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Role of Endoplasmic Reticulum Stress in Proinflammatory Cytokine-Mediated Inhibition of Trophoblast Invasion in Placenta-Related Complications of Pregnancy.

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cam.issuedOnline2018-11-15
dc.contributor.authorLee, Cheuk-Lun
dc.contributor.authorVeerbeek, Jan HW
dc.contributor.authorRana, Tirtha K
dc.contributor.authorvan Rijn, Bas B
dc.contributor.authorBurton, Graham J
dc.contributor.authorYung, Hong Wa
dc.contributor.orcidBurton, Graham [0000-0001-8677-4143]
dc.contributor.orcidYung, Billy [0000-0002-0869-7426]
dc.date.accessioned2018-12-10T00:30:13Z
dc.date.available2018-12-10T00:30:13Z
dc.date.issued2019-02
dc.description.abstractShallow 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.
dc.description.sponsorshipThis 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.
dc.format.mediumPrint-Electronic
dc.identifier.doi10.17863/CAM.33895
dc.identifier.eissn1525-2191
dc.identifier.issn0002-9440
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/286583
dc.languageeng
dc.language.isoeng
dc.publisherElsevier BV
dc.publisher.urlhttp://dx.doi.org/10.1016/j.ajpath.2018.10.015
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectCell Line, Tumor
dc.subjectCytokines
dc.subjectEndoplasmic Reticulum Stress
dc.subjectFemale
dc.subjectGene Expression Regulation
dc.subjectHumans
dc.subjectMAP Kinase Signaling System
dc.subjectPre-Eclampsia
dc.subjectPregnancy
dc.subjectPregnancy Proteins
dc.subjectTrophoblasts
dc.titleRole of Endoplasmic Reticulum Stress in Proinflammatory Cytokine-Mediated Inhibition of Trophoblast Invasion in Placenta-Related Complications of Pregnancy.
dc.typeArticle
dcterms.dateAccepted2018-10-23
prism.endingPage478
prism.issueIdentifier2
prism.publicationDate2019
prism.publicationNameAm J Pathol
prism.startingPage467
prism.volume189
pubs.funder-project-idWellcome Trust (084804/Z/08/Z)
rioxxterms.licenseref.startdate2019-02
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1016/j.ajpath.2018.10.015

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