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

TitleRole of Endoplasmic Reticulum Stress in Proinflammatory Cytokine–Mediated Inhibition of Trophoblast Invasion in Placenta-Related Complications of Pregnancy
Authors
Issue Date2019
PublisherElsevier Inc. The Journal's web site is located at http://ajp.amjpathol.org/
Citation
The American Journal of Pathology, 2019, v. 189 n. 2, p. 467-478 How to Cite?
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.
Persistent Identifierhttp://hdl.handle.net/10722/275186
ISSN
2023 Impact Factor: 4.7
2023 SCImago Journal Rankings: 1.647
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorLee, CL-
dc.contributor.authorVeerbeek, JHW-
dc.contributor.authorRana, TK-
dc.contributor.authorvan Rijn, BB-
dc.contributor.authorBurton, GJ-
dc.contributor.authorYung, HW-
dc.date.accessioned2019-09-10T02:37:20Z-
dc.date.available2019-09-10T02:37:20Z-
dc.date.issued2019-
dc.identifier.citationThe American Journal of Pathology, 2019, v. 189 n. 2, p. 467-478-
dc.identifier.issn0002-9440-
dc.identifier.urihttp://hdl.handle.net/10722/275186-
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.languageeng-
dc.publisherElsevier Inc. The Journal's web site is located at http://ajp.amjpathol.org/-
dc.relation.ispartofThe American Journal of Pathology-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titleRole of Endoplasmic Reticulum Stress in Proinflammatory Cytokine–Mediated Inhibition of Trophoblast Invasion in Placenta-Related Complications of Pregnancy-
dc.typeArticle-
dc.identifier.emailLee, CL: kcllee@hku.hk-
dc.identifier.authorityLee, CL=rp02515-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1016/j.ajpath.2018.10.015-
dc.identifier.pmid30448406-
dc.identifier.pmcidPMC6360351-
dc.identifier.scopuseid_2-s2.0-85060101208-
dc.identifier.hkuros303073-
dc.identifier.volume189-
dc.identifier.issue2-
dc.identifier.spage467-
dc.identifier.epage478-
dc.identifier.isiWOS:000458713400020-
dc.publisher.placeUnited States-
dc.identifier.issnl0002-9440-

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