Human cytomegalovirus-caused damage to placental trophoblasts mediated by immediate-early gene-induced tumor necrosis factor-α
Human cytomegalovirus-caused damage to placental trophoblasts mediated by immediate-early gene-induced tumor necrosis factor-α
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DOI：
10.1016/s0002-9440(10)64413-6
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发表时间：
2002-10-01
影响因子：
6
通讯作者：
Guilbert, LJ
中科院分区：
文献类型：
--
作者：
Chan, G;Hemmings, DG;Guilbert, LJ
人巨细胞病毒（HCMV）感染细化绒毛胎盘的胎儿上皮细胞（滋养层）伴随胎盘炎症和胎儿宫内生长受限。然而，绒毛滋养层感染的后果尚未探讨。我们发现，HCMV感染的初级未成熟（细胞滋养层样）或成熟（合胞体滋养层样）培养物的结果在病毒攻击后24小时内损失了一半的细胞。双色免疫荧光的HCMV立即早期（IEE）基因表达和凋亡（末端dUTP缺口末端标记）显示，凋亡仅在未感染的细胞。肿瘤坏死因子（TNF）-α抗体完全抑制感染诱导的滋养层细胞凋亡和细胞丢失，与表皮生长因子共孵育，已知抑制滋养层细胞凋亡。用HCMV立即早期（IE）1-72和IE 2 -86，但不是IE 2 -55，表达质粒转染;诱导旁分泌滋养层细胞凋亡，可由表皮生长因子或TNF-α抗体引起。这些结果表明，绒毛滋养层细胞的HCMV感染导致由病毒IE蛋白诱导的TNF-α分泌介导的邻近细胞的快速丧失。我们认为HCMV感染通过加速滋养细胞更新和降低其更新能力来破坏胎盘滋养细胞屏障。
Infection of the fetal epithelium (trophoblast) fining the villous placenta by human cytomegalovirus (HCMV) accompanies placental inflammations and fetal intrauterine growth restriction. However, the consequences of infection on the villous trophoblast have not been explored. We show that HCMV infection of primary immature (cytotrophoblast-like) or mature (syncytiotrophoblast-like) cultures results in loss of half of the cells within 24 hours of virus challenge. Two-color immunofluorescence of HCMV immediate early (IEE) gene expression and apoptosis (terminal dUTP nick-end labeling) revealed apoptosis only in uninfected cells. Antibody to tumor necrosis factor (TNF)-alpha completely inhibited infection-induced trophoblast apoptosis and cell loss, as did co-incubation with epidermal growth factor, known to inhibit trophoblast apoptosis. Transfection with HCMV immediate early- (IE)1-72 and IE2-86, but not IE2-55, expression plasmids; induced paracrine trophoblast apoptosis inhibitable by epidermal growth factor or antibody to TNF-alpha. These results show that HCMV infection of villous trophoblasts leads to rapid loss of neighboring cells mediated by viral IE protein-induced TNF-alpha secretion. We propose that HCMV infection damages the placental trophoblast barrier by accelerating trophoblast turnover and decreasing its capacity for renewal.