Prostaglandin F2alpha- and FAS-activating antibody-induced regression of the corpus luteum involves <it>caspase</it>-8 and is defective in <it>caspase</it>-3 deficient mice

• Main Authors: Flavell Richard A, Gonçalves Paulo Bayard D, Matikainen Tiina, Lynch Maureen P, Pru James K, Carambula Silvia F, Tilly Jonathan L, Rueda Bo R
• Format: Article
• Language: English
• Published: BMC 2003-02-01
• Series: Reproductive Biology and Endocrinology
• Online Access: http://www.RBEj.com/content/1/1/15

<p>Abstract</p> <p>We recently demonstrated that <it>caspase</it>-3 is important for apoptosis during spontaneous involution of the corpus luteum (CL). These studies tested if prostaglandin F_2α(PGF_2α) or FAS regulated luteal regression, utilize a <it>caspase</it>-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 <it>caspase</it>-3. Wild-type (WT) or <it>caspase</it>-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 PGF_2α(10 micrograms, i.p.) at 24 or 48 h post-ovulation. Ovaries from each group were collected 8 h later for assessment of active <it>caspase</it>-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 <it>caspase</it>-3 or apoptosis. However, PGF_2αor Jo2 at 48 h post-ovulation and collected 8 h later induced <it>caspase</it>-3 activation in 13.2 ± 1.8% and 13.7 ± 2.2 % of the cells, respectively and resulted in 16.35 ± 0.7% (PGF_2α) 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 <it>caspase</it>-3 deficient mice whether treated with PGF_2α, Jo2, or control IgG at 48 h post-ovulation showed little evidence of active <it>caspase</it>-3 or apoptosis. CL of WT mice treated with Jo2 at 48 h post-ovulation had an 8-fold increase in the activity of <it>caspase</it>-8, an activator of <it>caspase</it>-3 that is coupled to the FAS death receptor. Somewhat unexpectedly, however, treatment of WT mice with PGF_2αat 48 h post-ovulation resulted in a 22-fold increase in <it>caspase</it>-8 activity in the CL, despite the fact that the receptor for PGF_2αhas not been shown to be directly coupled to <it>caspase</it>-8 recruitment and activation. We hypothesize that PGF_2αinitiates luteolysis <it>in vivo</it>, 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 <it>caspase</it>-3-driven apoptosis during luteolysis.</p>