Progesterone Inhibits Basal and TNF-α-Induced Apoptosis in Fetal Membranes: A Novel Mechanism to Explain Progesterone-Mediated Prevention of Preterm Birth
Progesterone Inhibits Basal and TNF-α-Induced Apoptosis in Fetal Membranes: A Novel Mechanism to Explain Progesterone-Mediated Prevention of Preterm Birth
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DOI：
10.1177/1933719110363618
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发表时间：
2010-06-01
影响因子：
2.9
通讯作者：
Norwitz, Errol R.
中科院分区：
文献类型：
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作者：
Luo, Guoyang;Abrahams, Vikki M.;Norwitz, Errol R.
目的：孕激素补充剂可预防一些高危妇女的早产（PTB），但其作用机制尚不清楚。三分之一的PTB与早产胎膜早破（PPROM）有关。我们推测孕酮可能阻断促炎性孕酮诱导的胎膜凋亡，从而预防PPROM和PTB。研究方法：在足月择期重复剖宫产时收集胎膜（无分娩，无感染[n = 12]），清洗，并在含/不含孕酮（125-500 ng/mL）、17 α-羟孕酮己酸酯（125-500 ng/mL [17 P]）或醋酸甲羟孕酮（10（-7）-10（-6）mol/L [MPA]）的情况下培养24小时。然后用/不用脂多糖（[LPS] 100 ng/mL）或肿瘤坏死因子α（[TNF-α] 50 ng/mL）处理膜24至72小时，收获并匀浆。通过评估caspase-3、-8和-9活性来确定细胞凋亡。在光度计上测量以相对光单位表示的胱天蛋白酶活性，并针对总蛋白进行校正。结果：TNF-α和LPS均能显著增加足月胎膜中caspase-3、-8和-9的活性，并呈时间依赖性。孕酮、17 P和MPA显著降低TNF-α诱导的caspase-3活性，但不降低LPS诱导的caspase-3活性。有趣的是，孕酮和MPA，但不是17 P，也抑制基础caspase-3活性。结论：孕激素可抑制足月胎膜的基础和TNF-α诱导的细胞凋亡。这一新的观察结果可能部分解释了孕酮补充剂预防某些高危妇女PPROM和PTB的机制。孕酮对细胞凋亡基础水平的影响表明，这种机制对足月正常分娩也很重要。
Objective: Progesterone supplementation prevents preterm birth (PTB) in some high-risk women, but its mechanism of action is not known. One third of PTB is associated with preterm premature rupture of membranes (PPROM). We hypothesize that progesterone may block proinflammatory cytokine-induced apoptosis of fetal membrane, thereby preventing PPROM and PTB. Methods: Fetal membranes were collected at elective repeat cesarean at term (no labor, no infection [n = 12]), washed, and cultured with/without progesterone (125-500 ng/mL), 17 alpha-hydroxyprogesterone caproate (125-500 ng/mL [17P]), or medroxyprogesterone acetate (10(-7)-10(-6) mol/L [MPA]) for 24 hours. Membranes were then treated with/without lipopolysaccharide ([LPS] 100 ng/mL) or tumor necrosis factor alpha ([TNF-alpha] 50 ng/mL) for 24 to 72 hours, harvested, and homogenized. Apoptosis was determined by evaluating caspase-3, -8, and -9 activities. Caspase activity in relative light units was measured on a luminometer and corrected for total protein. Results: Both TNF-alpha and LPS significantly increased caspase-3, -8, and -9 activity in term fetal membranes in a time-dependent fashion. Progesterone, 17P, and MPA significantly reduced TNF-alpha, but not LPS, induced caspase-3 activity. Interestingly, progesterone and MPA, but not 17P, also inhibited basal caspase-3 activity. Conclusion: Progesterone inhibits basal and TNF-alpha-induced apoptosis in term fetal membranes. This novel observation may explain in part the mechanism by which progesterone supplementation prevents PPROM and PTB in some high-risk women. The effect of progesterone on the basal levels of apoptosis suggests that this mechanism may also be important for normal labor at term.