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Reproductive Biology and Endocrinology
Published in: Reproductive Biology and Endocrinology 1/2004

Open Access 01-12-2004 | Research

Factors involved in the inflammatory events of cervical ripening in humans

Authors: Ylva Stjernholm-Vladic, Denis Stygar, Christopher Mansson, Britt Masironi, Sonja Akerberg, Hong Wang, Gunvor Ekman-Ordeberg, Lena Sahlin

Published in: Reproductive Biology and Endocrinology | Issue 1/2004

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Abstract

Background

Cervical ripening is an inflammatory reaction. The glucocorticoid receptor (GR) mediates glucocorticoid anti-inflammatory reactions, whereas nuclear factor (NF)kappaB is a key pro-inflammatory transcription factor. Prostaglandins as well as platelet activating factor (PAF) are inflammatory mediators. Inducible nitric oxide synthase (iNOS) regulates the level of nitric oxide (NO) in response to various inflammatory stimuli. We hypothesize that a changed biological response to glucocorticoids could be a mechanism regulating the inflammatory events resulting in cervical ripening.

Methods

We monitored GR and NFkappaB, prostaglandin synthases cyclooxygenase (COX)-1 and -2, iNOS, as well as the PAF-receptor (PAF-R) in the uterine cervix from term pregnant women (with unripe cervices) before the onset of labor (TP), immediately after parturition (PP), as compared to non-pregnant (NP), using immunohistochemistry and RT-PCR.

Results

The GR protein was detected by immunohistochemistry in the nuclei of stroma and squamous epithelium (SQ). Stromal GR staining was increased in TP as compared to the NP group and decreased again after parturition. GR staining in SQ was decreased after parturition as compared to term. NFkappaB was present in SQ and glandular epithelium (GE), stroma and vascular endothelium. Increased nuclear NFkappaB staining was observed postpartum as compared to term pregnancy in stroma and GE. Stromal immunostaining for COX-1 as well as COX-2 was increased in the TP and PP groups as compared to the NP, and GE displayed an intensely increased COX-2 immunostaining at term and postpartum. Stromal PAF-R immunostaining was highest at term, while it was greatly increased in GE postpartum.
No difference in the immunostaining for iNOS was found between the groups. RT-PCR showed a predominance of GRalpha to GRbeta mRNA in cervical tissue. The COX-2 mRNA level was increased in the PP group as compared to the TP group.

Conclusions

There is a decrease in GR levels in human cervix at parturition. Concomitantly there is an increase of factors such as NFkappaB, PAF-R, COX-1 and COX-2, suggesting that they may participate in the sequence of events leading to the final cervical ripening.
Appendix
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Literature
1.
Ekman G, Malmström A, Uldbjerg N, Ulmsten U: Cervical collagen: an important regulator of cervical function in term labor. Obstet Gynecol. 1986, 67: 633-636.CrossRefPubMed
2.
Stygar D, Wang H, Stjernholm-Vladic Y, Ekman G, Eriksson H, Sahlin L: Co-localization of estrogen receptorβ and leukocyte markers in the human cervix. Mol Hum Reprod. 2001, 7: 881-886. 10.1093/molehr/7.9.881.CrossRefPubMed
3.
Osman I, Young A, Ledingham MA, Thomson AJ, Jordan F, Greer IA, Norman JE: Leukocyte density and pro-inflammatory cytokine expression in human fetal membranes, decidua, cervix and myometrium before and during labour at term. Mol Hum Reprod. 2003, 9: 41-45. 10.1093/molehr/gag001.CrossRefPubMed
4.
Sennström M, Ekman G, Westergren-Thorsson G, Malmström A, Byström B, Endresen U, Mlambo N, Norman M, Ståbi B, Brauner A: Human cervical ripening, an inflammatory process mediated by cytokines. Mol Hum Reprod. 2000, 6: 375-381. 10.1093/molehr/6.4.375.CrossRefPubMed
5.
McKay LI, Cidlowski JA: Molecular control of immune/inflammatory responses: Interactions between nuclear factor-κB and steroid receptor signaling pathways. Endocrine Rev. 1999, 20: 435-459. 10.1210/er.20.4.435.
6.
Mastorakos G, Ilias I: Maternal hypothalamic-pituitary-adrenal axis in pregnancy and the postpartum period. Ann NY Acad Sci. 2000, 900: 95-106.CrossRefPubMed
7.
Stenlund P, Ekman G, Aedo A, Bygdeman M: Induction of labor with mifepristone – a randomised double-blind study versus placebo. Acta Obstet Gynecol Scand. 1999, 78: 793-798. 10.1034/j.1600-0412.1999.780910.x.CrossRefPubMed
8.
Challis JRG, Matthews SG, Gibb W, Lye SJ: Endocrine and paracrine regulation of birth at term and preterm. Endocrine reviews. 2000, 21: 514-550. 10.1210/er.21.5.514.PubMed
9.
Petraglia F, Tabanelli S, Galassi MC, Garuti GC, Mancini AC, Genazzani AR, Gurpide E: Human deciduas and in vitro decidualized endometrial stroma dells at term contain immunoreactive corticotrophin-releasing factor (CRF) and CRF messenger ribonucleic acid. J Clin Endocrin Metab. 1992, 74: 1427-1431. 10.1210/jc.74.6.1427.
10.
McLean M, Bisits A, Davies J, Woods R, Lowry P, Smith R: A placental clock controlling the length of human pregnancy. Nature. 1995, 1: 460-463. 10.1038/nm0595-460.
11.
Hollenberg SM, Weinberger C, Ong ES, Cerelli G, Oro A, Lebo R, Thompson EB, Rosenfeld MG, Evans RM: Primary structure and expression of a functional human glucocorticoid receptor cDNA. Nature. 1985, 318: 635-641.CrossRefPubMed
12.
Strähle U, Boshart M, Klock G, Stewart F, Schutz G: Glucorticoid- and progesterone- specific effects are determined by differential expression of the respective hormone receptors. Nature. 1989, 339: 629-632. 10.1038/339629a0.CrossRefPubMed
13.
Pujols L, Mullol J, Roca-Ferrer J, Torrego A, Xaubet A, Cidlowski JA, Picado C: Expression of glucocorticoid receptor alpha - and beta -isoforms in human cells and tissues. Am J Physiol Cell Physiol. 2002, 283: C1324-1331.CrossRefPubMed
14.
Almawi WY, Melemedjian OK: Molecular mechanism of glucocorticoid antiproliferative effects; antagonism of transcription factor activity by glucocorticoid receptor. J Leukoc Biol. 2002, 71: 9-15.PubMed
15.
Kelly AJ, Kavanagh J, Thomas J: Vaginal prostaglandin (PGE2 and PGF2a) for induction of labour at term. Cochrane Database Syst Rev. 2001, CD003101-2
16.
Lee SH, Soyoola E, Chanmugam P, Hart S, Sun W, Zhong H, Liou S, Simmons D, Hwang D: Selective expression of mitogen-inducible cyclooxygenas in macrophages stimulated with lipopolysaccaride. J Biol Chem. 1992, 267: 25934-25938.PubMed
17.
Hertelendy F, Zakar T: Prostaglandins and the myometrium and cervix. Prostaglandins, leukotrienes and essential fatty acids. 2004, 70: 207-222. 10.1016/j.plefa.2003.04.009.CrossRef
18.
Sugano T, Narahara H, Nasu K, Arima K, Fujisawa K, Miyakawa I: Effects of platelet-activating factor on cytokine production by human uterine cervical fibroblasts. Mol Hum Reprod. 2001, 7: 475-481. 10.1093/molehr/7.5.475.CrossRefPubMed
19.
20.
Mutoh H, Kume K, Sato S, Kato S, Shimizu T: Positive and negative regulations of human platelet-activating factor receptor transcript 2 (tissue-type) by estrogen and TGF-beta 1. Biochem Biophys Res Commun. 1994, 205: 1130-1136. 10.1006/bbrc.1994.2783.CrossRefPubMed
21.
Predescu D, Ihida K, Predecsu S, Palade GE: The vascular distribution of the platelet-activating factor receptor. Eur J Cell Biol. 1996, 69: 86-98.PubMed
22.
Rosselli M: Nitric oxide and reproduction. Mol Hum Reprod. 1997, 3: 639-641. 10.1093/molehr/3.8.639.CrossRefPubMed
23.
Denison FC, Calder AA, Kelly RW: The action of prostaglandin E2 on the human cervix: stimulation of interleukin 8 and inhibition of secretory leukocyte protease inhibitor. Am J Obstet Gynecol. 1999, 180: 614-620.CrossRefPubMed
24.
Salvemini D, Misko TP, Masferrer JL, Seibert K, Currie MG, Needleman P: Nitric oxide activates cyclooxygenase enzymes. Proc Natl Acad Sci U S A. 1993, 90: 7240-7244.PubMedCentralCrossRefPubMed
25.
Salvemini D, Seibert K, Masferrer JL, Settle SL, Currie MG, Needleman P: Nitric Oxide Activates the Cyclooxygenase Pathway in Inflammation. Am J Ther. 1995, 2: 616-619.CrossRefPubMed
26.
Thomson AJ, Lunan CB, Cameron AD, Cameron IT, Greer IA, Norman JE: Nitric oxide donors induce ripening of the human uterine cervix: a randomised controlled trial. Br J Obstet Gynaecol. 1997, 104: 1054-1057.CrossRefPubMed
27.
Ekerhovd E, Wejdegård B, Brännström M, Mattsby-Baltzer I, Norström A: Nitric oxide induced cervical ripening in the human: Involvement of cyclic guanosine monophosphate, and prostaglandin F2α and prostaglandin E2. Am J Obstet Gynecol. 2002, 186: 745-750. 10.1067/mob.2002.121327.CrossRefPubMed
28.
Ekerhovd E, Bullarbo M, Andersch NB, Norström A: Vaginal administration of the nitric oxide donor isosorbide mononitrate for cervical ripening at term: a randomized controlled study. Am J Ostet Gynecol. 2003, 189: 1692-1697. 10.1016/S0002-9378(03)00865-2.CrossRef
29.
Piccinini F, Fano RA, Volpe A, Facchinetti F: Ripening of the cervix with sodium nitroprusside in nonpregnant women. J Soc Gynecol Investig. 2003, 10: 438-42. 10.1016/S1071-5576(03)00140-0.CrossRefPubMed
30.
Oakley RH, Sar M, Cidlowski JA: The human glucocorticoid receptor beta isoform. Expression, biochemical properties, and putative function. J Biol Chem. 1996, 271: 9550-9559. 10.1074/jbc.271.16.9550.CrossRefPubMed
31.
Funk CD, Funk LB, Kennedy ME, Pong AS, Fitzgerald GA: Human platelet/erythro-leukemia cell prostaglandin G/H synthase: cDNA cloning, expression, and gene chromosomal assignment. Faseb J. 1991, 5: 2304-2312.PubMed
32.
33.
Wang H, Masironi B, Eriksson H, Sahlin L: A comparative study of estrogen receptors α and β in the rat uterus. Biol Reprod. 1999, 61: 955-964.CrossRefPubMed
34.
Bamberger AM, Milde-Langosch K, Löning T, Bamberger CM: The glucocorticoid receptor is specifically expressed in the stromal compartment of the human endometrium. J Clin Endocrinol Metab. 2001, 86: 5071-5074. 10.1210/jc.86.10.5071.CrossRefPubMed
35.
Tobler A, Meier R, Seitz M, Dewald B, Baggiolini M, Fey MF: Glucocorticoids down-regulate gene expression of GSM-CSF-NAP1/IL-8, and IL-6, but not M-CSF, in human fibroblasts. Blood. 1992, 79: 45-51.PubMed
36.
Crinelli R, Antonelli A, Bianchi M, Gentilini L, Scaramucci S, Magnani M: Selective inhibition of NF-κB activation and TNF-α production in macrophages by red blood cell-mediated delivery of dexamethasone. Blood Cells Mol Dis. 2000, 26: 211-222. 10.1006/bcmd.2000.0298.CrossRefPubMed
37.
Cato AC, Wade E: Molecular mechanisms of anti-inflammatory action of glucocorticoids. Bioessays. 1996, 18: 371-378.CrossRefPubMed
38.
Tschugguel W, Schneeberger C, Lass H, Stonek F, Zaghlula MB, Czerwenka K, Schatten C, Kaider A, Husslein P, Huber JC: Human cervical ripening is associated with an increase in cervical inducible nitric oxide synthase expression. Biol Reprod. 1999, 60: 1367-1372.CrossRefPubMed
39.
Lindholm J, Schultz-Möller N: Plasma and urinary cortisol in pregnancy and during estrogen-gestagen treatment. Scand J Clin Lab Invest. 1973, 31: 119-122.CrossRefPubMed
40.
Pääby PA, Nielsen A, Raffn K: A monthly cycle in the adrenocortical function during third-trimester pregnancy. Acta Endocrinol. 1990, 122: 617-622.PubMed
41.
Challis JRG, Matthews SG, van Meir CA, Ramirez MM: Current topic: the placental corticotrophin-releasing hormone-adrenocorticotrophin axis. Placenta. 1995, 16: 481-502. 10.1016/0143-4004(95)90106-X.CrossRefPubMed
42.
Liggins GC: Cervical ripening as an inflammatory reaction. In The Cervix in Pregnancy and Labour, Clinical and Biochemical Investigations. Edited by: Ellwood DA, Anderson ABM. 1981, Edinburg, Scotland, UK: Churchill Livingstone, 1-9.
43.
Henderson TA, Saunders P, Moffett-King A, Groome NP, Critchley HO: Steroid receptor expression in uterine natural killer cells. J Clin Endocrinol Metab. 2003, 88: 440-449. 10.1210/jc.2002-021174.CrossRefPubMed
44.
Wu WX, Smith GCS, Rose J, Nathanielsz PW: Characterization of the concentration of prostaglandin H synthase 2 mRNA throughout the pregnant baboon uterus. J Endocr. 2004, 182: 241-248.CrossRefPubMed
45.
46.
Loudon JA, Elliott CL, Hills F, Bennett PR: Progesterone represses interleukin-8 and cyclo-oxygenase-2 in human lower segment fibroblast cells and amnion epithelial cells. Biol Reprod. 2003, 69: 331-337. 10.1095/biolreprod.102.013698.CrossRefPubMed
47.
Kosaka T, Miyata A, Ihara H, Hara S, Sugimoto T, Takeda O, Takahashi E, Tanabe T: Characterization of the human gene (PTGS2) encoding prostaglandin-endoperoxide synthase 2. Eur J Biochem. 1994, 221: 889-897.CrossRefPubMed
48.
Ledingham MA, Thomson AJ, Young A, Macara LM, Greer IA, Norman JE: Changes in the expression of nitric oxide synthase in the human uterine cervix during pregnancy and parturition. Mol Hum Reprod. 2000, 11: 1041-1048. 10.1093/molehr/6.11.1041.CrossRef
49.
Maul H, Shi L, Marx SG, Garfield RE, Saade GR: Local application of platelet activating factor induces cervical ripening accompanied by infiltration of polymorphonuclear leukocytes in rats. Am J Obstet Gynecol. 2002, 187: 829-833. 10.1067/mob.2002.126983.CrossRefPubMed
50.
Zhu YP, Hoffman DR, Hwang SB, Miyaura S, Johnston JM: Prolongation of parturition in the pregnant rat following treatment with a platelet activating factor receptor antagonist. Biol Reprod. 1991, 44: 39-42.CrossRefPubMed
51.
Sugano T, Nasu K, Narahara H, Kawano Y, Nishida Y, Miyakawa I: Platelet-activating factor induces an imbalance between matrix metalloproteinase-1 and tissue inhibitor of metalloproteinase expression in human uterine cervical fibroblasts. Biol Reprod. 2000, 62: 540-546.CrossRefPubMed
52.
Marrache AM, Gobeil F, Bernier SG, Stankova J, Rola-Pleszczynski M, Choufani S, Bkaily G, Bourdeau A, Sirois MG, Vazquez-Tello A, Fan L, Joyal JS, Filep JG, Varma DR, Ribeiro-Da-Silva A, Chemtob S: Proinflammatory gene induction by platelet-activating factor mediated via its cognate nuclear receptor. J Immunol. 2002, 169: 6474-6478.CrossRefPubMed
53.
Uldbjerg N, Ekman G, Malmström A, Olsson K, Ulmsten U: Ripening of the human uterine cervix related to changes in collagen, glycosaminoglycans and collagenolytic activity. AM J Obstet Gynecol. 1983, 147: 662-666.PubMed
54.
Haram K, Helge J, Mortensen S, Wollen A-L: Preterm delivery: an overview. Acta Obstet Gynecol Scand. 2003, 82: 687-704. 10.1034/j.1600-0412.2003.00181.x.CrossRefPubMed
Metadata
Title
Factors involved in the inflammatory events of cervical ripening in humans
Authors
Ylva Stjernholm-Vladic
Denis Stygar
Christopher Mansson
Britt Masironi
Sonja Akerberg
Hong Wang
Gunvor Ekman-Ordeberg
Lena Sahlin
Publication date
01-12-2004
Publisher
BioMed Central
Published in
Reproductive Biology and Endocrinology / Issue 1/2004
Electronic ISSN: 1477-7827
DOI
https://doi.org/10.1186/1477-7827-2-74

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