Genes for prostaglandin synthesis, transport and inactivation are differentially expressed in human uterine tissues, and the prostaglandin F synthase AKR1B1 is induced in myometrial cells by inflammatory cytokines

Abstract

Prostaglandins (PGs) are important factors in the physiology of human parturition and the control of uterine contractility. We have characterized the expression of 15 genes from all stages of the PG pathway in human pregnant and non-pregnant (NP) myometrium and in other uterine tissues at delivery, and the results show patterns indicative of different capacities for PG synthesis and catabolism in each tissue. In placenta, the PG synthase expression profile favours production of PGD₂, PGE₂ and PGF₂, with high levels of PG transporters and catabolic PG dehydrogenase suggesting rapid PG turnover. Choriodecidua is primed for PGE₂, PGF₂ and PGD₂ production and high PG turnover, whereas amnion expresses genes for PGE₂ synthesis with low levels of PG transporters and dehydrogenase. In umbilical cord, PGI₂ synthase is highly expressed. In pregnant myometrium, PGI₂, PGD₂ and PGF₂ synthases are highly expressed, whereas PG dehydrogenase is underexpressed. Myometrium from women with spontaneous or induced labour had higher expression of the PGH₂ synthase PTGS2 than tissue from women not-in-labour. Myometrium from NP women had lower levels of PG synthases and higher levels of PG dehydrogenase than pregnant myometrium. Discriminant function analysis showed that expression of selected genes in myometrium could distinguish groups of women with different modes of labour from each other and from NP women. In cultured myometrial cells, there was a dose-dependent stimulatory effect of interleukin 1β and tumour necrosis factor α on PTGS2, PTGES and AKR1B1 (PGF synthase) expression.

Neuromedin B and Its Receptor Influence the Activity of Myometrial Primary Cells In Vitro Through Regulation of Il6 Expression via the Rela/p65 Pathway in Mice1

“…These results suggest that the NMB elicit increased [Ca 2þ ] i depending on the joint presence of extracellular calcium via PKC, and it may involve other pathways in Nmbr-mediated effects on myometrial cell activity. Related studies have shown that Nmbr activation stimulates phospholipase A2 and phospholipase D via both PKC-dependent and independent mechanisms [29]. Phospholipase A2 activity is a crucial enzyme in the regulation of the production and release of prostaglandin, which induces myometrium contraction and cervix ripening [29,30].…”

“…Related studies have shown that Nmbr activation stimulates phospholipase A2 and phospholipase D via both PKC-dependent and independent mechanisms [29]. Phospholipase A2 activity is a crucial enzyme in the regulation of the production and release of prostaglandin, which induces myometrium contraction and cervix ripening [29,30]. Moreover, Nmbr stimulation also results in activation of tyrosine kinases and tyrosine phosphorylation of p125FAK by a phospholipase C-independent mechanism which requires p21 and the integrity of the actin cytoskeleton [31].…”

Prostaglandin pathway gene expression in human placenta, amnion and choriodecidua is differentially affected by preterm and term labour and by uterine inflammation

“…We previously compared the relative levels of expression of 15 genes acting in all stages of prostaglandin metabolism (their relationships are illustrated in Figure 1) in human uterine tissues [13], demonstrating specific capacities for synthesis and catabolism of PGD 2 , PGE 2 , PGF 2 and PGI 2 in each tissue. We have now made a detailed examination of these genes in samples of placenta, choriodecidua and amnion, demonstrating that factors such as gestational age and the incidence and duration of labour are associated with significant changes in expression patterns.…”

Central role for protein kinase C in oxytocin and epidermal growth factor stimulated cyclooxygenase 2 expression in human myometrial cells

“…During labour there is increased synthesis of prostaglandins (PGs) within the uterus via the induction of prostaglandin-endoperoxide synthase (PTGS), also known as cyclooxygenase (COX) [8]. COX is a rate limiting enzyme that is responsible for the conversion of arachidonic acid to prostaglandin endoperoxides, which are further converted into different prostaglandins (PGs) by cell specific terminal synthases [9-11]. Besides relaxation and contraction of the myometrium, PGs also stimulate cervical ripening.…”

“…epidermal growth factor (EGF)), phorbol esters (e.g. phorbol-12-myristate-13-acetate (PMA)) and by the potent uterotonic hormone oxytocin (OXT) [9,13-16]. …”