Effect of Inflammatory Signals on Progesterone Production at the Maternal-Fetal Interface
Main Article Content
Abstract
Introduction: In explant cultures of human fetal membranes (FM) granulocyte-macrophage-colony-stimulating-factor (GM-CSF) mediates the inflammation-induced FM weakening seen in preterm premature rupture of the membranes (pPROM) and exogenous progesterone (P4) inhibits GM-CSF and inflammation-induced FM weakening. Here we report that GM-CSF induces P4 production within the FM which then acts in a paracrine manner to counteract GM-CSF-induced weakening.
Methods: FM explants mounted in Transwell inserts were cultured with control media and increasing GM-CSF, RU486 (blocks P4 action), or trilostane (blocks P4 production). P4 production, matrix metalloproteinase-2 (MMP-2) and FM rupture strength were determined. Effects of GM-CSF on P4 production and abundance of the 3ß-hydroxysteroid dehydrogenase (3ßHSD) enzyme in the BeWo human trophoblast cell line were also determined.
Results: GM-CSF induced P4 production in both FM explants and BeWo cells in a concentration-dependent manner. GM-CSF also increased 3βHSD protein in BeWo cells. Incubation of FMs with RU486, or trilostane, each caused increased FM weakening. Trilostane also increased MMP-2. Exogenous P4 with trilostane repressed MMP-2 and restored FM strength.
Conclusion: GM-CSF induced P4 production by FM and trophoblastic cells suggesting that locally produced P4 is increased by factors that weaken FM. Inhibition of local P4 production or action resulted in FM weakening with concomitant MMP-2 induction suggesting local P4 maintains FM structural integrity. This weakening is reversed by exogenous P4. These data are consistent with a negative-feedback system whereby P4 induced by GM-CSF, the mediator of inflammation-induced FM weakening, counteracts GM-CSF, inhibiting both its production and downstream action with resultant preservation of FM structural integrity.
Keywords:
Fetal membranes, biomechanical weakening, GM-CSF, progesterone, TNFα, thrombin, cytotrophoblast, pPROM, MMP-2
Article Details
How to Cite
MOORE, R M et al.
Effect of Inflammatory Signals on Progesterone Production at the Maternal-Fetal Interface.
Medical Research Archives, [S.l.], v. 9, n. 11, nov. 2021.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/2584>. Date accessed: 26 apr. 2024.
doi: https://doi.org/10.18103/mra.v9i11.2584.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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3. Mercer BM. Preterm premature rupture of the membranes. Obstetrics and gynecology. 2003;101(1):178-193.
4. Mercer BM. Preterm premature rupture of the membranes: diagnosis and management. Clinics in perinatology. 2004;31(4):765-782, vi.
5. Lockwood CJ, Toti P, Arcuri F, et al. Mechanisms of abruption-induced premature rupture of the fetal membranes: thrombin-enhanced interleukin-8 expression in term decidua. The American journal of pathology. 2005;167(5):1443-1449.
6. Kumar D, Fung W, Moore RM, et al. Proinflammatory cytokines found in amniotic fluid induce collagen remodeling, apoptosis, and biophysical weakening of cultured human fetal membranes. Biology of reproduction. 2006;74(1):29-34.
7. Kumar D, Schatz F, Moore RM, et al. The effects of thrombin and cytokines upon the biomechanics and remodeling of isolated amnion membrane, in vitro. Placenta. 2011;32(3):206-213.
8. Menon R, Moore JJ. Fetal Membranes, Not a Mere Appendage of the Placenta, but a Critical Part of the Fetal-Maternal Interface Controlling Parturition. Obstetrics and gynecology clinics of North America. 2020;47(1):147-162.
9. Sinkey RG, Guzeloglu-Kayisli O, Arlier S, et al. Thrombin-Induced Decidual Colony-Stimulating Factor-2 Promotes Abruption-Related Preterm Birth by Weakening Fetal Membranes. The American journal of pathology. 2020;190(2):388-399.
10. Kumar D, Moore RM, Mercer BM, Mansour JM, Redline RW, Moore JJ. The physiology of fetal membrane weakening and rupture: Insights gained from the determination of physical properties revisited. Placenta. 2016;42:59-73.
11. Moore RM, Schatz F, Kumar D, et al. Alpha-lipoic acid inhibits thrombin-induced fetal membrane weakening in vitro. Placenta. 2010;31(10):886-892.
12. Arcuri F, Toti P, Buchwalder L, et al. Mechanisms of leukocyte accumulation and activation in chorioamnionitis: interleukin 1 beta and tumor necrosis factor alpha enhance colony stimulating factor 2 expression in term decidua. Reproductive sciences (Thousand Oaks, Calif). 2009;16(5):453-461.
13. Kumar D, Moore RM, Nash A, et al. Decidual GM-CSF is a critical common intermediate necessary for thrombin and TNF induced in-vitro fetal membrane weakening. Placenta. 2014;35(12):1049-1056.
14. Sharma A, Kumar D, Moore RM, et al. Granulocyte macrophage colony stimulating factor (GM-CSF), the critical intermediate of inflammation-induced fetal membrane weakening, primarily exerts its weakening effect on the choriodecidua rather than the amnion. Placenta. 2020;89:1-7.
15. Moore RM, Katri R, Kumar D, Mansour JM, Mercer B, Moore JJ. α-Lipoic acid blocks the GMCSF induced protease/protease inhibitor spectrum associated with fetal membrane weakening in-vitro. Placenta. 2020;97:79-88.
16. Kumar D, Springel E, Moore RM, et al. Progesterone inhibits in vitro fetal membrane weakening. American journal of obstetrics and gynecology. 2015;213(4):520.e521-529.
17. Kumar D, Moore RM, Mercer BM, et al. In an in-vitro model using human fetal membranes, 17-α hydroxyprogesterone caproate is not an optimal progestogen for inhibition of fetal membrane weakening. American journal of obstetrics and gynecology. 2017;217(6):695.e691-695.e614.
18. Kumar D, Moore RM, Sharma A, Mercer BM, Mansour JM, Moore JJ. In an in-vitro model using human fetal membranes, alpha-lipoic acid inhibits inflammation induced fetal membrane weakening. Placenta. 2018;68:9-14.
19. Moore RK, R;Kumar, D; Mansour, JM; Mercer, B; Moore, JJ. α-Lipoic Acid Blocks the GMCSF Induced Protease/Protease inhibitor Spectrum Associated with Fetal Membrane Weakening In-vitro. Placenta. 2020.
20. Kumar D, Moore RM, Mercer BM, Mansour JM, Moore JJ. Mechanism of Human Fetal Membrane Biomechanical Weakening, Rupture and Potential Targets for Therapeutic Intervention. Obstetrics and gynecology clinics of North America. 2020;47(4):523-544.
21. El Khwad M, Stetzer B, Moore RM, et al. Term human fetal membranes have a weak zone overlying the lower uterine pole and cervix before onset of labor. Biology of reproduction. 2005;72(3):720-726.
22. Kumar D, Moore RM, Mercer BM, et al. In an in-vitro model using human fetal membranes, 17-alpha hydroxyprogesterone caproate is not an optimal progestogen for inhibition of fetal membrane weakening. American journal of obstetrics and gynecology. 2017;217(6):695.e691-695.e614.
23. Mitchell BF, Powell WA. Progesterone production by human fetal membranes: an in vitro incubation system for studying hormone production and metabolism. American journal of obstetrics and gynecology. 1984;148(3):303-309.
24. Maldonado-Mercado MG, Espinosa-Garcia MT, Gomez-Concha C, Monreal-Flores J, Martinez F. Steroidogenesis in BeWo cells: role of protein kinase A and benzodiazepines. The international journal of biochemistry & cell biology. 2008;40(5):901-908.
25. Mitchell B, Cruickshank B, McLean D, Challis J. Local modulation of progesterone production in human fetal membranes. The Journal of clinical endocrinology and metabolism. 1982;55(6):1237-1239.
26. Mitchell BF, Challis JR, Lukash L. Progesterone synthesis by human amnion, chorion, and decidua at term. American journal of obstetrics and gynecology. 1987;157(2):349-353.
27. Malak TM, Mulholland G, Bell SC. Morphometric characteristics of the decidua, cytotrophoblast, and connective tissue of the prelabor ruptured fetal membranes. Annals of the New York Academy of Sciences. 1994;734:430-432.
28. McLaren J, Taylor DJ, Bell SC. Increased incidence of apoptosis in non-labour-affected cytotrophoblast cells in term fetal membranes overlying the cervix. Human reproduction (Oxford, England). 1999;14(11):2895-2900.
29. McLaren J, Malak TM, Bell SC. Structural characteristics of term human fetal membranes prior to labour: identification of an area of altered morphology overlying the cervix. Human reproduction (Oxford, England). 1999;14(1):237-241.
30. El Khwad M, Pandey V, Stetzer B, et al. Fetal membranes from term vaginal deliveries have a zone of weakness exhibiting characteristics of apoptosis and remodeling. Journal of the Society for Gynecologic Investigation. 2006;13(3):191-195.
31. Moore RM, Mansour JM, Redline RW, Mercer BM, Moore JJ. The physiology of fetal membrane rupture: insight gained from the determination of physical properties. Placenta. 2006;27(11-12):1037-1051.
32. Maymon E, Romero R, Pacora P, et al. A role for the 72 kDa gelatinase (MMP-2) and its inhibitor (TIMP-2) in human parturition, premature rupture of membranes and intraamniotic infection. Journal of perinatal medicine. 2001;29(4):308-316.
33. Fortunato SJ, Menon R, Lombardi SJ. MMP/TIMP imbalance in amniotic fluid during PROM: an indirect support for endogenous pathway to membrane rupture. Journal of perinatal medicine. 1999;27(5):362-368.
34. Fortunato SJ, Menon R, Lombardi SJ. Expression of a progelatinase activator (MT1-MMP) in human fetal membranes. American journal of reproductive immunology (New York, NY : 1989). 1998;39(5):316-322.
35. Fortunato SJ, Menon R. Distinct molecular events suggest different pathways for preterm labor and premature rupture of membranes. American journal of obstetrics and gynecology. 2001;184(7):1399-1405; discussion 1405-1396.
36. Tuckey RC. Progesterone synthesis by the human placenta. Placenta. 2005;26(4):273-281.
37. Costa MA. The endocrine function of human placenta: an overview. Reproductive biomedicine online. 2016;32(1):14-43.
38. Pulkkinen M.O. EK. The Progesterone Gradient of the Human Fetal Membranes. International Journal of Gynaecology and Obstetrics. 1972;10(3):93-94.
39. Grimshaw RN, Mitchell BF, Challis JR. Steroid modulation of pregnenolone to progesterone conversion by human placental cells in vitro. American journal of obstetrics and gynecology. 1983;145(2):234-238.
40. Bahn RS, Worsham A, Speeg KV, Jr., Ascoli M, Rabin D. Characterization of steroid production in cultured human choriocarcinoma cells. The Journal of clinical endocrinology and metabolism. 1981;52(3):447-450.
41. Tsui KH, Chen LY, Shieh ML, Chang SP, Yuan CC, Li HY. Interleukin-8 can stimulate progesterone secretion from a human trophoblast cell line, BeWo. In vitro cellular & developmental biology Animal. 2004;40(10):331-336.
42. McParland PC, Taylor DJ, Bell SC. Myofibroblast differentiation in the connective tissues of the amnion and chorion of term human fetal membranes-implications for fetal membrane rupture and labour. Placenta. 2000;21(1):44-53.
43. Malak TM, Bell SC. Structural characteristics of term human fetal membranes: a novel zone of extreme morphological alteration within the rupture site. Br J Obstet Gynaecol. 1994;101(5):375-386.
44. Canzoneri BJ, Feng L, Grotegut CA, Bentley RC, Heine RP, Murtha AP. The chorion layer of fetal membranes is prematurely destroyed in women with preterm premature rupture of the membranes. Reproductive sciences (Thousand Oaks, Calif). 2013;20(10):1246-1254.
45. George RB, Kalich J, Yonish B, Murtha AP. Apoptosis in the chorion of fetal membranes in preterm premature rupture of membranes. American journal of perinatology. 2008;25(1):29-32.
2. Mercer BM, Goldenberg RL, Moawad AH, et al. The preterm prediction study: effect of gestational age and cause of preterm birth on subsequent obstetric outcome. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. American journal of obstetrics and gynecology. 1999;181(5 Pt 1):1216-1221.
3. Mercer BM. Preterm premature rupture of the membranes. Obstetrics and gynecology. 2003;101(1):178-193.
4. Mercer BM. Preterm premature rupture of the membranes: diagnosis and management. Clinics in perinatology. 2004;31(4):765-782, vi.
5. Lockwood CJ, Toti P, Arcuri F, et al. Mechanisms of abruption-induced premature rupture of the fetal membranes: thrombin-enhanced interleukin-8 expression in term decidua. The American journal of pathology. 2005;167(5):1443-1449.
6. Kumar D, Fung W, Moore RM, et al. Proinflammatory cytokines found in amniotic fluid induce collagen remodeling, apoptosis, and biophysical weakening of cultured human fetal membranes. Biology of reproduction. 2006;74(1):29-34.
7. Kumar D, Schatz F, Moore RM, et al. The effects of thrombin and cytokines upon the biomechanics and remodeling of isolated amnion membrane, in vitro. Placenta. 2011;32(3):206-213.
8. Menon R, Moore JJ. Fetal Membranes, Not a Mere Appendage of the Placenta, but a Critical Part of the Fetal-Maternal Interface Controlling Parturition. Obstetrics and gynecology clinics of North America. 2020;47(1):147-162.
9. Sinkey RG, Guzeloglu-Kayisli O, Arlier S, et al. Thrombin-Induced Decidual Colony-Stimulating Factor-2 Promotes Abruption-Related Preterm Birth by Weakening Fetal Membranes. The American journal of pathology. 2020;190(2):388-399.
10. Kumar D, Moore RM, Mercer BM, Mansour JM, Redline RW, Moore JJ. The physiology of fetal membrane weakening and rupture: Insights gained from the determination of physical properties revisited. Placenta. 2016;42:59-73.
11. Moore RM, Schatz F, Kumar D, et al. Alpha-lipoic acid inhibits thrombin-induced fetal membrane weakening in vitro. Placenta. 2010;31(10):886-892.
12. Arcuri F, Toti P, Buchwalder L, et al. Mechanisms of leukocyte accumulation and activation in chorioamnionitis: interleukin 1 beta and tumor necrosis factor alpha enhance colony stimulating factor 2 expression in term decidua. Reproductive sciences (Thousand Oaks, Calif). 2009;16(5):453-461.
13. Kumar D, Moore RM, Nash A, et al. Decidual GM-CSF is a critical common intermediate necessary for thrombin and TNF induced in-vitro fetal membrane weakening. Placenta. 2014;35(12):1049-1056.
14. Sharma A, Kumar D, Moore RM, et al. Granulocyte macrophage colony stimulating factor (GM-CSF), the critical intermediate of inflammation-induced fetal membrane weakening, primarily exerts its weakening effect on the choriodecidua rather than the amnion. Placenta. 2020;89:1-7.
15. Moore RM, Katri R, Kumar D, Mansour JM, Mercer B, Moore JJ. α-Lipoic acid blocks the GMCSF induced protease/protease inhibitor spectrum associated with fetal membrane weakening in-vitro. Placenta. 2020;97:79-88.
16. Kumar D, Springel E, Moore RM, et al. Progesterone inhibits in vitro fetal membrane weakening. American journal of obstetrics and gynecology. 2015;213(4):520.e521-529.
17. Kumar D, Moore RM, Mercer BM, et al. In an in-vitro model using human fetal membranes, 17-α hydroxyprogesterone caproate is not an optimal progestogen for inhibition of fetal membrane weakening. American journal of obstetrics and gynecology. 2017;217(6):695.e691-695.e614.
18. Kumar D, Moore RM, Sharma A, Mercer BM, Mansour JM, Moore JJ. In an in-vitro model using human fetal membranes, alpha-lipoic acid inhibits inflammation induced fetal membrane weakening. Placenta. 2018;68:9-14.
19. Moore RK, R;Kumar, D; Mansour, JM; Mercer, B; Moore, JJ. α-Lipoic Acid Blocks the GMCSF Induced Protease/Protease inhibitor Spectrum Associated with Fetal Membrane Weakening In-vitro. Placenta. 2020.
20. Kumar D, Moore RM, Mercer BM, Mansour JM, Moore JJ. Mechanism of Human Fetal Membrane Biomechanical Weakening, Rupture and Potential Targets for Therapeutic Intervention. Obstetrics and gynecology clinics of North America. 2020;47(4):523-544.
21. El Khwad M, Stetzer B, Moore RM, et al. Term human fetal membranes have a weak zone overlying the lower uterine pole and cervix before onset of labor. Biology of reproduction. 2005;72(3):720-726.
22. Kumar D, Moore RM, Mercer BM, et al. In an in-vitro model using human fetal membranes, 17-alpha hydroxyprogesterone caproate is not an optimal progestogen for inhibition of fetal membrane weakening. American journal of obstetrics and gynecology. 2017;217(6):695.e691-695.e614.
23. Mitchell BF, Powell WA. Progesterone production by human fetal membranes: an in vitro incubation system for studying hormone production and metabolism. American journal of obstetrics and gynecology. 1984;148(3):303-309.
24. Maldonado-Mercado MG, Espinosa-Garcia MT, Gomez-Concha C, Monreal-Flores J, Martinez F. Steroidogenesis in BeWo cells: role of protein kinase A and benzodiazepines. The international journal of biochemistry & cell biology. 2008;40(5):901-908.
25. Mitchell B, Cruickshank B, McLean D, Challis J. Local modulation of progesterone production in human fetal membranes. The Journal of clinical endocrinology and metabolism. 1982;55(6):1237-1239.
26. Mitchell BF, Challis JR, Lukash L. Progesterone synthesis by human amnion, chorion, and decidua at term. American journal of obstetrics and gynecology. 1987;157(2):349-353.
27. Malak TM, Mulholland G, Bell SC. Morphometric characteristics of the decidua, cytotrophoblast, and connective tissue of the prelabor ruptured fetal membranes. Annals of the New York Academy of Sciences. 1994;734:430-432.
28. McLaren J, Taylor DJ, Bell SC. Increased incidence of apoptosis in non-labour-affected cytotrophoblast cells in term fetal membranes overlying the cervix. Human reproduction (Oxford, England). 1999;14(11):2895-2900.
29. McLaren J, Malak TM, Bell SC. Structural characteristics of term human fetal membranes prior to labour: identification of an area of altered morphology overlying the cervix. Human reproduction (Oxford, England). 1999;14(1):237-241.
30. El Khwad M, Pandey V, Stetzer B, et al. Fetal membranes from term vaginal deliveries have a zone of weakness exhibiting characteristics of apoptosis and remodeling. Journal of the Society for Gynecologic Investigation. 2006;13(3):191-195.
31. Moore RM, Mansour JM, Redline RW, Mercer BM, Moore JJ. The physiology of fetal membrane rupture: insight gained from the determination of physical properties. Placenta. 2006;27(11-12):1037-1051.
32. Maymon E, Romero R, Pacora P, et al. A role for the 72 kDa gelatinase (MMP-2) and its inhibitor (TIMP-2) in human parturition, premature rupture of membranes and intraamniotic infection. Journal of perinatal medicine. 2001;29(4):308-316.
33. Fortunato SJ, Menon R, Lombardi SJ. MMP/TIMP imbalance in amniotic fluid during PROM: an indirect support for endogenous pathway to membrane rupture. Journal of perinatal medicine. 1999;27(5):362-368.
34. Fortunato SJ, Menon R, Lombardi SJ. Expression of a progelatinase activator (MT1-MMP) in human fetal membranes. American journal of reproductive immunology (New York, NY : 1989). 1998;39(5):316-322.
35. Fortunato SJ, Menon R. Distinct molecular events suggest different pathways for preterm labor and premature rupture of membranes. American journal of obstetrics and gynecology. 2001;184(7):1399-1405; discussion 1405-1396.
36. Tuckey RC. Progesterone synthesis by the human placenta. Placenta. 2005;26(4):273-281.
37. Costa MA. The endocrine function of human placenta: an overview. Reproductive biomedicine online. 2016;32(1):14-43.
38. Pulkkinen M.O. EK. The Progesterone Gradient of the Human Fetal Membranes. International Journal of Gynaecology and Obstetrics. 1972;10(3):93-94.
39. Grimshaw RN, Mitchell BF, Challis JR. Steroid modulation of pregnenolone to progesterone conversion by human placental cells in vitro. American journal of obstetrics and gynecology. 1983;145(2):234-238.
40. Bahn RS, Worsham A, Speeg KV, Jr., Ascoli M, Rabin D. Characterization of steroid production in cultured human choriocarcinoma cells. The Journal of clinical endocrinology and metabolism. 1981;52(3):447-450.
41. Tsui KH, Chen LY, Shieh ML, Chang SP, Yuan CC, Li HY. Interleukin-8 can stimulate progesterone secretion from a human trophoblast cell line, BeWo. In vitro cellular & developmental biology Animal. 2004;40(10):331-336.
42. McParland PC, Taylor DJ, Bell SC. Myofibroblast differentiation in the connective tissues of the amnion and chorion of term human fetal membranes-implications for fetal membrane rupture and labour. Placenta. 2000;21(1):44-53.
43. Malak TM, Bell SC. Structural characteristics of term human fetal membranes: a novel zone of extreme morphological alteration within the rupture site. Br J Obstet Gynaecol. 1994;101(5):375-386.
44. Canzoneri BJ, Feng L, Grotegut CA, Bentley RC, Heine RP, Murtha AP. The chorion layer of fetal membranes is prematurely destroyed in women with preterm premature rupture of the membranes. Reproductive sciences (Thousand Oaks, Calif). 2013;20(10):1246-1254.
45. George RB, Kalich J, Yonish B, Murtha AP. Apoptosis in the chorion of fetal membranes in preterm premature rupture of membranes. American journal of perinatology. 2008;25(1):29-32.