Corticotropin-releasing hormone stimulates expression of leptin, 11beta-HSD2 and syncytin-1 in primary human trophoblasts

Reproductive Biology and Endocrinology

Jörg Dötsch¹  Wolfgang Rascher³  Manfred Rauh³  Reiner Strick²  Carlos Menendez-Castro³  Andrea Hartner³  Ramona Offergeld³  Gudrun Volkert³  Matthias Ruebner²  Fabian B Fahlbusch³ 

[1] Childrens’ and Adolescents’ Hospital, University of Cologne, Cologne, Germany;Department of Gynecology and Obstetrics, University of Erlangen-Nürnberg, Erlangen, Germany;Department of Pediatrics and Adolescent Medicine, University of Erlangen-Nürnberg, Erlangen, Germany

关键词: Placenta;    Syncytiotrophoblast;    Trophoblast;    Syncytin-1;    11beta-HSD2;    leptin;    CRH;   

Others  :  1150063
DOI  :  10.1186/1477-7827-10-80

 received in 2012-01-13, accepted in 2012-09-04,  发布年份 2012

【 摘 要 】

Background

The placental syncytiotrophoblast is the major source of maternal plasma corticotropin-releasing hormone (CRH) in the second half of pregnancy. Placental CRH exerts multiple functions in the maternal organism: It induces the adrenal secretion of cortisol via the stimulation of adrenocorticotropic hormone, regulates the timing of birth via its actions in the myometrium and inhibits the invasion of extravillous trophoblast cells in vitro. However, the auto- and paracrine actions of CRH on the syncytiotrophoblast itself are unknown. Intrauterine growth restriction (IUGR) is accompanied by an increase in placental CRH, which could be of pathophysiological relevance for the dysregulation in syncytialisation seen in IUGR placentas.

Methods

We aimed to determine the effect of CRH on isolated primary trophoblastic cells in vitro. After CRH stimulation the trophoblast syncytialisation rate was monitored via syncytin-1 gene expression and beta-hCG (beta-human chorionic gonadotropine) ELISA in culture supernatant. The expression of the IUGR marker genes leptin and 11beta-hydroxysteroid dehydrogenase 2 (11beta-HSD2) was measured continuously over a period of 72 h. We hypothesized that CRH might attenuate syncytialisation, induce leptin, and reduce 11beta-HSD2 expression in primary villous trophoblasts, which are known features of IUGR.

Results

CRH did not influence the differentiation of isolated trophoblasts into functional syncytium as determined by beta-hCG secretion, albeit inducing syncytin-1 expression. Following syncytialisation, CRH treatment significantly increased leptin and 11beta-HSD2 expression, as well as leptin secretion into culture supernatant after 48 h.

Conclusion

The relevance of CRH for placental physiology is underlined by the present in vitro study. The induction of leptin and 11beta-HSD2 in the syncytiotrophoblast by CRH might promote fetal nutrient supply and placental corticosteroid metabolism in the phase before labour induction.

【 授权许可】

   
2012 Fahlbusch et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Shibasaki T, Odagiri E, Shizume K, Ling N: Corticotropin-releasing factor-like activity in human placental extracts. J Clin Endocrinol Metab 1982, 55:384-386.
• [2]Petraglia F, Florio P, Gallo R, Simoncini T, Saviozzi M, Di Blasio AM, Vaughan J, Vale W: Human placenta and fetal membranes express human urocortin mRNA and peptide. J Clin Endocrinol Metab 1996, 81:3807-3810.
• [3]Kalantaridou SN, Makrigiannakis A, Mastorakos G, Chrousos GP: Roles of reproductive corticotropin-releasing hormone. Ann N Y Acad Sci 2003, 997:129-135.
• [4]McLean M, Smith R: Corticotropin-releasing Hormone in Human Pregnancy and Parturition. Trends Endocrinol Metab 1999, 10:174-178.
• [5]Mastorakos G, Scopa CD, Vryonidou A, Friedman TC, Kattis D, Phenekos C, Merino MJ, Chrousos GP: Presence of immunoreactive corticotropin-releasing hormone in normal and polycystic human ovaries. J Clin Endocrinol Metab 1994, 79:1191-1197.
• [6]Di Blasio AM, Pecori Giraldi F, Vigano P, Petraglia F, Vignali M, Cavagnini F: Expression of corticotropin-releasing hormone and its R1 receptor in human endometrial stromal cells. J Clin Endocrinol Metab 1997, 82:1594-1597.
• [7]Petraglia F, Tabanelli S, Galassi MC, Garuti GC, Mancini AC, Genazzani AR, Gurpide E: Human decidua and in vitro decidualized endometrial stromal cells at term contain immunoreactive corticotropin-releasing factor (CRF) and CRF messenger ribonucleic acid. J Clin Endocrinol Metab 1992, 74:1427-1431.
• [8]Rodriguez-Linares B, Linton EA, Phaneuf S: Expression of corticotrophin-releasing hormone receptor mRNA and protein in the human myometrium. J Endocrinol 1998, 156:15-21.
• [9]Gao L, He P, Sha J, Liu C, Dai L, Hui N, Ni X: Corticotropin-releasing hormone receptor type 1 and type 2 mediate differential effects on 15-hydroxy prostaglandin dehydrogenase expression in cultured human chorion trophoblasts. Endocrinology 2007, 148:3645-3654.
• [10]Karteris E, Grammatopoulos D, Dai Y, Olah KB, Ghobara TB, Easton A, Hillhouse EW: The human placenta and fetal membranes express the corticotropin-releasing hormone receptor 1alpha (CRH-1alpha) and the CRH-C variant receptor. J Clin Endocrinol Metab 1998, 83:1376-1379.
• [11]Lockwood CJ, Radunovic N, Nastic D, Petkovic S, Aigner S, Berkowitz GS: Corticotropin-releasing hormone and related pituitary-adrenal axis hormones in fetal and maternal blood during the second half of pregnancy. J Perinat Med 1996, 24:243-251.
• [12]Grammatopoulos D, Dai Y, Chen J, Karteris E, Papadopoulou N, Easton AJ, Hillhouse EW: Human corticotropin-releasing hormone receptor: differences in subtype expression between pregnant and nonpregnant myometria. J Clin Endocrinol Metab 1998, 83:2539-2544.
• [13]Stevens MY, Challis JR, Lye SJ: Corticotropin-releasing hormone receptor subtype 1 is significantly up-regulated at the time of labor in the human myometrium. J Clin Endocrinol Metab 1998, 83:4107-4115.
• [14]Tzschoppe A, Fahlbusch F, Seidel J, Dorr HG, Rascher W, Goecke TW, Beckmann MW, Schild RL, Struwe E, Dotsch J: Dexamethasone stimulates the expression of leptin and 11beta-HSD2 in primary human placental trophoblastic cells. Eur J Obstet Gynecol Reprod Biol 2011, 156(1):50-55. Epub 2011 Feb 2
• [15]van Beek JP, Guan H, Julan L, Yang K: Glucocorticoids stimulate the expression of 11beta-hydroxysteroid dehydrogenase type 2 in cultured human placental trophoblast cells. J Clin Endocrinol Metab 2004, 89:5614-5621.
• [16]Grammatopoulos DK, Hillhouse EW: Role of corticotropin-releasing hormone in onset of labour. Lancet 1999, 354:1546-1549.
• [17]Tyson EK, Smith R, Read M: Evidence that corticotropin-releasing hormone modulates myometrial contractility during human pregnancy. Endocrinology 2009, 150:5617-5625.
• [18]Aggelidou E, Hillhouse EW, Grammatopoulos DK: Up-regulation of nitric oxide synthase and modulation of the guanylate cyclase activity by corticotropin-releasing hormone but not urocortin II or urocortin III in cultured human pregnant myometrial cells. Proc Natl Acad Sci U S A 2002, 99:3300-3305.
• [19]Clifton VL, Read MA, Leitch IM, Giles WB, Boura AL, Robinson PJ, Smith R: Corticotropin-releasing hormone-induced vasodilatation in the human fetal-placental circulation: involvement of the nitric oxide-cyclic guanosine 3',5'-monophosphate-mediated pathway. J Clin Endocrinol Metab 1995, 80:2888-2893.
• [20]Bamberger AM, Minas V, Kalantaridou SN, Radde J, Sadeghian H, Loning T, Charalampopoulos I, Brummer J, Wagener C, Bamberger CM, et al.: Corticotropin-releasing hormone modulates human trophoblast invasion through carcinoembryonic antigen-related cell adhesion molecule-1 regulation. Am J Pathol 2006, 168:141-150.
• [21]Kadyrov M, Kingdom JC, Huppertz B: Divergent trophoblast invasion and apoptosis in placental bed spiral arteries from pregnancies complicated by maternal anemia and early-onset preeclampsia/intrauterine growth restriction. Am J Obstet Gynecol 2006, 194:557-563.
• [22]Roberts JM, Taylor RN, Musci TJ, Rodgers GM, Hubel CA, McLaughlin MK: Preeclampsia: an endothelial cell disorder. Am J Obstet Gynecol 1989, 161:1200-1204.
• [23]Tzschoppe AA, Struwe E, Dorr HG, Goecke TW, Beckmann MW, Schild RL, Dotsch J: Differences in gene expression dependent on sampling site in placental tissue of fetuses with intrauterine growth restriction. Placenta 2010, 31:178-185.
• [24]Dotsch J, Nusken KD, Knerr I, Kirschbaum M, Repp R, Rascher W: Leptin and neuropeptide Y gene expression in human placenta: ontogeny and evidence for similarities to hypothalamic regulation. J Clin Endocrinol Metab 1999, 84:2755-2758.
• [25]Goland RS, Jozak S, Warren WB, Conwell IM, Stark RI, Tropper PJ: Elevated levels of umbilical cord plasma corticotropin-releasing hormone in growth-retarded fetuses. J Clin Endocrinol Metab 1993, 77:1174-1179.
• [26]Goland RS, Tropper PJ, Warren WB, Stark RI, Jozak SM, Conwell IM: Concentrations of corticotrophin-releasing hormone in the umbilical-cord blood of pregnancies complicated by pre-eclampsia. Reprod Fertil Dev 1995, 7:1227-1230.
• [27]Ruebner M, Strissel PL, Langbein M, Fahlbusch F, Wachter DL, Faschingbauer F, Beckmann MW, Strick R: Impaired cell fusion and differentiation in placentae from patients with intrauterine growth restriction correlate with reduced levels of HERV envelope genes. J Mol Med 2010, 88:1143-1156.
• [28]McCarthy C, Cotter FE, McElwaine S, Twomey A, Mooney EE, Ryan F, Vaughan J: Altered gene expression patterns in intrauterine growth restriction: potential role of hypoxia. Am J Obstet Gynecol 2007, 196(70):e71-e76.
• [29]Dy J, Guan H, Sampath-Kumar R, Richardson BS, Yang K: Placental 11beta-hydroxysteroid dehydrogenase type 2 is reduced in pregnancies complicated with idiopathic intrauterine growth Restriction: evidence that this is associated with an attenuated ratio of cortisone to cortisol in the umbilical artery. Placenta 2008, 29:193-200.
• [30]Voigt M, Schneider KT, Jahrig K: Analysis of a 1992 birth sample in Germany 1: New percentile values of the body weight of newborn infants. Geburtshilfe Frauenheilkd 1996, 56:550-558.
• [31]Kliman HJ, Nestler JE, Sermasi E, Sanger JM, Strauss JF 3rd: Purification, characterization, and in vitro differentiation of cytotrophoblasts from human term placentae. Endocrinology 1986, 118:1567-1582.
• [32]Schild RL, Sonnenberg-Hirche CM, Schaiff WT, Bildirici I, Nelson DM, Sadovsky Y: The kinase p38 regulates peroxisome proliferator activated receptor-gamma in human trophoblasts. Placenta 2006, 27:191-199.
• [33]Ruebner M, Strissel PL, Langbein M, Fahlbusch F, Wachter DL, Faschingbauer F, Beckmann MW, Strick R: Impaired cell fusion and differentiation in placentae from patients with intrauterine growth restriction correlate with reduced levels of HERV envelope genes. J Mol Med (Berl) 2010, 88:1143-1156.
• [34]Guilbert LJ, Winkler-Lowen B: Placental alkaline phosphatase (PLAP) staining and human chorionic gonadotropin (hCG) production in cultures of fresh and cryopreserved cytotrophoblasts isolated by CD9/MHC class I/MHC class II immunoelimination. Placenta 2007, 28:348-349.
• [35]Ruebner M, Langbein M, Strissel PL, Henke C, Schmidt D, Goecke TW, Faschingbauer F, Schild RL, Beckmann MW, Strick R: Regulation of the human endogenous retroviral Syncytin-1 and cell-cell fusion by the nuclear hormone receptors PPARgamma/RXRalpha in placentogenesis. J Cell Biochem 2012, 113:2383-2396.
• [36]Legrand C, Bour JM, Jacob C, Capiaumont J, Martial A, Marc A, Wudtke M, Kretzmer G, Demangel C, Duval D, et al.: Lactate dehydrogenase (LDH) activity of the cultured eukaryotic cells as marker of the number of dead cells in the medium [corrected]. J Biotechnol 1992, 25:231-243.
• [37]Mallet F, Bouton O, Prudhomme S, Cheynet V, Oriol G, Bonnaud B, Lucotte G, Duret L, Mandrand B: The endogenous retroviral locus ERVWE1 is a bona fide gene involved in hominoid placental physiology. Proc Natl Acad Sci U S A 2004, 101:1731-1736.
• [38]Ashworth CJ, Hoggard N, Thomas L, Mercer JG, Wallace JM, Lea RG: Placental leptin. Rev Reprod 2000, 5:18-24.
• [39]Riley SC, Walton JC, Herlick JM, Challis JR: The localization and distribution of corticotropin-releasing hormone in the human placenta and fetal membranes throughout gestation. J Clin Endocrinol Metab 1991, 72:1001-1007.
• [40]Watson AL, Palmer ME, Burton G: Human chorionic gonadotrophin release and tissue viability in placental organ culture. Hum Reprod 1995, 10:2159-2164.
• [41]Florio P, Franchini A, Reis FM, Pezzani I, Ottaviani E, Petraglia F: Human placenta, chorion, amnion and decidua express different variants of corticotropin-releasing factor receptor messenger RNA. Placenta 2000, 21:32-37.
• [42]Perrin MH, Vale WW: Corticotropin releasing factor receptors and their ligand family. Ann N Y Acad Sci 1999, 885:312-328.
• [43]Hatzoglou A, Margioris AN, Bakogeorgou E, Gravanis A, Castanas E: Identification, characterization and localization of corticotropin-releasing hormone receptors in human placenta. Life Sci 1996, 59:1871-1879.
• [44]Seres J, Bornstein SR, Seres P, Willenberg HS, Schulte KM, Scherbaum WA, Ehrhart-Bornstein M: Corticotropin-releasing hormone system in human adipose tissue. J Clin Endocrinol Metab 2004, 89:965-970.
• [45]Markovic D, Papadopoulou N, Teli T, Randeva H, Levine MA, Hillhouse EW, Grammatopoulos DK: Differential responses of corticotropin-releasing hormone receptor type 1 variants to protein kinase C phosphorylation. J Pharmacol Exp Ther 2006, 319:1032-1042.
• [46]Audette MC, Greenwood SL, Sibley CP, Jones CJ, Challis JR, Matthews SG, Jones RL: Dexamethasone stimulates placental system A transport and trophoblast differentiation in term villous explants. Placenta 2010, 31:97-105.
• [47]Delidaki M, Gu M, Hein A, Vatish M, Grammatopoulos DK: Interplay of cAMP and MAPK pathways in hCG secretion and fusogenic gene expression in a trophoblast cell line. Mol Cell Endocrinol 2011, 332:213-220.
• [48]Graziani G, Tentori L, Portarena I, Barbarino M, Tringali G, Pozzoli G, Navarra P: CRH inhibits cell growth of human endometrial adenocarcinoma cells via CRH-receptor 1-mediated activation of cAMP-PKA pathway. Endocrinology 2002, 143:807-813.
• [49]Strick R, Ackermann S, Langbein M, Swiatek J, Schubert SW, Hashemolhosseini S, Koscheck T, Fasching PA, Schild RL, Beckmann MW, Strissel PL: Proliferation and cell-cell fusion of endometrial carcinoma are induced by the human endogenous retroviral Syncytin-1 and regulated by TGF-beta. J Mol Med (Berl) 2007, 85:23-38.
• [50]Dermitzaki I, Tsatsanis C, Alexaki VI, Castanas E, Margioris AN: Roles of protein kinase A (PKA) and PKC on corticotropin-releasing hormone (CRH)-induced elevation of cytosolic calcium from extra-and intra-cellular sources. Hormones (Athens) 2004, 3:252-258.
• [51]Kalantaridou SN, Zoumakis E, Makrigiannakis A, Godoy H, Chrousos GP: The role of corticotropin-releasing hormone in blastocyst implantation and early fetal immunotolerance. Horm Metab Res 2007, 39:474-477.
• [52]Kammerer U, Germeyer A, Stengel S, Kapp M, Denner J: Human endogenous retrovirus K (HERV-K) is expressed in villous and extravillous cytotrophoblast cells of the human placenta. J Reprod Immunol 2011, 91:1-8.
• [53]Mangeney M, Renard M, Schlecht-Louf G, Bouallaga I, Heidmann O, Letzelter C, Richaud A, Ducos B, Heidmann T: Placental syncytins: Genetic disjunction between the fusogenic and immunosuppressive activity of retroviral envelope proteins. Proc Natl Acad Sci U S A 2007, 104:20534-20539.
• [54]Ponferrada VG, Mauck BS, Wooley DP: The envelope glycoprotein of human endogenous retrovirus HERV-W induces cellular resistance to spleen necrosis virus. Arch Virol 2003, 148:659-675.
• [55]Sun K, Yang K, Challis JR: Differential regulation of 11 beta-hydroxysteroid dehydrogenase type 1 and 2 by nitric oxide in cultured human placental trophoblast and chorionic cell preparation. Endocrinology 1997, 138:4912-4920.
• [56]Li JN, Ge YC, Yang Z, Guo CM, Duan T, Myatt L, Guan H, Yang K, Sun K: The Sp1 transcription factor is crucial for the expression of 11beta-hydroxysteroid dehydrogenase type 2 in human placental trophoblasts. J Clin Endocrinol Metab 2011, 96:E899-E907.
• [57]Friedberg M, Zoumakis E, Hiroi N, Bader T, Chrousos GP, Hochberg Z: Modulation of 11 beta-hydroxysteroid dehydrogenase type 1 in mature human subcutaneous adipocytes by hypothalamic messengers. J Clin Endocrinol Metab 2003, 88:385-393.
• [58]Sharma A, Guan H, Yang K: The p38 mitogen-activated protein kinase regulates 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) expression in human trophoblast cells through modulation of 11beta-HSD2 messenger ribonucleic acid stability. Endocrinology 2009, 150:4278-4286.
• [59]Bodner J, Ebenbichler CF, Wolf HJ, Muller-Holzner E, Stanzl U, Gander R, Huter O, Patsch JR: Leptin receptor in human term placenta: in situ hybridization and immunohistochemical localization. Placenta 1999, 20:677-682.
• [60]Linnemann K, Malek A, Sager R, Blum WF, Schneider H, Fusch C: Leptin production and release in the dually in vitro perfused human placenta. J Clin Endocrinol Metab 2000, 85:4298-4301.
• [61]Senaris R, Garcia-Caballero T, Casabiell X, Gallego R, Castro R, Considine RV, Dieguez C, Casanueva FF: Synthesis of leptin in human placenta. Endocrinology 1997, 138:4501-4504.
• [62]Ertl T, Funke S, Sarkany I, Szabo I, Rascher W, Blum WF, Sulyok E: Postnatal changes of leptin levels in full-term and preterm neonates: their relation to intrauterine growth, gender and testosterone. Biol Neonate 1999, 75:167-176.
• [63]Smith R, Mesiano S, Chan EC, Brown S, Jaffe RB: Corticotropin-releasing hormone directly and preferentially stimulates dehydroepiandrosterone sulfate secretion by human fetal adrenal cortical cells. J Clin Endocrinol Metab 1998, 83:2916-2920.
• [64]McMinn J, Wei M, Schupf N, Cusmai J, Johnson EB, Smith AC, Weksberg R, Thaker HM, Tycko B: Unbalanced placental expression of imprinted genes in human intrauterine growth restriction. Placenta 2006, 27:540-549.
• [65]White V, Gonzalez E, Capobianco E, Pustovrh C, Martinez N, Higa R, Baier M, Jawerbaum A: Leptin modulates nitric oxide production and lipid metabolism in human placenta. Reprod Fertil Dev 2006, 18:425-432.