Kilani R T, Mackova M, Davidge S T, Winkler-Lowen B, Demianczuk N, Guilbert L J
University of Alberta Perinatal Research Centre, Edmonton, Canada.
Reproduction. 2007 Jan;133(1):257-64. doi: 10.1530/REP-06-0080.
Tumor necrosis factor alpha (TNFalpha) has been implicated in the abnormally high levels of trophoblast apoptosis seen in placentae from pregnancies complicated by small births. We examined the hypothesis that at physiological (35-50 mmHg) oxygen tensions, the production of TNFalpha stimulates the apoptosis of placental trophoblasts associated with infants that are intrauterine growth-restricted (IUGR). Highly purified cytotrophoblasts (CT) from IUGR-complicated pregnancies spontaneously underwent a higher rate of apoptosis after 24 h of culture at a normoxic (for villous CT) tension of 38 mmHg than did CT from normal placentae. Real-time PCR analysis of TNFalpha mRNA revealed approximately threefold higher levels in IUGR trophoblasts after culturing at a pO2 of 38 mmHg. A higher level of TNFalpha receptor p55 (which mediates apoptosis) was found in IUGR CT by western blot analysis at pO2 of <10, 38, and 140 mmHg. Neutralizing antibody to TNFalpha significantly inhibited the apoptosis of IUGR trophoblasts cultured at 38 mmHg and addition of TNFalpha significantly elevated apoptosis of normal and IUGR trophoblasts but less in IUGR cells cultured at <10 mmHg. We conclude that at physiological oxygen tensions (38 mmHg), villous CT from IUGR pregnancies, when compared with uncomplicated pregnancies, undergo more TNFalpha-induced apoptosis both because of elevated expression of TNFalpha and TNF receptor p55.
肿瘤坏死因子α（TNFα）与妊娠合并低体重儿的胎盘组织中出现的滋养层细胞异常高凋亡水平有关。我们检验了以下假说：在生理氧分压（35 - 50 mmHg）下，TNFα的产生会刺激与宫内生长受限（IUGR）婴儿相关的胎盘滋养层细胞凋亡。与正常胎盘的细胞滋养层（CT）相比，来自合并IUGR妊娠的高度纯化的细胞滋养层在38 mmHg的常氧（针对绒毛CT）张力下培养24小时后，自发凋亡率更高。对TNFα mRNA进行实时PCR分析发现，在38 mmHg的pO₂下培养后，IUGR滋养层细胞中的TNFα mRNA水平大约高出三倍。通过蛋白质印迹分析发现在pO₂为<10、38和140 mmHg时，IUGR CT中TNFα受体p55（介导细胞凋亡）的水平更高。抗TNFα中和抗体显著抑制了在38 mmHg下培养的IUGR滋养层细胞的凋亡，添加TNFα显著提高了正常和IUGR滋养层细胞的凋亡率，但在<10 mmHg下培养的IUGR细胞中凋亡增加较少。我们得出结论，在生理氧分压（38 mmHg）下，与未合并并发症的妊娠相比，IUGR妊娠的绒毛CT由于TNFα和TNF受体p55表达升高，会经历更多TNFα诱导的凋亡。
