Inteleukin-6 secretion during pathophysiological events of pregnancy – preterm birth, preeclampsia, fetal growth restriction, gestational diabetes mellitus
DOI:
https://doi.org/10.20883/medical.e984Keywords:
amniotic fluid, cervicovaginal fluid, amniotic cavity, cytokinesAbstract
Cytokines play a role in nearly all reproductive and pregnancy processes. These proteins are expressed in various body fluids and tissues related to reproduction. Interleukin-6 (IL-6) stands out as one of the best-characterized members of the cytokine family. This protein has an immense and imperfectly understood impact on both normal and pathological aspects of human pregnancy. IL-6 exerts a wide range of effects on the immune system, and it plays crucial roles in regulating inflammation processes and homeostasis. Herein, we summarize current knowledge on IL-6 secretion during pathophysiological events of pregnancy: preterm birth, preeclampsia, fetal growth restriction and gestational diabetes mellitus. Cytokines, particularly interleukin-6, play crucial roles in regulating pregnancy physiology. Maintaining IL-6 homeostasis is essential for the health of both the mother and fetus. IL-6 supports pregnancy by influencing uterine receptivity, trophoblast function, and immune interactions at the feto–maternal interface. Disrupted IL-6 expression may contribute to various pregnancy complications. A deeper understanding of IL-6 regulation can help detect dysregulation and potentially optimizing pregnancy outcomes. Addressing knowledge gaps identified in this review is vital for improving current practices and enhancing pregnancy outcomes.
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Elmslie RE, Dow SW, Ogilvie GK. Interleukins: biological properties and therapeutic potential. J Vet Intern Med. 1991 Sep-Oct;5(5):283-93. doi: 10.1111/j.1939-1676.1991.tb03135.x.
Holmström E, Myntti T, Sorsa T, Kruit H, Juhila J, Paavonen J, Rahkonen L, Stefanovic V. Cervical and Amniotic Fluid Matrix Metalloproteinase-8 and Interleukin-6 Concentrations in Preterm Pregnancies with or without Preterm Premature Rupture of Membranes. Fetal Diagn Ther. 2019;46(2):103-110. doi: 10.1159/000493207.
Romero R, Espinoza J, Gonçalves LF, Kusanovic JP, Friel LA, Nien JK. Inflammation in preterm and term labour and delivery. Semin Fetal Neonatal Med. 2006 Oct;11(5):317-26. doi: 10.1016/j.siny.2006.05.001.
Del Barco E, Franco-Jarava C, Vargas M, Maíz N, Arevalo S, Sánchez MÁ, Avilés MT, Rodó C, Mendoza M, Goya M, Hernández-González M, Carreras E. Reference values for interleukin-6 in the amniotic fluid of asymptomatic pregnant women. Acta Obstet Gynecol Scand. 2023 Apr;102(4):480-485. doi: 10.1111/aogs.14524.
Kirici P, Cagiran FT, Kali Z. Impact of spontaneous preterm birth on amniotic fluid NF-κB, IL-6, TNF-α and IL-1β levels in singleton pregnancies conceived after IVF/ICSI treatment or natural conception. Eur Rev Med Pharmacol Sci. 2022 Nov;26(22):8395-8400. doi: 10.26355/eurrev_202211_30374.
Leaños-Miranda A, Nolasco-Leaños AG, Carrillo-Juárez RI, Molina-Pérez CJ, Isordia-Salas I, Ramírez-Valenzuela KL. Interleukin-6 in Amniotic Fluid: A Reliable Marker for Adverse Outcomes in Women in Preterm Labor and Intact Membranes. Fetal Diagn Ther. 2021;48(4):313-320. doi: 10.1159/000514898.
Heng YJ, Liong S, Permezel M, Rice GE, Di Quinzio MK, Georgiou HM. Human cervicovaginal fluid biomarkers to predict term and preterm labor. Front Physiol. 2015 May 13;6:151. doi: 10.3389/fphys.2015.00151.
Park S, You YA, Yun H, Choi SJ, Hwang HS, Choi SK, Lee SM, Kim YJ. Cervicovaginal fluid cytokines as predictive markers of preterm birth in symptomatic women. Obstet Gynecol Sci. 2020 Jul;63(4):455-463. doi: 10.5468/ogs.19131.
Polettini J, Cobo T, Kacerovsky M, Vinturache AE, Laudanski P, Peelen MJ, Helmer H, Lamont RF, Takeda J, Lapointe J, Torloni MR, Zhong N, Menon R. Biomarkers of spontaneous preterm birth: a systematic review of studies using multiplex analysis. J Perinat Med. 2017 Jan 1;45(1):71-84. doi: 10.1515/jpm-2016-0097.
Soucek O, Kacerovsky M, Kacerovska Musilova I, Stranik J, Kukla R, Bolehovska R, Andrys C. Amniotic fluid CD36 in pregnancies complicated by spontaneous preterm delivery: a retrospective cohort study. J Matern Fetal Neonatal Med. 2023;36(1):2214838. doi: 10.1080/14767058.2023.2214838.
Gomez-Lopez N, Galaz J, Miller D, Farias-Jofre M, Liu Z, Arenas-Hernandez M, Garcia-Flores V, Shaffer Z, Greenberg JM, Theis KR, Romero R. The immunobiology of preterm labor and birth: intra-amniotic inflammation or breakdown of maternal-fetal homeostasis. Reproduction. 2022 Jun 20;164(2):R11-R45. doi: 10.1530/REP-22-0046.
Amabebe E, Chapman DR, Stern VL, Stafford G, Anumba DOC. Mid-gestational changes in cervicovaginal fluid cytokine levels in asymptomatic pregnant women are predictive markers of inflammation-associated spontaneous preterm birth. J Reprod Immunol. 2018 Apr;126:1-10. doi: 10.1016/j.jri.2018.01.001.
Son KA, Kim M, Kim YM, Kim SH, Choi SJ, Oh SY, Roh CR, Kim JH. Prevalence of vaginal microorganisms among pregnant women according to trimester and association with preterm birth. Obstet Gynecol Sci. 2018 Jan;61(1):38-47. doi: 10.5468/ogs.2018.61.1.38.
Bogavac M, Brkić S, Celić D, Simin N, Matijasević J, Ilić T. Interferon gamma, interleukin 8 and interleukin 10 in serum of patients with the cervical infection and symptoms of the imminent preterm delivery. Srp Arh Celok Lek. 2013 Sep-Oct;141(9-10):623-8. doi: 10.2298/sarh1310623b.
Wassenaar TM, Panigrahi P. Is a foetus developing in a sterile environment? Lett Appl Microbiol. 2014 Dec;59(6):572-9. doi: 10.1111/lam.12334.
Collado MC, Rautava S, Aakko J, Isolauri E, Salminen S. Human gut colonisation may be initiated in utero by distinct microbial communities in the placenta and amniotic fluid. Sci Rep. 2016 Mar 22;6:23129. doi: 10.1038/srep23129.
Zhu L, Luo F, Hu W, Han Y, Wang Y, Zheng H, Guo X, Qin J. Bacterial Communities in the Womb During Healthy Pregnancy. Front Microbiol. 2018 Sep 6;9:2163. doi: 10.3389/fmicb.2018.02163.
Kusanovic JP, Jung E, Romero R, Mittal Green P, Nhan-Chang CL, Vaisbuch E, Erez O, Kim CJ, Gonçalves LF, Espinoza J, Mazaki-Tovi S, Chaiworapongsa T, Diaz-Primera R, Yeo L, Suksai M, Gotsch F, Hassan SS. Characterization of amniotic fluid sludge in preterm and term gestations. J Matern Fetal Neonatal Med. 2022 Dec;35(25):9770-9779. doi: 10.1080/14767058.2022.2053102.
Romero R, Gervasi MT, DiGiulio DB, Jung E, Suksai M, Miranda J, Theis KR, Gotsch F, Relman DA. Are bacteria, fungi, and archaea present in the midtrimester amniotic fluid? J Perinat Med. 2023 May 17;51(7):886-890. doi: 10.1515/jpm-2022-0604.
Kim SA, Park KH, Lee SM, Kim YM, Hong S. Inflammatory Proteins in the Amniotic Fluid, Plasma, and Cervicovaginal Fluid for the Prediction of Intra-Amniotic Infection/Inflammation and Imminent Preterm Birth in Preterm Labor. Am J Perinatol. 2022 May;39(7):766-775. doi: 10.1055/s-0040-1718575.
Park H, Park KH, Kim YM, Kook SY, Jeon SJ, Yoo HN. Plasma inflammatory and immune proteins as predictors of intra-amniotic infection and spontaneous preterm delivery in women with preterm labor: a retrospective study. BMC Pregnancy Childbirth. 2018 May 9;18(1):146. doi: 10.1186/s12884-018-1780-7.
Tanaka T, Narazaki M, Kishimoto T. IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol. 2014 Sep 4;6(10):a016295. doi: 10.1101/cshperspect.a016295.
Oh KJ, Lee J, Romero R, Park HS, Hong JS, Yoon BH. A new rapid bedside test to diagnose and monitor intraamniotic inflammation in preterm PROM using transcervically collected fluid. Am J Obstet Gynecol. 2020 Sep;223(3):423.e1-423.e15. doi: 10.1016/j.ajog.2020.02.037.
Balciuniene G, Gulbiniene V, Dumalakiene I, Viliene R, Bartkeviciene D, Pilypiene I, Drasutiene GS, Ramasauskaite D. Prognostic Markers for Chorioamnionitis: IL-6, TNF-α, and MMP-8 in Vaginally Obtained Amniotic Fluid. J Clin Med. 2021 Mar 8;10(5):1136. doi: 10.3390/jcm10051136.
Ran Y, Huang D, Mei Y, Liu Z, Zhou Y, He J, Zhang H, Yin N, Qi H. Identification of the correlations between interleukin-27 (IL-27) and immune-inflammatory imbalance in preterm birth. Bioengineered. 2021 Dec;12(1):3201-3218. doi: 10.1080/21655979.2021.1945894.
Jung EY, Park JW, Ryu A, Lee SY, Cho SH, Park KH. Prediction of impending preterm delivery based on sonographic cervical length and different cytokine levels in cervicovaginal fluid in preterm labor. J Obstet Gynaecol Res. 2016 Feb;42(2):158-65. doi: 10.1111/jog.12882.
Amabebe E, Reynolds S, He X, Wood R, Stern V, Anumba DOC. Infection/inflammation-associated preterm delivery within 14 days of presentation with symptoms of preterm labour: A multivariate predictive model. PLoS One. 2019 Sep 12;14(9):e0222455. doi: 10.1371/journal.pone.0222455.
Hadzi Lega M, Daneva Markova A, Stefanovic M, Tanturovski M. Interleukin 6 and fetal fibronectin as a predictors of preterm delivery in symptomatic patients. Bosn J Basic Med Sci. 2015 Jan 8;15(1):51-6. doi: 10.17305/bjbms.2015.1.93.
Lee SY, Buhimschi IA, Dulay AT, Ali UA, Zhao G, Abdel-Razeq SS, Bahtiyar MO, Thung SF, Funai EF, Buhimschi CS. IL-6 trans-signaling system in intra-amniotic inflammation, preterm birth, and preterm premature rupture of the membranes. J Immunol. 2011 Mar 1;186(5):3226-36. doi: 10.4049/jimmunol.1003587.
Marcellin L, Batteux F, Chouzenoux S, Schmitz T, Lorthe E, Mehats C, Goffinet F, Kayem G. Second-trimester amniotic fluid proteins changes in subsequent spontaneous preterm birth. Acta Obstet Gynecol Scand. 2023 May;102(5):597-604. doi: 10.1111/aogs.14544.
Khedagi AM, Bello NA. Hypertensive Disorders of Pregnancy. Cardiol Clin. 2021 Feb;39(1):77-90. doi: 10.1016/j.ccl.2020.09.005.
Ovayolu A, Turksoy VA, Ovayolu G, Ozek MA, Dogan I, Karaman E. Analyses of interleukin-6, presepsin and pentraxin-3 in the diagnosis and severity of late-onset preeclampsia. J Matern Fetal Neonatal Med. 2022 Jan;35(2):299-307. doi: 10.1080/14767058.2020.1716718.
Rana S, Lemoine E, Granger JP, Karumanchi SA. Preeclampsia: Pathophysiology, Challenges, and Perspectives. Circ Res. 2019 Mar 29;124(7):1094-1112. doi: 10.1161/CIRCRESAHA.118.313276. Erratum in: Circ Res. 2020 Jan 3;126(1):e8. doi: 10.1161/RES.0000000000000315.
Roberts JM, Escudero C. The placenta in preeclampsia. Pregnancy Hypertens. 2012 Apr 1;2(2):72-83. doi: 10.1016/j.preghy.2012.01.001.
Lamarca B, Brewer J, Wallace K. IL-6-induced pathophysiology during pre-eclampsia: potential therapeutic role for magnesium sulfate? Int J Interferon Cytokine Mediat Res. 2011 Jul 1;2011(3):59-64. doi: 10.2147/IJICMR.S16320.
Aggarwal R, Jain AK, Mittal P, Kohli M, Jawanjal P, Rath G. Association of pro- and anti-inflammatory cytokines in preeclampsia. J Clin Lab Anal. 2019 May;33(4):e22834. doi: 10.1002/jcla.22834.
Tosun M, Celik H, Avci B, Yavuz E, Alper T, Malatyalioğlu E. Maternal and umbilical serum levels of interleukin-6, interleukin-8, and tumor necrosis factor-alpha in normal pregnancies and in pregnancies complicated by preeclampsia. J Matern Fetal Neonatal Med. 2010 Aug;23(8):880-6. doi: 10.3109/14767051003774942.
Chen W, Guo Y, Yao X, Zhao D. Correlation of Blood Lipid and Serum Inflammatory Factor Levels With Hypertensive Disorder Complicating Pregnancy. Front Surg. 2022 Jun 17;9:917458. doi: 10.3389/fsurg.2022.917458.
Liu Y, Hou X, Yu M, Zhou J. Clinical Analysis of Echocardiography and Serum IL-6 and TNF-α Changes in Pregnant Women with Hypertension. Scanning. 2022 Aug 30;2022:9299746. doi: 10.1155/2022/9299746. Retraction in: Scanning. 2023 Oct 11;2023:9897839. doi: 10.1155/2023/9897839.
Lumbreras-Marquez MI, Lumbreras-Marquez J, Barraza-Salas M, Castillo-Reyther RA, De la Maza-Labastida S, Hernandez-Rayon YI, Farber MK, Vazquez-Alaniz F. Maternal and umbilical cord procalcitonin, high-sensitivity C-reactive protein, and interleukin-6 levels in preeclamptic and normotensive patients: A cross-sectional study. Pregnancy Hypertens. 2020 Jul;21:218-223. doi: 10.1016/j.preghy.2020.04.009.
Szarka A, Rigó J Jr, Lázár L, Beko G, Molvarec A. Circulating cytokines, chemokines and adhesion molecules in normal pregnancy and preeclampsia determined by multiplex suspension array. BMC Immunol. 2010 Dec 2;11:59. doi: 10.1186/1471-2172-11-59.
Sapmaz E, Çelik A, Bulut V, İlhan F, Hanay F. Preeklampsi Olgularında İnterlökin-6, CRP, Nötrofil ve Platelet Düzeylerinin İncelenmesi. J Clin Obstet Gynecol. 2006;16(6):218-223.
Valencia-Ortega J, Zárate A, Saucedo R, Hernández-Valencia M, Cruz JG, Puello E. Placental Proinflammatory State and Maternal Endothelial Dysfunction in Preeclampsia. Gynecol Obstet Invest. 2019;84(1):12-19. doi: 10.1159/000491087.
Nzelu D, Dumitrascu-Biris D, Karampitsakos T, Nicolaides KK, Kametas NA. First trimester inflammatory mediators in women with chronic hypertension. Acta Obstet Gynecol Scand. 2020 Sep;99(9):1198-1205. doi: 10.1111/aogs.13857.
Kara AE, Guney G, Tokmak A, Ozaksit G. The role of inflammatory markers hs-CRP, sialic acid, and IL-6 in the pathogenesis of preeclampsia and intrauterine growth restriction. Eur Cytokine Netw. 2019 Mar 1;30(1):29-33. doi: 10.1684/ecn.2019.0423.
Staff AC, Johnsen GM, Dechend R, Redman CWG. Preeclampsia and uteroplacental acute atherosis: immune and inflammatory factors. J Reprod Immunol. 2014 Mar;101-102:120-126. doi: 10.1016/j.jri.2013.09.001.
Martinez-Fierro ML, Castruita-De La Rosa C, Garza-Veloz I, Cardiel-Hernandez RM, Espinoza-Juarez MA, Delgado-Enciso I, Castañeda-Lopez ME, Cardenas-Vargas E, Trejo-Vázquez F, Sotelo-Ham EI, Castañeda-Miranda R, Cid-Baez MA, Ortiz-Rodriguez JM, Solis-Sanchez LO, Aviles AG, Ortiz-Castro Y. Early pregnancy protein multiplex screening reflects circulating and urinary divergences associated with the development of preeclampsia. Hypertens Pregnancy. 2018 Feb;37(1):37-50. doi: 10.1080/10641955.2017.1411946.
Figueras F, Gratacós E. Update on the diagnosis and classification of fetal growth restriction and proposal of a stage-based management protocol. Fetal Diagn Ther. 2014;36(2):86-98. doi: 10.1159/000357592.
Crovetto F, Crispi F, Scazzocchio E, Mercade I, Meler E, Figueras F, Gratacos E. First-trimester screening for early and late small-for-gestational-age neonates using maternal serum biochemistry, blood pressure and uterine artery Doppler. Ultrasound Obstet Gynecol. 2014 Jan;43(1):34-40. doi: 10.1002/uog.12537.
Lausten-Thomsen U, Olsen M, Greisen G, Schmiegelow K. Inflammatory markers in umbilical cord blood from small-for-gestational-age newborns. Fetal Pediatr Pathol. 2014 Apr;33(2):114-8. doi: 10.3109/15513815.2013.879239.
Yue SL, Eke AC, Vaidya D, Northington FJ, Everett AD, Graham EM. Perinatal blood biomarkers for the identification of brain injury in very low birth weight growth-restricted infants. J Perinatol. 2021 Sep;41(9):2252-2260. doi: 10.1038/s41372-021-01112-8.
Alfian I, Chakraborty A, Yong HEJ, Saini S, Lau RWK, Kalionis B, Dimitriadis E, Alfaidy N, Ricardo SD, Samuel CS, Murthi P. The Placental NLRP3 Inflammasome and Its Downstream Targets, Caspase-1 and Interleukin-6, Are Increased in Human Fetal Growth Restriction: Implications for Aberrant Inflammation-Induced Trophoblast Dysfunction. Cells. 2022 Apr 21;11(9):1413. doi: 10.3390/cells11091413.
Al-Azemi M, Raghupathy R, Azizieh F. Pro-inflammatory and anti-inflammatory cytokine profiles in fetal growth restriction. Clin Exp Obstet Gynecol. 2017;44(1):98-103. PMID: 29714875.
de Mendonça ELSS, Fragoso MBT, de Oliveira JM, Xavier JA, Goulart MOF, de Oliveira ACM. Gestational Diabetes Mellitus: The Crosslink among Inflammation, Nitroxidative Stress, Intestinal Microbiota and Alternative Therapies. Antioxidants (Basel). 2022 Jan 7;11(1):129. doi: 10.3390/antiox11010129.
Kim SY, England L, Wilson HG, Bish C, Satten GA, Dietz P. Percentage of gestational diabetes mellitus attributable to overweight and obesity. Am J Public Health. 2010 Jun;100(6):1047-52. doi: 10.2105/AJPH.2009.172890.
Choudhury AA, Devi Rajeswari V. Gestational diabetes mellitus - A metabolic and reproductive disorder. Biomed Pharmacother. 2021 Nov;143:112183. doi: 10.1016/j.biopha.2021.112183.
Al-Badri MR, Zantout MS, Azar ST. The role of adipokines in gestational diabetes mellitus. Ther Adv Endocrinol Metab. 2015 Jun;6(3):103-8. doi: 10.1177/2042018815577039.
Miehle K, Stepan H, Fasshauer M. Leptin, adiponectin and other adipokines in gestational diabetes mellitus and pre-eclampsia. Clin Endocrinol (Oxf). 2012 Jan;76(1):2-11. doi: 10.1111/j.1365-2265.2011.04234.x.
Abell SK, De Courten B, Boyle JA, Teede HJ. Inflammatory and Other Biomarkers: Role in Pathophysiology and Prediction of Gestational Diabetes Mellitus. Int J Mol Sci. 2015 Jun 11;16(6):13442-73. doi: 10.3390/ijms160613442.
Zhang J, Chi H, Xiao H, Tian X, Wang Y, Yun X, Xu Y. Interleukin 6 (IL-6) and Tumor Necrosis Factor α (TNF-α) Single Nucleotide Polymorphisms (SNPs), Inflammation and Metabolism in Gestational Diabetes Mellitus in Inner Mongolia. Med Sci Monit. 2017 Aug 28;23:4149-4157. doi: 10.12659/msm.903565.
Francis EC, Li M, Hinkle SN, Cao Y, Chen J, Wu J, Zhu Y, Cao H, Kemper K, Rennert L, Williams J, Tsai MY, Chen L, Zhang C. Adipokines in early and mid-pregnancy and subsequent risk of gestational diabetes: a longitudinal study in a multiracial cohort. BMJ Open Diabetes Res Care. 2020 Jul;8(1):e001333. doi: 10.1136/bmjdrc-2020-001333.
Zhao X, Liu J, Shen L, Wang A, Wang R. Correlation between inflammatory markers (hs-CRP, TNF-α, IL-1β, IL-6, IL-18), glucose intolerance, and gestational diabetes mellitus in pregnant women [Internet]. Vol. 11, Int J Clin Exp Med. 2018. Available from: www.ijcem.com.
Siddiqui S, Waghdhare S, Goel C, Panda M, Soneja H, Sundar J, Banerjee M, Jha S, Dubey S. Augmentation of IL-6 production contributes to development of gestational diabetes mellitus: An Indian study. Diabetes Metab Syndr. 2019 Mar-Apr;13(2):895-899. doi: 10.1016/j.dsx.2018.12.023.
Xiang LL, Chen C, Wang QY, Zhu YT, Chen YJ, Zeng Y. Impact of inflammatory factors, hemoglobin A1c, and platelet parameters in gestational diabetes mellitus. Arch Gynecol Obstet. 2023 Feb;307(2):439-446. doi: 10.1007/s00404-022-06528-x.
Morisset AS, Dubé MC, Côté JA, Robitaille J, Weisnagel SJ, Tchernof A. Circulating interleukin-6 concentrations during and after gestational diabetes mellitus. Acta Obstet Gynecol Scand. 2011 May;90(5):524-30. doi: 10.1111/j.1600-0412.2011.01094.x.
Kuzmicki M, Telejko B, Szamatowicz J, Zonenberg A, Nikolajuk A, Kretowski A, Gorska M. High resistin and interleukin-6 levels are associated with gestational diabetes mellitus. Gynecol Endocrinol. 2009 Apr;25(4):258-63. doi: 10.1080/09513590802653825.
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Accepted 2024-04-28
Published 2024-06-19