Matrix Metalloproteinase 9 (MMP9) Expression in Preeclamptic Decidua and MMP9 Induction by Tumor Necrosis Factor Alpha and Interleukin 1 Beta in Human First Trimester Decidual Cells1

Abstract

Extravillous trophoblasts (EVTs) invade human decidua via sequential integrin-mediated binding and proteolysis of basement membrane proteins in the extracellular matrix (ECM). In preeclampsia, shallow EVT invasion impairs spiral artery and arteriole remodeling to reduce uteroplacental blood flow. Excess decidual cell-expressed matrix metalloproteinases (MMPs) 2 and 9, in response to preeclampsia-related interleukin 1 beta (IL1B) and tumor necrosis factor alpha (TNF), may inappropriately degrade these basement membrane proteins and impede EVT invasion. This study found significantly higher immunohistochemical MMP9 levels in decidual cells and adjacent interstitial trophoblasts in placental sections of preeclamptic versus gestational age-matched control women. In contrast, immunostaining for MMP2 and tissue inhibitor of matrix metalloproteinases 1 and 2 (TIMP1 and TIMP2) were similar in preeclamptic and control groups. First-trimester decidual cells were incubated with estradiol (E(2)) or E(2) + medroxyprogesterone acetate (MPA), with or without TNF or IL1B. As measured by ELISA, both cytokines elicited concentration-dependent increases in secreted MMP9 levels that were unaffected by MPA. In contrast, secreted levels of MMP2, TIMP1, and TIMP2 were unchanged in all treatment groups. Substrate gel zymography and Western blotting confirmed that each cytokine increased secreted levels of MMP9 but not MMP2. Similarly, quantitative RT-PCR found that TNF and IL1B enhanced MMP9, but not MMP2, mRNA levels. At the implantation site, inflammatory cytokine-enhanced MMP9 may promote preeclampsia by disrupting the decidual ECM to interfere with normal stepwise EVT invasion.

Imbalance between matrix metalloproteinases and their tissue inhibitors in preeclampsia and gestational trophoblastic diseases

“…In this study, the development of preeclampsia was found to be associated with deregulation in the levels of H3K9/27me3, showing increased levels of H3K9me3 and both H3K9/27me3 associated with low expression of MMP2 and MMP9 respectively. These results support the documented deficient expression of MMP2 and MMP9, in preeclampsia (Lockwood et al 2008, Zhang et al 2011. MMPs also play important role in controlling the bioactivity of growth factors, angiogenic factors, cytokines (Staun-Ram & Shalev 2005), and release of VEGF (Monaco et al 2006), thus their deficient expression in preeclampsia might also be hampering the VEGF release, as supported by lower levels of VEGF reported in preeclampsia (Levine et al 2004).…”

Weakening and Rupture of Human Fetal Membranes – Biochemistry and Biomechanics

“…TNF and IL-1 specifically have been shown to induce apoptosis, induce MMP 9 and increase PGE 2 production in chorioamnion and cultured primary amnion cells (R.M. Moore et al, 2009b;Runic et al, 1998;Fortunato et al, 2001;Furuta et al, 2000;LundinSchiller et al, 1991;Garcia-Lloret et al, 1996;Lockwood et al, 2008). We previously reported that several physiological agents and reactive oxygen species (hydrogen peroxide) induce apoptosis with concomitant PGE 2 release in amnion derived WISH cells, primary amnion cells and intact amnion (Kumar et al, 2004(Kumar et al, a, 2004.…”

TNFR1 mediates TNF-α-induced tumour lymphangiogenesis and metastasis by modulating VEGF-C-VEGFR3 signalling

“…TNF-a induces EMT transition in epithelial carcinomas and thus promotes tumour invasion 41 , and promotes tumour invasion by activation of MMPs such as MMP9 (ref. 42). In a recent study, it has been shown that soluble and membrane-bound TNF-a may display opposing effects on tumour growth and tumour-associated myeloid cells 43 .…”