Prostaglandin F2alpha- and FAS-activating antibody-induced regression of the corpus luteum involves caspase-8 and is defective in caspase-3 deficient mice.
Prostaglandin F2alpha- and FAS-activating antibody-induced regression of the corpus luteum involves caspase-8 and is defective in caspase-3 deficient mice.
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DOI：
10.1186/1477-7827-1-15
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发表时间：
2003-02-11
影响因子：
4.4
通讯作者：
Rueda, Bo R
中科院分区：
文献类型：
--
作者：
Carambula, Silvia F;Pru, James K;Lynch, Maureen P;Matikainen, Tiina;Goncalves, Paulo Bayard D;Flavell, Richard A;Tilly, Jonathan L;Rueda, Bo R
我们最近证明，半胱天冬酶-3对于黄体（CL）自发退化期间的细胞凋亡很重要。这些研究检测了前列腺素F2α（PGF 2 α）或FAS是否调节黄体退化，利用caspase-3依赖性途径执行黄体细胞凋亡，以及两种受体是否通过独立或潜在共享的细胞内信号传导组分/途径激活caspase-3。将25-26日龄的野生型（WT）或caspase-3缺陷型雌性小鼠腹腔内（IP）给予10 IU马绒毛膜促性腺激素（eCG），46 h后给予10 IU人绒毛膜促性腺激素（hCG）IP以同步排卵。然后给动物注射IgG（2微克，静脉注射），FAS活化抗体Jo 2（2微克，静脉内），或PGF 2 α（10微克，i. p.）在排卵后24或48小时。8 h后收集各组卵巢，用于评估CL中活性caspase-3酶和细胞凋亡（通过TUNEL测定）。无论基因型或治疗，从排卵后24小时注射的小鼠收集的卵巢中的CL显示没有活性半胱天冬酶-3或细胞凋亡的证据。然而，在排卵后48小时和8小时后收集的PGF 2 α或Jo 2分别诱导13.2 ± 1.8%和13.7 ± 2.2%的细胞中的半胱天冬酶-3活化，并导致16.35 ± 0.7%（PGF 2 α）和14.3 ± 2.5%的TUNEL阳性细胞，而IgG处理的对照组中CL细胞为1.48 ± 0.8%。相比之下，从caspase-3缺陷小鼠收集的卵巢中的CL，无论是用PGF 2 α、Jo 2还是对照IgG处理，在排卵后48小时，几乎没有活性caspase-3或细胞凋亡的证据。排卵后48小时用Jo 2处理的WT小鼠的CL的半胱天冬酶-8的活性增加了8倍，半胱天冬酶-3的激活剂与FAS死亡受体偶联。然而，有点出乎意料的是，在排卵后48小时用PGF 2 α处理WT小鼠，导致CL中的半胱天冬酶-8活性增加了22倍，尽管事实上PGF 2 α的受体尚未被证明直接偶联到半胱天冬酶-8募集和激活。我们推测，PGF 2 α在体内至少部分通过增加细胞因子（如FasL）的生物活性或生物利用度来启动黄体溶解，并且多种内分泌因子在黄体溶解过程中协同作用以激活caspase-3驱动的凋亡。
We recently demonstrated that caspase-3 is important for apoptosis during spontaneous involution of the corpus luteum (CL). These studies tested if prostaglandin F2α (PGF2α) or FAS regulated luteal regression, utilize a caspase-3 dependent pathway to execute luteal cell apoptosis, and if the two receptors work via independent or potentially shared intracellular signaling components/pathways to activate caspase-3. Wild-type (WT) or caspase-3 deficient female mice, 25–26 days old, were given 10 IU equine chorionic gonadotropin (eCG) intraperitoneally (IP) followed by 10 IU human chorionic gonadotropin (hCG) IP 46 h later to synchronize ovulation. The animals were then injected with IgG (2 micrograms, i.v.), the FAS-activating antibody Jo2 (2 micrograms, i.v.), or PGF2α (10 micrograms, i.p.) at 24 or 48 h post-ovulation. Ovaries from each group were collected 8 h later for assessment of active caspase-3 enzyme and apoptosis (measured by the TUNEL assay) in the CL. Regardless of genotype or treatment, CL in ovaries collected from mice injected 24 h after ovulation showed no evidence of active caspase-3 or apoptosis. However, PGF2α or Jo2 at 48 h post-ovulation and collected 8 h later induced caspase-3 activation in 13.2 ± 1.8% and 13.7 ± 2.2 % of the cells, respectively and resulted in 16.35 ± 0.7% (PGF2α) and 14.3 ± 2.5% TUNEL-positive cells when compared to 1.48 ± 0.8% of cells CL in IgG treated controls. In contrast, CL in ovaries collected from caspase-3 deficient mice whether treated with PGF2α , Jo2, or control IgG at 48 h post-ovulation showed little evidence of active caspase-3 or apoptosis. CL of WT mice treated with Jo2 at 48 h post-ovulation had an 8-fold increase in the activity of caspase-8, an activator of caspase-3 that is coupled to the FAS death receptor. Somewhat unexpectedly, however, treatment of WT mice with PGF2α at 48 h post-ovulation resulted in a 22-fold increase in caspase-8 activity in the CL, despite the fact that the receptor for PGF2α has not been shown to be directly coupled to caspase-8 recruitment and activation. We hypothesize that PGF2α initiates luteolysis in vivo, at least in part, by increasing the bioactivity or bioavailability of cytokines, such as FasL and that multiple endocrine factors work in concert to activate caspase-3-driven apoptosis during luteolysis.