Role of Endoplasmic Reticulum Stress in Proinflammatory Cytokine-Mediated Inhibition of Trophoblast Invasion in Placenta-Related Complications of Pregnancy.
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Authors
Lee, Cheuk-Lun
Veerbeek, Jan HW
Rana, Tirtha K
van Rijn, Bas B
Burton, Graham J
Yung, Hong Wa
Publication Date
2019-02Journal Title
Am J Pathol
ISSN
0002-9440
Publisher
Elsevier BV
Volume
189
Issue
2
Pages
467-478
Language
eng
Type
Article
This Version
VoR
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Lee, C., Veerbeek, J. H., Rana, T. K., van Rijn, B. B., Burton, G. J., & Yung, H. W. (2019). Role of Endoplasmic Reticulum Stress in Proinflammatory Cytokine-Mediated Inhibition of Trophoblast Invasion in Placenta-Related Complications of Pregnancy.. Am J Pathol, 189 (2), 467-478. https://doi.org/10.1016/j.ajpath.2018.10.015
Abstract
Shallow extravillous trophoblast (EVT) invasion is central to the pathophysiology of many pregnancy complications. Invasion is mediated partially by matrix metalloproteinases (MMPs). MMP-2 is highly expressed in early pregnancy. MMP activity can be regulated by proinflammatory cytokines, which also induce endoplasmic reticulum (ER) stress in other cells. We investigated whether proinflammatory cytokines regulate MMP-2 activity through ER stress response pathways in trophoblast before exploring potential regulatory mechanisms. There was increased immunoreactivity of heat shock 70-kDa protein 5, also known as 78-kDa glucose regulated protein, in cells of the placental bed, including EVTs, in cases of early-onset preeclampsia compared with normotensive controls. Treating EVT-like JEG-3 and HTR8/SVneo cells with ER stress inducers (tunicamycin and thapsigargin) suppressed MMP2 mRNA and protein expression, secretion, and activity and reduced their invasiveness. A cocktail of proinflammatory cytokines (IL-1β, tumor necrosis factor-α, and interferon-γ) suppressed MMP-2 activity in JEG-3 cells and was accompanied by activation of the PKR-like ER kinase (PERK)-eukaryotic translation initiation factor 2A (EIF2A) arm of the ER stress pathway. Knockdown of ATF4, a downstream transcriptional factor of the PERK-EIF2A pathway, by small interference RNA, restored MMP2 expression but not cellular proteins. However, suppression of EIF2A phosphorylation with a PERK inhibitor, GSK2606414, under ER stress, restored MMP-2 protein. ER stress regulates MMP-2 expression at both the transcriptional and translational levels. This study provides the first mechanistic linkage by which proinflammatory cytokines may modulate trophoblast invasion through ER stress pathways.
Keywords
Cell Line, Tumor, Cytokines, Endoplasmic Reticulum Stress, Female, Gene Expression Regulation, Humans, MAP Kinase Signaling System, Pre-Eclampsia, Pregnancy, Pregnancy Proteins, Trophoblasts
Sponsorship
This work was funded by the Wellcome Trust (084804/2/08/Z) to GJB. C.L. Lee was partially supported by the University of Hong Kong / China Medical Board Grants and a Doris Zimmern HKU-Cambridge Hughes Hall Fellowship.
Funder references
Wellcome Trust (084804/Z/08/Z)
Identifiers
External DOI: https://doi.org/10.1016/j.ajpath.2018.10.015
This record's URL: https://www.repository.cam.ac.uk/handle/1810/286583
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