IL-1β Inhibits Connexin 43 and Disrupts Decidualization of Human Endometrial Stromal Cells Through ERK1/2 and P38 MAP Kinase

Overview

Journal Endocrinology

Publisher Oxford University Press

Specialty Endocrinology

Date 2017 Sep 23

PMID 28938400

Citations 23

Authors

Jie Yu

Sarah L Berga

Wei Zou

D Grace Yook

Joshua C Pan

Aurora Arroyo Andrade

Lijuan Zhao

Neil Sidell

Indrani C Bagchi

Milan K Bagchi

Robert N Taylor

Affiliations

Soon will be listed here.

Abstract

Inflammation can interfere with endometrial receptivity. We examined how interleukin 1β (IL-1β) affects expression of the uterine gap junction protein connexin 43 (Cx43), which is known to be critical for embryonic implantation. We used an in vitro model of human endometrial stromal cells (ESCs), Western blotting, and a combination of validated, selective kinase inhibitors to evaluate five canonical IL-1β signaling pathways. Cx43 and two other markers of ESC differentiation (prolactin and VEGF) were inhibited predominantly via IL-1β-activated ERK1/2 and p38 MAP kinase cascades. The findings were corroborated using small interfering RNA to silence critical genes in either pathway. By contrast, upregulation of endogenous pro-IL-1α and pro-IL-1β following recombinant IL-1β treatment was mediated via the Jun N-terminal kinase pathway. The clinicopharmacological significance of our findings is that multiple signaling cascades may need to be neutralized to reverse deleterious effects of IL-1β on human endometrial function.

Citing Articles

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References

Schatz F, Guzeloglu-Kayisli O, Arlier S, Kayisli U, Lockwood C . The role of decidual cells in uterine hemostasis, menstruation, inflammation, adverse pregnancy outcomes and abnormal uterine bleeding. Hum Reprod Update. 2016; 22(4):497-515. PMC: 4917742. DOI: 10.1093/humupd/dmw004. View

Gellersen B, Brosens I, Brosens J . Decidualization of the human endometrium: mechanisms, functions, and clinical perspectives. Semin Reprod Med. 2007; 25(6):445-53. DOI: 10.1055/s-2007-991042. View

Konno R, Fujiwara H, Netsu S, Odagiri K, Shimane M, Nomura H . Gene expression profiling of the rat endometriosis model. Am J Reprod Immunol. 2007; 58(4):330-43. DOI: 10.1111/j.1600-0897.2007.00507.x. View

Bren G, Solan N, Miyoshi H, Pennington K, Pobst L, Paya C . Transcription of the RelB gene is regulated by NF-kappaB. Oncogene. 2001; 20(53):7722-33. DOI: 10.1038/sj.onc.1204868. View

Shifren J, Tseng J, Zaloudek C, Ryan I, Meng Y, Ferrara N . Ovarian steroid regulation of vascular endothelial growth factor in the human endometrium: implications for angiogenesis during the menstrual cycle and in the pathogenesis of endometriosis. J Clin Endocrinol Metab. 1996; 81(8):3112-8. DOI: 10.1210/jcem.81.8.8768883. View

Romero R, Dey S, Fisher S . Preterm labor: one syndrome, many causes. Science. 2014; 345(6198):760-5. PMC: 4191866. DOI: 10.1126/science.1251816. View

Ramathal C, Bagchi I, Taylor R, Bagchi M . Endometrial decidualization: of mice and men. Semin Reprod Med. 2010; 28(1):17-26. PMC: 3095443. DOI: 10.1055/s-0029-1242989. View

Hornung D, Klingel K, DOHRN K, Kandolf R, Wallwiener D, Taylor R . Regulated on activation, normal T-cell-expressed and -secreted mRNA expression in normal endometrium and endometriotic implants: assessment of autocrine/paracrine regulation by in situ hybridization. Am J Pathol. 2001; 158(6):1949-54. PMC: 1891998. DOI: 10.1016/S0002-9440(10)64664-0. View

Fitzgerald H, Salamonsen L, Rombauts L, Vollenhoven B, Edgell T . The proliferative phase underpins endometrial development: Altered cytokine profiles in uterine lavage fluid of women with idiopathic infertility. Cytokine. 2016; 88:12-19. DOI: 10.1016/j.cyto.2016.08.001. View

10.

Makrigiannakis A, Petsas G, Toth B, Relakis K, Jeschke U . Recent advances in understanding immunology of reproductive failure. J Reprod Immunol. 2011; 90(1):96-104. DOI: 10.1016/j.jri.2011.03.006. View

11.

Velarde M, Aghajanova L, Nezhat C, Giudice L . Increased mitogen-activated protein kinase kinase/extracellularly regulated kinase activity in human endometrial stromal fibroblasts of women with endometriosis reduces 3',5'-cyclic adenosine 5'-monophosphate inhibition of cyclin D1. Endocrinology. 2009; 150(10):4701-12. PMC: 2754675. DOI: 10.1210/en.2009-0389. View

12.

Mendelson C . Minireview: fetal-maternal hormonal signaling in pregnancy and labor. Mol Endocrinol. 2009; 23(7):947-54. PMC: 2703595. DOI: 10.1210/me.2009-0016. View

13.

Yu J, Berga S, Johnston-MacAnanny E, Sidell N, Bagchi I, Bagchi M . Endometrial Stromal Decidualization Responds Reversibly to Hormone Stimulation and Withdrawal. Endocrinology. 2016; 157(6):2432-46. PMC: 4891781. DOI: 10.1210/en.2015-1942. View

14.

Liu X, Ye F, Xiong H, Hu D, Limb G, Xie T . IL-1β Upregulates IL-8 Production in Human Müller Cells Through Activation of the p38 MAPK and ERK1/2 Signaling Pathways. Inflammation. 2014; 37(5):1486-95. DOI: 10.1007/s10753-014-9874-5. View

15.

Tseng J, Ryan I, Milam T, Murai J, Schriock E, Landers D . Interleukin-6 secretion in vitro is up-regulated in ectopic and eutopic endometrial stromal cells from women with endometriosis. J Clin Endocrinol Metab. 1996; 81(3):1118-22. DOI: 10.1210/jcem.81.3.8772585. View

16.

Bergqvist A, Bruse C, Carlberg M, Carlstrom K . Interleukin 1beta, interleukin-6, and tumor necrosis factor-alpha in endometriotic tissue and in endometrium. Fertil Steril. 2001; 75(3):489-95. DOI: 10.1016/s0015-0282(00)01752-0. View

17.

Ryan I, Schriock E, Taylor R . Isolation, characterization, and comparison of human endometrial and endometriosis cells in vitro. J Clin Endocrinol Metab. 1994; 78(3):642-9. DOI: 10.1210/jcem.78.3.8126136. View

18.

Noyes R, HAMAN J . Accuracy of endometrial dating; correlation of endometrial dating with basal body temperature and menses. Fertil Steril. 1953; 4(6):504-17. DOI: 10.1016/s0015-0282(16)31446-7. View

19.

Irwin J, Las Fuentes L, Giudice L . Growth factors and decidualization in vitro. Ann N Y Acad Sci. 1994; 734:7-18. DOI: 10.1111/j.1749-6632.1994.tb21730.x. View

20.

Huang F, Cao J, Liu Q, Zou Y, Li H, Yin T . MAPK/ERK signal pathway involved expression of COX-2 and VEGF by IL-1β induced in human endometriosis stromal cells in vitro. Int J Clin Exp Pathol. 2013; 6(10):2129-36. PMC: 3796235. View