Abstract
Severe preeclampsia (PE) is a major cause of maternal mortality and morbidity worldwide. Signal transducer and activator of transcription 3 (Stat3) signal pathway can modulate various fundamental cellular processes. However, whether Stat3 plays a role in the pathogenesis of severe PE is unknown. Therefore, in this study, the expression levels of Stat3 pathway-related genes and proteins, Stat3, pStat3, IL-6, Mcl-1L, Bcl-xL, survivin, MMP-2, and MMP-9, were evaluated by immunohistochemistry (IHC), Western blot analysis and real-time PCR in the severe preeclamptic placentas. Our results showed that Stat3 and pStat3 immunoreactivity were localized in both extravillous cytotrophoblast cells and villous trophoblast cells in the placentas. As compared with normotensive pregnancies, significantly decreased expressions of Stat3 and pStat3 proteins were observed in extravillous cytotrophoblast cells, villous trophoblast cells and entire placentas in patients with severe PE. The expression levels of Stat3, IL-6, survivin and MMP-2 mRNA were significantly decreased in severe preeclamptic placentas, while Mcl-1L, Bcl-xL and MMP-9 mRNA levels were unchanged. IHC results further confirmed that there was a significant decrease of IL-6, survivin and MMP-2 proteins expression in the severe preeclamptic placentas compared with the normal specimens. These findings suggested that decreased expression and activation of the Stat3 may be caused by decreased expression of a Stat3 upstream gene, such as IL-6. Decreased Stat3 expression and activation may play an important role in the pathogenesis of PE through regulation of the transcription of the Stat3 targeted genes survivin and MMP-2 to modulate apoptosis and invasion of placental trophoblastic cells.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Benyo DF, Smarason A, Redman CW, Sims C, Conrad KP (2001) Expression of inflammatory cytokines in placentas from women with preeclampsia. J Clin Endocrinol Metab 86:2505–2512
Castellucci M, Kaufmann P (2006) Basic structure of the villous trees. In: Pathology of the human placenta. Springer, New York, pp 50–120. doi:10.1007/0-387-26742-5_6
Chen Q, Stone P, Ching LM, Chamley L (2009) A role for interleukin-6 in spreading endothelial cell activation after phagocytosis of necrotic trophoblastic material: implications for the pathogenesis of pre-eclampsia. J Pathol 217:122–130. doi:10.1002/path.2425
Corvinus FM, Fitzgerald JS, Friedrich K, Markert UR (2003) Evidence for a correlation between trophoblast invasiveness and STAT3 activity. Am J Reprod Immunol 50:316–321
Cozzi V, Garlanda C, Nebuloni M, Maina V, Martinelli A, Calabrese S, Cetin I (2012) PTX3 as a potential endothelial dysfunction biomarker for severity of preeclampsia and IUGR. Placenta 33:1039–1044. doi:10.1016/j.placenta.2012.09.009
Crocker IP, Cooper S, Ong SC, Baker PN (2003) Differences in apoptotic susceptibility of cytotrophoblasts and syncytiotrophoblasts in normal pregnancy to those complicated with preeclampsia and intrauterine growth restriction. Am J Pathol 162:637–643. doi:10.1016/S0002-9440(10)63857-6
Davison JM et al (2004) New aspects in the pathophysiology of preeclampsia. J Am Soc Nephrol 15:2440–2448. doi:10.1097/01.ASN.0000135975.90889.60
Demendi C, Borzsonyi B, Vegh V, Nagy ZB, Rigo J Jr, Pajor A, Joo JG (2012) Gene expression patterns of the Bcl-2 and Bax genes in preterm birth. Acta Obstet Gynecol Scand 91:1212–1217. doi:10.1111/j.1600-0412.2012.01428.x
DiFederico E, Genbacev O, Fisher SJ (1999) Preeclampsia is associated with widespread apoptosis of placental cytotrophoblasts within the uterine wall. Am J Pathol 155:293–301. doi:10.1016/S0002-9440(10)65123-1
Fitzgerald JS, Poehlmann TG, Schleussner E, Markert UR (2008) Trophoblast invasion: the role of intracellular cytokine signalling via signal transducer and activator of transcription 3 (STAT3). Hum Reprod Update 14:335–344. doi:10.1093/humupd/dmn010
Garcia MG et al (2007) High expression of survivin and down-regulation of Stat-3 characterize the feto-maternal interface in failing murine pregnancies during the implantation period. Placenta 28:650–657. doi:10.1016/j.placenta.2006.09.010
Gulati S, Bhatnagar S, Raghunandan C, Bhattacharjee J (2012) Interleukin-6 as a predictor of subclinical chorioamnionitis in preterm premature rupture of membranes. Am J Reprod Immunol 67:235–240. doi:10.1111/j.1600-0897.2011.01084.x
Guo Y, Xu F, Lu T, Duan Z, Zhang Z (2012) Interleukin-6 signaling pathway in targeted therapy for cancer. Cancer Treat Rev 38:904–910. doi:10.1016/j.ctrv.2012.04.007
Halperin R, Peller S, Rotschild M, Bukovsky I, Schneider D (2000) Placental apoptosis in normal and abnormal pregnancies. Gynecol Obstet Investig 50:84–87
Heazell AE, Crocker IP (2008) Live and let die—regulation of villous trophoblast apoptosis in normal and abnormal pregnancies. Placenta 29:772–783. doi:10.1016/j.placenta.2008.07.003
Heazell AE, Buttle HR, Baker PN, Crocker IP (2008) Altered expression of regulators of caspase activity within trophoblast of normal pregnancies and pregnancies complicated by preeclampsia. Reprod Sci 15:1034–1043. doi:10.1177/1933719108322438
Hirano T, Ishihara K, Hibi M (2000) Roles of STAT3 in mediating the cell growth, differentiation and survival signals relayed through the IL-6 family of cytokine receptors. Oncogene 19:2548–2556. doi:10.1038/sj.onc.1203551
Hu C, Smith SD, Pang L, Sadovsky Y, Nelson DM (2006) Enhanced basal apoptosis in cultured term human cytotrophoblasts is associated with a higher expression and physical interaction of p53 and Bak. Placenta 27:978–983. doi:10.1016/j.placenta.2005.11.004
Huang WL, Yeh HH, Lin CC, Lai WW, Chang JY, Chang WT, Su WC (2010) Signal transducer and activator of transcription 3 activation up-regulates interleukin-6 autocrine production: a biochemical and genetic study of established cancer cell lines and clinical isolated human cancer cells. Mol Cancer 9:309. doi:10.1186/1476-4598-9-309
Huppertz B (2008) Placental origins of preeclampsia: challenging the current hypothesis. Hypertension 51:970–975. doi:10.1161/HYPERTENSIONAHA.107.107607
Isaka K et al (2003) Expression and activity of matrix metalloproteinase 2 and 9 in human trophoblasts. Placenta 24:53–64
Ishihara N, Matsuo H, Murakoshi H, Laoag-Fernandez JB, Samoto T, Maruo T (2002) Increased apoptosis in the syncytiotrophoblast in human term placentas complicated by either preeclampsia or intrauterine growth retardation. Am J Obstet Gynecol 186:158–166
Jovanovic M, Vicovac L (2009) Interleukin-6 stimulates cell migration, invasion and integrin expression in HTR-8/SVneo cell line. Placenta 30:320–328. doi:10.1016/j.placenta.2009.01.013
Leung DN, Smith SC, To KF, Sahota DS, Baker PN (2001) Increased placental apoptosis in pregnancies complicated by preeclampsia. Am J Obstet Gynecol 184:1249–1250. doi:10.1067/mob.2001.112906
Li JJ et al (2008) Mcl-1 is regulated by IL-6 and mediates the survival activity of the cytokine in a model of late stage prostate carcinoma. In: Hormonal carcinogenesis V, vol 617. Advances in experimental medicine and biology. Springer, New York, pp 547–555. doi:10.1007/978-0-387-69080-3_56
Li CF, Gou WL, Li XL, Wang SL, Yang T, Chen Q (2012) Reduced expression of survivin, the inhibitor of apoptosis protein correlates with severity of preeclampsia. Placenta 33:47–51. doi:10.1016/j.placenta.2011.10.008
Liu H, Ma Y, Cole SM, Zander C, Chen KH, Karras J, Pope RM (2003) Serine phosphorylation of STAT3 is essential for Mcl-1 expression and macrophage survival. Blood 102:344–352. doi:10.1182/blood-2002-11-3396
Lockwood CJ et al (2008a) Preeclampsia-related inflammatory cytokines regulate interleukin-6 expression in human decidual cells. Am J Pathol 172:1571–1579. doi:10.2353/ajpath.2008.070629
Lockwood CJ et al (2008b) Preeclampsia-related inflammatory cytokines regulate interleukin-6 expression in human decidual cells. Am J Pathol 172:1571–1579. doi:10.2353/ajpath.2008.070629
Lyall F (2011) The placenta in preeclampsia. In: The placenta. Wiley-Blackwell, pp 246–252. doi:10.1002/9781444393927.ch32
Muschol-Steinmetz C, Friemel A, Kreis NN, Reinhard J, Yuan J, Louwen F (2013) Function of survivin in trophoblastic cells of the placenta PloS one 8:e73337. doi:10.1371/journal.pone.0073337
Myatt L (2002) Role of placenta in preeclampsia. Endocrine 19:103–111. doi:10.1385/ENDO:19:1:103
Omran OM, Shokry M, Ismail H, Omar G, Rezk M (2011) Expression of matrix metalloproteinases 2 and 9 in human trophoblasts of normal and preeclamptic placentas. Int J Health Sci 5:21–23
Onogi A et al (2011) Hypoxia inhibits invasion of extravillous trophoblast cells through reduction of matrix metalloproteinase (MMP)-2 activation in the early first trimester of human pregnancy. Placenta 32:665–670. doi:10.1016/j.placenta.2011.06.023
Palei AC, Sandrim VC, Amaral LM, Machado JS, Cavalli RC, Duarte G, Tanus-Santos JE (2012) Association between matrix metalloproteinase (MMP)-2 polymorphisms and MMP-2 levels in hypertensive disorders of pregnancy. Exp Mol Pathol 92:217–221. doi:10.1016/j.yexmp.2012.01.008
Rampersad R, Nelson DM (2007) Trophoblast biology, responses to hypoxia and placental dysfunction in preeclampsia. Front Biosci J Virtual Library 12:2447–2456
Robinson CJ, Johnson DD, Chang EY, Armstrong DM, Wang W (2006) Evaluation of placenta growth factor and soluble Fms-like tyrosine kinase 1 receptor levels in mild and severe preeclampsia. Am J Obstet Gynecol 195:255–259. doi:10.1016/j.ajog.2005.12.049
Shiozaki A, Kataoka K, Fujimura M, Yuki H, Sakai M, Saito S (2003) Survivin inhibits apoptosis in cytotrophoblasts. Placenta 24:65–76
Sibai B, Dekker G, Kupferminc M (2005) Pre-eclampsia. Lancet 365:785–799. doi:10.1016/S0140-6736(05)17987-2
Smith SC, Baker PN (1999) Placental apoptosis is increased in post-term pregnancies. Br J Obstet Gynaecol 106:861–862
Soleymanlou N et al (2007) Hypoxic switch in mitochondrial myeloid cell leukemia factor-1/Mtd apoptotic rheostat contributes to human trophoblast cell death in preeclampsia. Am J Pathol 171:496–506. doi:10.2353/ajpath.2007.070094
Staun-Ram E, Goldman S, Gabarin D, Shalev E (2004) Expression and importance of matrix metalloproteinase 2 and 9 (MMP-2 and -9) in human trophoblast invasion. Reprod Biol Endocrinol 2:59. doi:10.1186/1477-7827-2-59
Takeda K et al (1997) Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. Proc Natl Acad Sci USA 94:3801–3804
Tomas SZ, Prusac IK, Roje D, Tadin I (2011) Trophoblast apoptosis in placentas from pregnancies complicated by preeclampsia. Gynecol Obstet Investig 71:250–255. doi:10.1159/000320289
Unek G, Ozmen A, Mendilcioglu I, Simsek M, Korgun ET (2014) Immunohistochemical distribution of cell cycle proteins p27, p57, cyclin D3, PCNA and Ki67 in normal and diabetic human placentas. J Mol Histol 45:21–34. doi:10.1007/s10735-013-9534-3
Wang L, Zhang D, Yu Y, Guan H, Qiao C, Shang T (2013) RNA interference-mediated silencing of laminin receptor 1 (LR1) suppresses migration and invasion and down-regulates matrix metalloproteinase (MMP)-2 and MMP-9 in trophoblast cells: implication in the pathogenesis of preeclampsia. J Mol Histol 44:661–668. doi:10.1007/s10735-013-9515-6
Weber M, Kuhn C, Schulze S, Jeschke U, Markert UR (2009) Immunohistochemical analysis of STAT3 and its phosphorylated forms in human placenta. J Reprod Immunol 81:172. doi:10.1016/j.jri.2009.06.249
Weber M et al (2012) Expression of signal transducer and activator of transcription 3 (STAT3) and its activated forms is negatively altered in trophoblast and decidual stroma cells derived from preeclampsia placentae. Histopathology 60:657–662. doi:10.1111/j.1365-2559.2011.04063.x
Xie TX, Wei D, Liu M, Gao AC, Ali-Osman F, Sawaya R, Huang S (2004) Stat3 activation regulates the expression of matrix metalloproteinase-2 and tumor invasion and metastasis. Oncogene 23:3550–3560. doi:10.1038/sj.onc.1207383
Xie C, Yao MZ, Liu JB, Xiong LK (2011) A meta-analysis of tumor necrosis factor-alpha, interleukin-6, and interleukin-10 in preeclampsia. Cytokine 56:550–559. doi:10.1016/j.cyto.2011.09.021
Xu L, Lee M, Jeyabalan A, Roberts JM (2014) The relationship of hypovitaminosis D and IL-6 in preeclampsia. Am J Obstet Gynecol 210(149):e141–e147. doi:10.1016/j.ajog.2013.09.037
Zhang H, Long Q, Ling L, Gao A, Li H, Lin Q (2011a) Elevated expression of KiSS-1 in placenta of preeclampsia and its effect on trophoblast. Reprod Biol 11:99–115
Zhang X et al (2011b) Carnosine pretreatment protects against hypoxia-ischemia brain damage in the neonatal rat model. Eur J Pharmacol 667:202–207. doi:10.1016/j.ejphar.2011.06.003
Zhang Z, Zhang L, Jia L, Wang P, Gao Y (2013a) Association of Wnt2 and sFRP4 expression in the third trimester placenta in women with severe preeclampsia. Reprod Sci (Thousand Oaks, Calif) 20:981–989. doi:10.1177/1933719112472740
Zhang Z, Zhang L, Jia L, Wang P, Gao Y (2013b) Association of Wnt2 and sFRP4 expression in the third trimester placenta in women with severe preeclampsia. Reprod Sci. doi:10.1177/1933719112472740
Acknowledgments
This work was supported by Grants from the Science and Technology Fund for Innovative Talents of Henan Province (No. 124200510005), the Key Scientific and Technological Project of Henan Province (No. 112102310089), and the Science and Technology Fund for Innovation Leading Research Team of Zhengzhou City (No. 131PCXTD624).
Conflict of interest
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Zhang, Z., Yang, X., Zhang, L. et al. Decreased expression and activation of Stat3 in severe preeclampsia. J Mol Hist 46, 205–219 (2015). https://doi.org/10.1007/s10735-015-9613-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10735-015-9613-8