Differential Expression of Transforming Growth Factor-β1 and Transforming Growth Factor-β Receptors in Myometrium of Women With Failed Induction of Labor,No Labor,and Preterm Labor

Abstract

Objective: Comparative analysis of transforming growth factor-β1 (TGF-β1) and TGF-β receptor type I and type II messenger RNA (mRNA) and protein expression in myometrium of women who had unsuccessful labor induction, with those without labor or in preterm labor complicated by chorioamnionitis.

Methods: Small segments of myometrium were collected from women who were undergoing cesarean delivery for unsuccessful labor induction (n = 5), elective cesarean without labor (n = 5), or cesarean delivery for complications related to preterm labor and chorioamnionitis (n = 5). Total RNA was isolated from these tissues and subjected to competitive quantitative reverse-transcription-polymerase chain reaction (Q-RT-PCR) to determine the level of TGF-β1, and TGF-β type I and type II receptor mRNA expression. Tissue sections were prepared from paraffin-embedded specimens and immunostained for TGF-β1 and receptor proteins using specific polycolonal antibodies. The data were analyzed by unpaired Student t test and Kruskal-Wallis analysis of variance.

Results: Myometrium from women who had unsuccessful labor induction expressed higher levels of TGF-β1 mRNA (2.21 ± 0.28 × 10⁶ copies/μg of total cellular RNA) than those with preterm labor (4.53 ± 0.2 × 10⁵ copies), or without labor [3.13 ± 2.6 × 10⁴ copies (P < .05)]. The level of TGF-β type I receptor mRNA expression did not vary; however, type II receptor expression was significantly lower in myometrium from preterm labor (1.36 ± 0.36 × 10⁵ copies) compared with those from unsuccessful labor induction (3.42 ± × 10⁶ copies) or without labor (9.65 ± 3.2 × 10⁵ copies). Immunoreactive TGF-β1 and TGF-β receptor proteins were present in all myometrial tissues, and their intensity reflected that of the mRNA expression in these tissues.

Conclusion: TGF-β1 and TFG-β type II receptors are expressed differently in myometrium of women who had unsuccessful labor induction compared with those without labor or with preterm labor complicated by chorioamnionitis. Because TGF-β is a key regulator of tissue remodeling which is central to initiation of normal labor, alterations in TGF-β and/or TGF-β receptor expression may lead to changes in the outcome of labor, at least at the myometrial level.

Keywords

TGF-β TGF-β receptors expression myometrium labor

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References

1. Osmers RG , Adelmann-Grill BC , Rath W , Stuhlsatz HW , Tschesche H , Kuhn W . Biochemical events in cervical ripening dilatation during pregnancy and parturition. J Obstet Gynecol 1995;21:185-194.

2. Gomez R , Romero R , Edwin SS , David C . Pathogenesis of preterm labor and preterm premature rupture of membranes associated with intra-amniotic infection. Infect Dis Clin North Am 1997;11:135-176.

3. Wray S . Uterine contraction and physiological mechanisms of modulation. Am J Physiol 1993;264:C1-C18.

4. Balducci J , Risek B , Gilula NB , Hand A , Egan JF , Vintzileos AM . Gap junction formation in human myometrium: A key to preterm labor? Am J Obstet Gynecol 1993;168:1609-16915.

5. Riemer RK , Heymann MA . Regulation of uterine smooth muscle function during gestation. Pediatr Res 1998;44:615-627.

6. Gibb W . The role of prostaglandins in human parturition. Ann Med 1998;30:235-241.

7. Wetzka B , Schafer W , Scheibel M , Nusing R , Zahradnik HP . Eicosanoids production by intrauterine tissues before and adter labor in short-term tissue culture. Prostaglandins 1993;45:571-581.

8. Dudley DJ , Collmer D , Mitchell MD , Trautman MS . Inflammatory cytokine mRNA in human gestational tissues: Implications for term and preterm labor. J Soc Gynecol Invest 1996;3:328-335.

9. Gomez R , Ghezzi F , Romero R , Munoz H , Tolosa-JE , Rojas I . Premature labor and intra-amniotic infection: Clinical aspects and role of the cytokines in diagnosis and pathophysiology. Clin Perinatol 1995;22:281-342.

10.

10. Menon R , Swan KF , Lyden TW , Rote NS , Fortunato SJ . Expression of inflammatory cytokines (interleukin-1β and interleukin-6) in amniochorionic membranes. Am J Obstet Gynecol 1995;172:493-500.

11.

11. Fortunato SJ , Menon RP , Swan KF , Menon R . Inflammatory cytokine (interleukins 1, 6 and 8 and tumor necrosis factor-alpha) released from cultured human fetal membranes in response to endotoxin lipopolysaccharide mirrors amniotic fluid concentrations. Am J Obstet Gynecol 1996;174:1855-1862.

12.

12. Li Y , Ohls RK , Rosa C , Shah M , Richards DS , Christensen RD . Maternal and umbilical cord serum concentrations of granulocyte colony-stimulating factor in women with clinical chorioamnionitis. Obstet Gynecol 1995;86:428-432.

13.

13. Hulboy DL , Rudolph LA , Matrisian LM . Matrix metalloproteineases as mediators of reproductive function. Mol Hum Reprod 1997;3:27-45.

14.

14. Lei H , Furth EE , Kalluri R , et al. A program of cell death and extracellular matrix degradation is activated in the amnion before the onset of labor. J Clin Invest 1996;98:1971-1978.

15.

15. Bryant-Greenwood GD , Yamamoto SY . Control of peripartal collagenolysis in the human chorion-decidua. Am J Obstet Gynecol 1995;172:63-70.

16.

16. Takahashi S , Sato T , Ito A , et al. Involvement of protein kinase C in the interleukin 1 alpha-induced gene expression of matrix metalloproteinases and tissue inhibitor-1 of metalloproteinases (TIMP-1) in human uterine cervical fibroblasts. Biochem Biophys Acta 1993;1220:57-65.

17.

17. Lockwood CJ , Kuczynski E . Markers of risk for preterm delivery. J Perinat Med 1999;27:5-20.

18.

18. Romero R , Wu YK , Oyarzun E , Hobbins JC , Mitchell MD . A potential role for epidermal growth factor/alpha transforming growth factor in human parturition. Eur J Obstet Gynecol Reprod Biol 1989;33:55-60.

19.

19. Fortunato SJ , Menon R , Lambardi Sj . Interleukin-10 and transforming growth factor-β inhibit amnicohorion turmor necrosis factorsα by contrasting mechanisms of action: Therapeutic implications in prematurity. Am J Obstet Gynecol 1997;177:803-809.

20.

20. Bry K , Lappalainen U . Interleukin 4 and transforming growth factor-beta 1 modulate the production of interleukin-1 receptor antagonist and of prostaglandin E2 by decidual cells. Am J Obstet Gynecol 1994;170:1194-1198.

21.

21. Lawrence DA . Transforming growth factor-beta: A general review. Eur Cytokine Netw 1996;7:363-374.

22.

22. Tang XM , Ghahary A , Chegini N . The interaction between transforming growth factor β and relaxin leads to modulation of matrix and matrix metalloproteinases expression in human uterus [abstract]. J Soc Gynecol Invest 1996;3:256-256.

23.

23. Goldenberg RL , Mercer BM , Iams JD , et al. The preterm prediction study: Patterns of cervicovaginal fetal fibronectin as predictors of spontaneous preterm delivery. Am J Obstet Gynecol 1997;177:8-12.

24.

24. Ma C , Chegini N . Modulation of matrix metalloproteinases and tissue inhibitor of MMPs (TIMPs) expression in human myometrial smooth muscle cell by transforming growth factor β1. Mol Hum Reprod 1999;5-5 (in press).

25.

25. Mitchell MD . The regulation of decidual prostaglandin biosynthesis by growth factors, phorbol esters, and calcium. Biol Reprod 1991;44:871-874.

26.

26. Kniss DA , Zimmerman PD , Fertel RH , Iams JD . Pro-inflammatory cytokines interact synergistically with epidermal growth factor to stimulate PGE2 production in amnion-derived cells. Prostaglandins 1992;44:237-244.

27.

27. Watanabe H . Epidermal growth factor in urine of pregnant women and in amniotic fluid throughout pregnancy. Gynecol Endocrinol 1990;4:43-50.

28.

28. Tahara M , Tasaka K , Masumoto N , Adachi K , Adachi H , Ikebuchi Y , et al. Expression of messenger ribonucleic acid for epidermal growth factor (EGF), transforming growth factor-alpha (TGF-α, and EGF receptor in human amnion cells: Possible role of TGF-αin prostaglandin E2 synthesis and cell proliferation. J Clin Endocrinol Metab 1995;80:138-146.

29.

29. Faber BM , Metz SA , Chegini N . Immunolocalization of eicosanoid enzymes and growth factors in human myometrium and fetoplacental tissues in failed labor inductions. Obstet Gynecol 1996;88:174-179.

30.

30. Baggia S , Gravett MG , Witkin SS , Haluska GJ , Novy MJ . Interleukin-1 β intra-amniotic infusion induces tumor necrosis factor-α, prostaglandin production, and preterm contractions in pregnant rhesus monkeys. J Soc Gynecol Invest 1996;3:121-126.

31.

31. Brand T , Schneider MD . Transforming growth factor beta signal transduction. Cirt Res 1996;78:173-176.

32.

32. Chegini N , Zhao Y , Williams RS , Flanders KC . Human uterine tissue throughout the menstrual cycle expresses TGF-β1, TGF-β2, TGF-β3 and TGF-β type II receptor mRNA and protein and contain 125I-TGF-β1 binding sites. Endocrinology 1994;135:439-449.

33.

33. Tang X-M , Dou Q , Zhao Y , Davis J , McLean WF , Chegini N . Expression of mRNA and protein for TGF-β isoforms and TGF-β type I-III receptor in human myometrial smooth muscle cells and their effect on DNA synthesis and protein degradation in vitro. Mol Hum Reprod 1997;3:233-240.

34.

34. Dou Q , Zhao Y , Tarnuzzer RW , et al. Suppression of TGF-βs and TGF-β receptors mRNA and protein expression in leiomyomata in women receiving gonadotropin releasing hormone agonist therapy. J Clin Endocrinol Metab 1996;81:3222-3230.

35.

35. Dou Q , Tarnuzzer RW , Williams RS , Schultz GS , Chegini N . Differential expression of matrix metalloproteinases and their tissue inhibitors in leiomyomata: A mechanism for gonadotropin releasing hormone agonist induced tumour regression. Mol Hum Reprod 1997;3:1005-1014.