title: Interferon-γ protects first-trimester decidual cells against aberrant matrix metalloproteinases 1, 3, and 9 expression in preeclampsia.
abstract: Human extravillous trophoblast (EVT) invades the decidua via integrin receptors and subsequently degrades extracellular matrix proteins. In preeclampsia (PE), shallow EVT invasion elicits incomplete spiral artery remodeling, causing reduced uteroplacental blood flow. Previous studies show that preeclamptic decidual cells, but not interstitial EVTs, display higher levels of extracellular matrix-degrading matrix metalloproteinase (MMP)-9, but not MMP-2. Herein, we extend our previous PE-related assessment of MMP-2 and MMP-9 to include MMP-1, which preferentially degrades fibrillar collagens, and MMP-3, which can initiate a local proteolytic cascade. In human first-trimester decidual cells incubated with estradiol, tumor necrosis factor-α (TNF-α) significantly enhanced MMP-1, MMP-3, and MMP-9 mRNA and protein levels and activity measured by real-time quantitative RT-PCR, ELISA, immunoblotting, and zymography, respectively. In contrast, interferon γ (IFN-γ) reversed these effects and medroxyprogesterone acetate elicited further reversal. Immunoblotting revealed that p38 mitogen-activated protein kinase signaling mediated TNF-α enhancement of MMP-1, MMP-3, and MMP-9, whereas IFN-γ inhibited p38 mitogen-activated protein kinase phosphorylation. Unlike highly regulated MMP-1, MMP-3, and MMP-9, MMP-2 mRNA and protein expression was constitutive in decidual cells. Because inflammation underlies PE-associated shallow EVT invasion, these results suggest that excess macrophage-derived TNF-α augments expression of MMP-1, MMP-3, and MMP-9 in decidual cells to interfere with normal stepwise EVT invasion of the decidua. In contrast, decidual natural killer cell-derived IFN-γ reverses such TNF-α-induced MMPs to protect against PE.
authors: Department of Obstetrics and Gynecology, The Ohio State University College of Medicine, Columbus, Ohio. Electronic address: charles.lockwood@osumc.edu.
authors: Charles J
authors: CJ
authors: Lockwood
authors: Department of Obstetrics and Gynecology, The Ohio State University College of Medicine, Columbus, Ohio.
authors: Murat
authors: M
authors: Basar
authors: Department of Obstetrics and Gynecology, The Ohio State University College of Medicine, Columbus, Ohio.
authors: Umit A
authors: UA
authors: Kayisli
authors: Department of Obstetrics and Gynecology, The Ohio State University College of Medicine, Columbus, Ohio.
authors: Ozlem
authors: O
authors: Guzeloglu-Kayisli
authors: Department of Chronic Disease Epidemiology, School of Public Health, Yale University, New Haven, Connecticut.
authors: William
authors: W
authors: Murk
authors: Department of Obstetrics and Gynecology, School of Medicine, Yale University, New Haven, Connecticut.
authors: Jenny
authors: J
authors: Wang
authors: Department of Obstetrics and Gynecology, School of Medicine, Yale University, New Haven, Connecticut.
authors: Nicole
authors: N
authors: De Paz
authors: Department of Obstetrics and Gynecology, The Ohio State University College of Medicine, Columbus, Ohio.
authors: John P
authors: JP
authors: Shapiro
authors: Beth Israel Medical Center, Albert Einstein College of Medicine, New York, New York.
authors: Rachel J
authors: RJ
authors: Masch
authors: Department of Obstetrics and Gynecology, The Ohio State University College of Medicine, Columbus, Ohio.
authors: Nihan
authors: N
authors: Semerci
authors: Department of Obstetrics and Gynecology, The Ohio State University College of Medicine, Columbus, Ohio.
authors: S Joseph
authors: SJ
authors: Huang
authors: Department of Obstetrics and Gynecology, The Ohio State University College of Medicine, Columbus, Ohio.
authors: Frederick
authors: F
authors: Schatz
mesh_terms: D015153:Blotting, Western; D003656:Decidua / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D053505:Matrix Metalloproteinases, Secreted / Q000032:analysis / Q000096:biosynthesis*; D011225:Pre-Eclampsia / Q000378:metabolism*; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D007371:Interferon-gamma; D053505:Matrix Metalloproteinases, Secreted; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1