Elevated Expression of Glucocorticoid-Induced Leucine Zipper in Placental Endothelial Cells and Trophoblasts in Preeclampsia
Objectives: The objective of this study was to investigate the association between normal and preeclamptic glucocorticoid-induced leucine zipper (GILZ) levels in the placenta.
Methods: Placental paraffin sections (5 μm) were obtained from gestational age-matched normal (n=9) and (PE) (n=9) pregnancies. Tissue sections were immunostained with rabbit monoclonal anti-human GILZ antibodies. Staining intensity of GILZ was evaluated with a histologic scoring (HSCORE) system. Parametric (t-test) and non-parametric tests (Mann–Whitney U) were used for statistical analysis, and a p value of <0.05 was considered significant.
Results: Trophoblasts and endothelial cells were shown to be the source of GILZ release. Compared with the control, PE placental samples displayed significantly increased GILZ immunostaining HSCOREs in trophoblast cell nucleus (mean±SEM, 106.8±12.1 vs 167.9±14.9; p=0.006) and endothelial cells (95.0±8.1 vs 147.2±12.3; p=0.003).
Conclusion: This study suggests that GILZ release by placental trophoblasts and endothelial cells may contribute to PE pathogenesis.
1. Amaral LM, Wallace K, Owens M, LaMarca B. Pathophysiology and Current Clinical Management of Preeclampsia. Curr Hypertens Rep 2017;19:61. [CrossRef]
2. Xia Y, Kellems RE. Angiotensin receptor agonistic autoantibodies and hypertension: preeclampsia and beyond. Circ Res 2013;113:78–87. [CrossRef]
3. Boeldt DS, Bird IM. Vascular adaptation in pregnancy and endothelial dysfunction in preeclampsia. J Endocrinol 2017;232:R27–44. [CrossRef]
4. Vianna P, Bauer ME, Dornfeld D, Chies JA. Distress conditions during pregnancy may lead to pre-eclampsia by increasing cortisol levels and altering lymphocyte sensitivity to glucocorticoids. Med Hypotheses 2011;77:188–91. [CrossRef]
5. Riccardi C, Cifone MG, Migliorati G. Glucocorticoid hormone-induced modulation of gene expression and regulation of T-cell death: role of GITR and GILZ, two dexamethasone-induced genes. Cell Death Differ 1999;6:1182–9. [CrossRef]
6. Ayroldi E, Riccardi C. Glucocorticoid-induced leucine zipper (GILZ): a new important mediator of glucocorticoid action. FASEB J 2009;23:3649–58. [CrossRef]
7. Zhang D, Liu H, Zeng J, Miao X, Huang W, Chen H, et al. Glucocorticoid exposure in early placentation induces preeclampsia in rats via interfering trophoblast development. Gen Comp Endocrinol 2016;225:61–70. [CrossRef]
8. Michael AE, Papageorghiou AT. Potential significance of physiological and pharmacological glucocorticoids in early pregnancy. Hum Reprod Update 2008;14:497–517. [CrossRef]
9. Tuzcu ZB, Asicioglu E, Sunbul M, Ozben B, Arikan H, Koc M. Circulating endothelial cell number and markers of endothelial dysfunction in previously preeclamptic women. Am J Obstet Gynecol 2015;213:533.e1–7. [CrossRef]
10. Var A, Yildirim Y, Onur E, Kuscu NK, Uyanik BS, Goktalay K, et al. Endothelial dysfunction in preeclampsia. Increased homocysteine and decreased nitric oxide levels. Gynecol Obstet Invest 2003;56:221–4. [CrossRef]
11. Budak E, Madazli R, Aksu MF, Benian A, Gezer A, Palit N, et al. Vascular cell adhesion molecule-1 (VCAM-1) and leukocyte activation in pre-eclampsia and eclampsia. Int J Gynaecol Obstet 1998;63:115–21. [CrossRef]
12. Dietrich S, Falk CS, Benner A, Karamustafa S, Hahn E, Andrulis M, et al. Endothelial vulnerability and endothelial damage are associated with risk of graft-versus-host disease and response to steroid treatment. Biol Blood Marrow Transplant 2013;19:22–7. [CrossRef]
13. Ferrelli F, Pastore D, Capuani B, Lombardo MF, Blot-Chabaud M, Coppola A, et al. Serum glucocorticoid inducible kinase (SGK)-1 protects endothelial cells against oxidative stress and apoptosis induced by hyperglycaemia. Acta Diabetol 2015;52:55-64. [CrossRef]
14. D'Adamio F, Zollo O, Moraca R, Ayroldi E, Bruscoli S, Bartoli A, et al. A new dexamethasone-induced gene of the leucine zipper family protects T lymphocytes from TCR/CD3-activated cell death. Immunity 1997;7:803–12. [CrossRef]
15. Ricci E, Ronchetti S, Pericolini E, Gabrielli E, Cari L, Gentili M, et al. Role of the glucocorticoid-induced leucine zipper gene in dexamethasone-induced inhibition of mouse neutrophil migration via control of annexin A1 expression. FASEB J 2017;31:3054–65. [CrossRef]
16. Calmette J, Bertrand M, Vétillard M, Ellouze M, Flint S, Nicolas V, et al. Glucocorticoid-Induced Leucine Zipper Protein Controls Macropinocytosis in Dendritic Cells. J Immunol 2016;197:4247–56. [CrossRef]
17. Hahn RT, Hoppstädter J, Hirschfelder K, Hachenthal N, Diesel B, Kessler SM, et al. Downregulation of the glucocorticoid-induced leucine zipper (GILZ) promotes vascular inflammation. Atherosclerosis 2014;234:391–400. [CrossRef]
18. Lingen MW. Role of leukocytes and endothelial cells in the development of angiogenesis in inflammation and wound healing. Arch Pathol Lab Med 2001;125:67–71.
19. Wang Y, Ma YY, Song XL, Cai HY, Chen JC, Song LN, et al. Upregulations of glucocorticoid-induced leucine zipper by hypoxia and glucocorticoid inhibit proinflammatory cytokines under hypoxic conditions in macrophages. J Immunol 2012;188:222–9. [CrossRef]
20. Cheng Q, Fan H, Ngo D, Beaulieu E, Leung P, Lo CY, et al. GILZ overexpression inhibits endothelial cell adhesive function through regulation of NF-κB and MAPK activity. J Immunol 2013;191:424–33. [CrossRef]
21. Bansal AS, Bora SA, Saso S, Smith JR, Johnson MR, Thum MY. Mechanism of human chorionic gonadotrophin-mediated immunomodulation in pregnancy. Expert Rev Clin Immunol 2012;8:747–53. [CrossRef]
22. Robinson DP, Klein SL. Pregnancy and pregnancy-associated hormones alter immune responses and disease pathogenesis. Horm Behav 2012;62:263–71. [CrossRef]
23. Pramanik SS, Pramanik T, Mondal SC, Chanda R. Number, maturity and phagocytic activity of neutrophils in the three trimesters of pregnancy. East Mediterr Health J 2007;13:862–7.
24. Lim W, Park C, Shim MK, Lee YH, Lee YM, Lee Y. Glucocorticoids suppress hypoxia-induced COX-2 and hypoxia inducible factor-1α expression through the induction of glucocorticoid-induced leucine zipper. Br J Pharmacol 2014;171:735–45.
25. Yang N, Zhang W, Shi XM. Glucocorticoid-induced leucine zipper (GILZ) mediates glucocorticoid action and inhibits inflammatory cytokine-induced COX-2 expression. J Cell Biochem 2008;103:1760–71. [CrossRef]
26. Tsuboi K, Iwane A, Nakazawa S, Sugimoto Y, Ichikawa A. Role of prostaglandin H2 synthase 2 in murine parturition: study on ovariectomy-induced parturition in prostaglandin F receptor-deficient mice. Biol Reprod 2003;69:195–201. [CrossRef]
27. Jia Y, Li T, Huang X, Xu X, Zhou X, Jia L, et al. Dysregulated DNA Methyltransferase 3A Upregulates IGFBP5 to Suppress Trophoblast Cell Migration and Invasion in Preeclampsia. Hypertension 2017;69:356–66. [CrossRef]
28. Paiva P, Salamonsen LA, Manuelpillai U, Walker C, Tapia A, Wallace EM, et al. Interleukin-11 promotes migration, but not proliferation, of human trophoblast cells, implying a role in placentation. Endocrinology 2007;148:5566–72. [CrossRef]
29. Yang Y, Zhang J, Gong Y, Liu X, Bai Y, Xu W, et al. Increased expression of prostasin contributes to early-onset severe preeclampsia through inhibiting trophoblast invasion. J Perinatol 2015;35:16–22. [CrossRef]
30. Mukherjee S, James JL, Thilaganathan B, Whitley GS, Michael AE, Cartwright JE. Elevated glucocorticoid metabolism in placental tissue from first trimester pregnancies at increased risk of pre-eclampsia. Placenta 2011;32:687–93. [CrossRef]