The single most effective predictor of preterm birth is the state of cervix during pregnancy upon presentation with symptoms of preterm labor. The mechanisms underlying physiological cervical ripening at term are largely unknown, and the causes of preterm cervical dilation are even more elusive. It is well-established, however, that (i exogenous topically-applied prostaglandins induce cervical ripening at any stage of pregnancy, and (ii) inhibitors of PGH2S (cyclooxygenase 2, COX-2) are successful in blocking preterm cervical ripening. PGE2 is the major COX2-derived prostanoid in the cervix. It is surprising, therefore, that the downstream targets of PGE2 signaling in the cervix are not known. By way of preliminary studies, we found that PGE2 and prostaglandin analogs commonly used for cervical ripening in women (i.e., Dinoprostone (PGE2) and Misoprostol (PGE1)) suppress 15-PGDH gene expression through complex stromal cell-specific mechanisms. Importantly, PGE2-induced down regulation of 15- PGDH was mediated through EP2 receptors, highly expressed in human cervical stromal cells. These findings led us to propose the hypothesis that PGE2-EP2 interactions play important roles in regulating the transcriptional program of cervical stromal cells during cervical ripening.
The aims of this proposal, therefore, are to (i) explore the global effects of PGE2-mediated gene expression in human cervical stromal cells, (ii) define the cellular signal transduction mechanisms by which activation of EP2 receptors leads to loss of MiTF-CX and 15-PGDH gene expression in cervical stromal cells, and (iv) determine if EP receptor antagonists regulate preterm cervical ripening in vivo.
Cervical ripening has been characterized as an inflammatory response in which IL-8 and other markers of chemotaxis increase culminating in inflammatory cell infiltration and protease activation. Our studies using cervical tissues from humans, mice, and guinea pigs, however, indicate that IL-8, other chemotactic molecules, and leukocytes do not increase until cervical dilation and labor. COX-2, on the other hand, is an early gene product activated in the ripe cervix before labor at term and during preterm labor. To make an impact on the preterm delivery rate, we need to understand the function of the downstream metabolite of COX-2 in the cervix, PGE2, and if its bioactivity can be blocked to prevent preterm cervical ripening, a major contribution to preterm birth.
| Kishore, Annavarapu Hari; Liang, Hanquan; Kanchwala, Mohammed et al. (2017) Prostaglandin dehydrogenase is a target for successful induction of cervical ripening. Proc Natl Acad Sci U S A 114:E6427-E6436 |
| Kishore, A Hari; Owens, David; Word, R Ann (2014) Prostaglandin E2 regulates its own inactivating enzyme, 15-PGDH, by EP2 receptor-mediated cervical cell-specific mechanisms. J Clin Endocrinol Metab 99:1006-18 |
| Lindqvist, Annika; Manders, Dustin; Word, R Ann (2013) The impact of reference gene selection in quantification of gene expression levels in guinea pig cervical tissues and cells. BMC Res Notes 6:34 |
