Differential Regulation of Prostaglandin Production Mediated by Corticotropin-Releasing Hormone Receptor Type 1 and Type 2 in Cultured Human Placental Trophoblasts

Abstract

Prostaglandin (PG) production by intrauterine tissues plays a key part in the control of pregnancy and parturition. The present study was to investigate the role of placenta-derived CRH and CRH-related peptides in the regulation of PG synthesis and metabolism. We found that placental trophoblasts expressed both CRH-R1 and CRH-R2. Treatment of cultured placental cells with either a CRH or urocortin I (UCNI) antibody resulted in a significant decrease in PGE2 release. Both CRH and UCNI antibodies significantly decreased mRNA and protein expression of synthetic enzymes cytosolic phospholipase A2 (cPLA2) and cyclooxygenase (COX)-2 and increased mRNA and protein expression of 15-hydroxyprostaglandin dehydrogenase (PGDH), the key enzyme of PG metabolism. CRH-R1/-R2 antagonist astressin and CRH-R1 antagonist antalarmin significantly inhibited PGE2 release, whereas CRH-R2 antagonist astressin-2b had no effect on PGE(2) release. Administration of astressin decreased expression of cPLA2 but had no effect on COX-2 expression. Antalarmin reduced cPLA2 and COX-2 expression, whereas astressin-2b did not alter cPLA2 expression but increased COX-2 expression. PGDH expression was enhanced by these three antagonists. Cells treated with exogenous CRH and UCNI showed an increase in PGE(2) release and expression of cPLA2 and COX-2 but a decrease in PGDH expression. UCNII and UCNIII had no effect on PGE2 release but decreased COX-2 and PGDH expression. Our results suggested CRH and CRH-related peptides act on CRH-R1 and CRH-R2 to exert different effects on PG biosynthetic enzymes cPLA2 and COX-2 and thereby modulate output of PGs from placenta, which would be important for controlling pregnancy and parturition.

Corticotropin-releasing hormone receptors mediate apoptosis via cytosolic calcium-dependent phospholipase A2 and migration in prostate cancer cell RM-1

“…Inhibition of iPLA 2 expression by urocortin provides critical insights into the effect of CRH family peptides on expressions of PLA 2 groups. Gao et al (2008) reported that both CRH and Ucn1 increased mRNA and protein expression of cPLA 2 via CRHR1 in human placental trophoblasts, which is in part consistent with our present data on prostate cancer cells. However, the role of CRHR2 in cPLA 2 inhibition was also detected in our experiment.…”

“…It has been reported that cPLA 2 is present in all prostate cancer cell lines and that eicosanoids contribute to cancer progression (Patel et al 2008). Gao et al (2008) demonstrated that CRH and Ucn1 increased mRNA and protein expression of cPLA 2 via CRHR1 but not CRHR2 in human placental trophoblasts.…”

Corticotrophin-releasing factor participates in S1PR3-dependent cPLA2 expression and cell motility in vascular smooth muscle cells

“…In HUVECs, UCN time-dependently increased cPLA2 expression and activity via both CRFR1 and CRFR2 [19]. Similarly, both CRF and UCN increased cPLA2 expression in cultured human placental trophoblasts [36]. Moreover, UCN was found to significantly suppress iPLA2 expression and activity to prevent the ischemia-induced cell death [37,38].…”

Expression and subcellular localization of CRH and its receptors in human endometrial cancer

“…To reduce non specific binding, the sections were preincubated with 20% normal swine serum for 30 min at room temperature. Human trophoblast tissue was used as positive control, since human placenta has been shown to express CRH as well as both CRH receptor subtypes (Wetzka et al, 2003, Gao et al, 2008. Human placenta was obtained from a healthy subject undergoing elective caesarean section at term of gestation before the onset of labor.…”