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.
Highlights
Shallow extravillous trophoblast (EVT) invasion is central to the pathophysiology of many pregnancy complications
Immunohistochemistry was performed for HSPA5 and cytokeratin 7 (CK7) on serial sections to confirm the existence of high level of endoplasmic reticulum (ER) stress in EVTs within placental
ATF4 nuclear localization was largely absent in the presence of GSK2606414, whereas there was clearly nuclear staining of ATF4 in untreated cells on ER stress (Figure 5F). These results strongly suggest that the expression of matrix metalloproteinases (MMPs)-2 is regulated both transcriptionally and translationally by the PKR-like ER kinase (PERK)-eeukaryotic translation initiation factor 2A (EIF2A)-ATF4 pathway in response to ER stress
Summary
Shallow extravillous trophoblast (EVT) invasion is central to the pathophysiology of many pregnancy complications. Proinflammatory cytokines have been demonstrated to suppress trophoblast migration,[8] invasion,[19] and integration,[20] resulting in deficient spiral artery remodeling.21e23 The major source of proinflammatory cytokines in the decidua is the immune cells, of which approximately 70% are decidual natural killer cells and approximately 20% are macrophages.[24] Decidual natural killer cells have a unique phenotype and properties compared with their peripheral blood counterparts and secrete cytokines and other soluble factors to modulate implantation, placental function, and fetal development Aberrant behavior of these cells has been suggested to contribute to the pathogenesis of preeclampsia.25e30 the mechanisms by which these cytokines inhibit trophoblast invasion remain unknown.[31] Coincidently, proinflammatory cytokines induce ER stress in other mammalian cell types.32e34 we investigated the potential role of ER stress in the regulation of trophoblast MMP-2 activity, thereby modulating EVT invasion during early pregnancy
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