtained. Expression and localization of the receptor for AGEs (RAGE) was examined by western blotting and immunohistochemistry. Macrophage inflammatory protein (MIP)-1alpha and MIP-1beta, regulated upon activation, normal T-cell expressed and secreted (RANTES), and human chorionic gonadotropin (hCG) in culture medium were measured by ELISA. Trophoblastic apoptosis was evaluated by the Hoechst 33258 staining and the in situ nick end labeling technique. RESULTS: RAGE was localized in trophoblasts. AGEs significantly stimulated secretion of both MIP-1alpha and MIP-1beta from trophoblasts in a time- and dose-dependent manner. AGEs significantly induced apoptosis and reduced secretion of hCG. Increased secretions of MIP-1alpha and MIP-1beta by AGEs were significantly suppressed by inhibitors of nitric oxide synthase (NOS) or nafamostat mesilate, a synthetic serine protease inhibitor and a suppressor of transcription factor, NF-kappaB activation. These agents also suppressed the effects of AGEs on hCG secretion and trophoblastic apoptosis. CONCLUSIONS: These AGE-mediated changes in trophoblasts may lead to impairment of implantation and placentation. NOS inhibitors or nafamostat mesilate may modify these effects.