Prostaglandin E2 Receptor 4 (EP4) Affects Trophoblast Functions Via Activating the CAMP-PKA-pCREB Signaling Pathway at the Maternal-Fetal Interface in Unexplained Recurrent Miscarriage

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2021 Sep 10

PMID 34502044

Citations 2

Authors

Lin Peng

Anca Chelariu-Raicu

Yao Ye

Zhi Ma

Huixia Yang

Hellen Ishikawa-Ankerhold

Martina Rahmeh

Sven Mahner

Udo Jeschke

Viktoria von Schonfeldt

Affiliations

Soon will be listed here.

Abstract

Implantation consists of a complex process based on coordinated crosstalk between the endometrium and trophoblast. Furthermore, it is known that the microenvironment of this fetal-maternal interface plays an important role in the development of extravillous trophoblast cells. This is mainly due to the fact that tissues mediate embryonic signaling biologicals, among other molecules, prostaglandins. Prostaglandins influence tissue through several cell processes including differentiation, proliferation, and promotion of maternal immune tolerance. The aim of this study is to investigate the potential pathological mechanism of the prostaglandin E2 receptor 4 (EP4) in modulating extravillous trophoblast cells (EVTs) in unexplained recurrent marriage (uRM). Our results indicated that the expression of EP4 in EVTs was decreased in women experiencing uRM. Furthermore, silencing of EP4 showed an inhibition of the proliferation and induced apoptosis in vitro. In addition, our results demonstrated reductions in β- human chorionic gonadotropin (hCG), progesterone, and interleukin (IL)-6, which is likely a result from the activation of the cyclic adenosine monophosphate (cAMP)- cAMP-dependent protein kinase A (PKA)-phosphorylating CREB (pCREB) pathway. Our data might provide insight into the mechanisms of EP4 linked to trophoblast function. These findings help build a more comprehensive understanding of the effects of EP4 on the trophoblast at the fetal-maternal interface in the first trimester of pregnancy.

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References

Pakrasi P, Jain A . Cyclooxygenase-2 derived PGE2 and PGI2 play an important role via EP2 and PPARdelta receptors in early steps of oil induced decidualization in mice. Placenta. 2008; 29(6):523-30. DOI: 10.1016/j.placenta.2008.03.001. View

Ziecik A, Waclawik A, Kaczmarek M, Blitek A, Moza Jalali B, Andronowska A . Mechanisms for the establishment of pregnancy in the pig. Reprod Domest Anim. 2011; 46 Suppl 3:31-41. DOI: 10.1111/j.1439-0531.2011.01843.x. View

Sullivan M . Endocrine cell lines from the placenta. Mol Cell Endocrinol. 2004; 228(1-2):103-19. DOI: 10.1016/j.mce.2003.03.001. View

Mitsunari M, Yoshida S, Shoji T, Tsukihara S, Iwabe T, Harada T . Macrophage-activating lipopeptide-2 induces cyclooxygenase-2 and prostaglandin E(2) via toll-like receptor 2 in human placental trophoblast cells. J Reprod Immunol. 2006; 72(1-2):46-59. DOI: 10.1016/j.jri.2006.02.003. View

Niringiyumukiza J, Cai H, Xiang W . Prostaglandin E2 involvement in mammalian female fertility: ovulation, fertilization, embryo development and early implantation. Reprod Biol Endocrinol. 2018; 16(1):43. PMC: 5928575. DOI: 10.1186/s12958-018-0359-5. View

Bogacka I, Bogacki M, Gaglewska M, Kurzynska A, Wasielak M . In vitro effect of peroxisome proliferator activated receptor (PPAR) ligands on prostaglandin E2 synthesis and secretion by porcine endometrium during the estrous cycle and early pregnancy. J Physiol Pharmacol. 2013; 64(1):47-54. View

Sato T, Keelan J, Mitchell M . Critical paracrine interactions between TNF-alpha and IL-10 regulate lipopolysaccharide-stimulated human choriodecidual cytokine and prostaglandin E2 production. J Immunol. 2002; 170(1):158-66. DOI: 10.4049/jimmunol.170.1.158. View

Kowalewski M, Fox B, Gram A, Boos A, Reichler I . Prostaglandin E2 functions as a luteotrophic factor in the dog. Reproduction. 2013; 145(3):213-26. DOI: 10.1530/REP-12-0419. View

Red-Horse K, Zhou Y, Genbacev O, Prakobphol A, Foulk R, McMaster M . Trophoblast differentiation during embryo implantation and formation of the maternal-fetal interface. J Clin Invest. 2004; 114(6):744-54. PMC: 516273. DOI: 10.1172/JCI22991. View

10.

Diehl S, Rincon M . The two faces of IL-6 on Th1/Th2 differentiation. Mol Immunol. 2002; 39(9):531-6. DOI: 10.1016/s0161-5890(02)00210-9. View

11.

Sirotkin A, Ben O A, Tandlmajerova A, Laukova M, Vasi Ek D, Laurin Ik J . cAMP response element-binding protein 1 controls porcine ovarian cell proliferation, apoptosis, and FSH and insulin-like growth factor 1 response. Reprod Fertil Dev. 2018; 30(8):1145-1153. DOI: 10.1071/RD17508. View

12.

Burton G, Jauniaux E, Charnock-Jones D . The influence of the intrauterine environment on human placental development. Int J Dev Biol. 2009; 54(2-3):303-12. DOI: 10.1387/ijdb.082764gb. View

13.

Loch-Caruso R, Korte C, Hogan K, Liao S, Harris C . Tert-Butyl Hydroperoxide Stimulated Apoptosis Independent of Prostaglandin E and IL-6 in the HTR-8/SVneo Human Placental Cell Line. Reprod Sci. 2020; 27(11):2104-2114. PMC: 7529854. DOI: 10.1007/s43032-020-00231-5. View

14.

Abbas Y, Turco M, Burton G, Moffett A . Investigation of human trophoblast invasion in vitro. Hum Reprod Update. 2020; 26(4):501-513. PMC: 7473396. DOI: 10.1093/humupd/dmaa017. View

15.

Ye Y, Peng L, Vattai A, Deuster E, Kuhn C, Dannecker C . Prostaglandin E2 receptor 3 (EP3) signaling promotes migration of cervical cancer via urokinase-type plasminogen activator receptor (uPAR). J Cancer Res Clin Oncol. 2020; 146(9):2189-2203. PMC: 7382663. DOI: 10.1007/s00432-020-03272-0. View

16.

Tarrade A, Schoonjans K, Guibourdenche J, Bidart J, Vidaud M, Auwerx J . PPAR gamma/RXR alpha heterodimers are involved in human CG beta synthesis and human trophoblast differentiation. Endocrinology. 2001; 142(10):4504-14. DOI: 10.1210/endo.142.10.8448. View

17.

Waclawik A, Jabbour H, Blitek A, Ziecik A . Estradiol-17beta, prostaglandin E2 (PGE2), and the PGE2 receptor are involved in PGE2 positive feedback loop in the porcine endometrium. Endocrinology. 2009; 150(8):3823-32. PMC: 2714846. DOI: 10.1210/en.2008-1499. View

18.

Peng L, Yang H, Ye Y, Ma Z, Kuhn C, Rahmeh M . Role of Peroxisome Proliferator-Activated Receptors (PPARs) in Trophoblast Functions. Int J Mol Sci. 2021; 22(1). PMC: 7795665. DOI: 10.3390/ijms22010433. View

19.

Jovanovic M, Vicovac L . Interleukin-6 stimulates cell migration, invasion and integrin expression in HTR-8/SVneo cell line. Placenta. 2009; 30(4):320-8. DOI: 10.1016/j.placenta.2009.01.013. View

20.

Nicola C, Timoshenko A, Dixon S, Lala P, Chakraborty C . EP1 receptor-mediated migration of the first trimester human extravillous trophoblast: the role of intracellular calcium and calpain. J Clin Endocrinol Metab. 2005; 90(8):4736-46. DOI: 10.1210/jc.2005-0413. View