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

Carambula SF, Pru JK, Lynch MP, Matikainen T, Gonçalves PB, Flavell RA, Tilly JL, Rueda BR - Reprod. Biol. Endocrinol. (2003)

Bottom Line: The animals were then injected with IgG (2 micrograms, i.v.), the FAS-activating antibody Jo2 (2 micrograms, i.v.), or PGF2alpha (10 micrograms, i.p.) at 24 or 48 h post-ovulation.However, PGF2alpha 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% (PGF2alpha) and 14.3 PlusMinus; 2.5% TUNEL-positive cells when compared to 1.48 +/- 0.8% of cells CL in IgG treated controls.We hypothesize that PGF2alpha 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts 02114, USA. silviafc@hcv.ufsm.br

ABSTRACT
We recently demonstrated that caspase-3 is important for apoptosis during spontaneous involution of the corpus luteum (CL). These studies tested if prostaglandin F2alpha (PGF2alpha) 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 PGF2alpha (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, PGF2alpha 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% (PGF2alpha) and 14.3 PlusMinus; 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 PGF2alpha, 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 PGF2alpha 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 PGF2alpha has not been shown to be directly coupled to caspase-8 recruitment and activation. We hypothesize that PGF2alpha 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.

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Quantitative analysis of Caspase-8 activity in CL in response to IgG, Jo2 or PGF2α in vivo. The level of caspase-8 activity was determined in CL isolated from ovaries collected from WT mice 8 h following injection IgG (2 μg/IV), Jo2 (2 μg/IV) or PGF2α (10 μg/IP). The asterisk (*) represent differences from the control P < 0.05. The experiment was replicated three separate times (n = 3) with different groups of mice.
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Figure 4: Quantitative analysis of Caspase-8 activity in CL in response to IgG, Jo2 or PGF2α in vivo. The level of caspase-8 activity was determined in CL isolated from ovaries collected from WT mice 8 h following injection IgG (2 μg/IV), Jo2 (2 μg/IV) or PGF2α (10 μg/IP). The asterisk (*) represent differences from the control P < 0.05. The experiment was replicated three separate times (n = 3) with different groups of mice.

Mentions: In a final set of experiments, the level of caspase-8 activity was determined in CL isolated from ovaries collected from WT mice 8 h following injection with IgG, Jo2 or PGF2α, at 48 h post-ovulation. Treatment with Jo2 resulted in an 8-fold increase (P < 0.04) in caspase-8 activity over the IgG treated controls (Fig. 4). In addition, CL of PGF2α-treated mice had a 22-fold increase (P < 0.0003) in caspase-8 activity over controls (Fig. 4).


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

Carambula SF, Pru JK, Lynch MP, Matikainen T, Gonçalves PB, Flavell RA, Tilly JL, Rueda BR - Reprod. Biol. Endocrinol. (2003)

Quantitative analysis of Caspase-8 activity in CL in response to IgG, Jo2 or PGF2α in vivo. The level of caspase-8 activity was determined in CL isolated from ovaries collected from WT mice 8 h following injection IgG (2 μg/IV), Jo2 (2 μg/IV) or PGF2α (10 μg/IP). The asterisk (*) represent differences from the control P < 0.05. The experiment was replicated three separate times (n = 3) with different groups of mice.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC152637&req=5

Figure 4: Quantitative analysis of Caspase-8 activity in CL in response to IgG, Jo2 or PGF2α in vivo. The level of caspase-8 activity was determined in CL isolated from ovaries collected from WT mice 8 h following injection IgG (2 μg/IV), Jo2 (2 μg/IV) or PGF2α (10 μg/IP). The asterisk (*) represent differences from the control P < 0.05. The experiment was replicated three separate times (n = 3) with different groups of mice.
Mentions: In a final set of experiments, the level of caspase-8 activity was determined in CL isolated from ovaries collected from WT mice 8 h following injection with IgG, Jo2 or PGF2α, at 48 h post-ovulation. Treatment with Jo2 resulted in an 8-fold increase (P < 0.04) in caspase-8 activity over the IgG treated controls (Fig. 4). In addition, CL of PGF2α-treated mice had a 22-fold increase (P < 0.0003) in caspase-8 activity over controls (Fig. 4).

Bottom Line: The animals were then injected with IgG (2 micrograms, i.v.), the FAS-activating antibody Jo2 (2 micrograms, i.v.), or PGF2alpha (10 micrograms, i.p.) at 24 or 48 h post-ovulation.However, PGF2alpha 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% (PGF2alpha) and 14.3 PlusMinus; 2.5% TUNEL-positive cells when compared to 1.48 +/- 0.8% of cells CL in IgG treated controls.We hypothesize that PGF2alpha 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts 02114, USA. silviafc@hcv.ufsm.br

ABSTRACT
We recently demonstrated that caspase-3 is important for apoptosis during spontaneous involution of the corpus luteum (CL). These studies tested if prostaglandin F2alpha (PGF2alpha) 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 PGF2alpha (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, PGF2alpha 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% (PGF2alpha) and 14.3 PlusMinus; 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 PGF2alpha, 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 PGF2alpha 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 PGF2alpha has not been shown to be directly coupled to caspase-8 recruitment and activation. We hypothesize that PGF2alpha 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.

Show MeSH
Related in: MedlinePlus