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.

Context: Chorioamnionitis (CAM)-elicited preterm delivery (PTD) is associated with elevated amniotic fluid levels of IL-1␤ and TNF-␣. We hypothesized that IL-1␤ and TNF-␣ may induce matrix metalloproteinase (MMP)-1 and MMP-3 activity to promote PTD by degrading decidual and fetal membranes and cervical extracellular matrix.Objective: Our objective was to evaluate: 1) MMP-1 and MMP-3 expression in decidual sections from uncomplicated term, idiopathic preterm, and CAM-complicated deliveries, and 2) the separate and interactive effects of IL-1␤, TNF-␣, medroxyprogesterone acetate (MPA), and a p38 MAPK inhibitor (SB203580) on MMP-1 and MMP-3 expression in term decidual cells (DCs). Interventions and Main Outcome Measures:Decidua were immunostained for MMP-1 and MMP-3. Cultured term DCs were incubated with estradiol (E2) or E2 plus MPA with or without IL-1␤ or TNF-␣ with or without SB203580. ELISA and Western blotting assessed secreted MMP-1 and MMP-3 levels, quantitative real-time RT-PCR assessed mRNA levels, and substrate gel zymography was used to determined MMP-1 and MMP-3 proteolytic activity.Results: MMP-1 and MMP-3 immunostaining was more prominent in CAM-complicated decidua vs. control preterm and term decidual specimens (P Ͻ 0.05). Compared with basal outputs by DCs incubated with E2, TNF-␣ enhanced MMP-1 and MMP-3 secretion by 14 Ϯ 3-and 9 Ϯ 2-fold, respectively, and IL-1␤ increased MMP-1 and MMP-3 secretion by 13 Ϯ 3-and 19 Ϯ 2-fold, respectively (P Ͻ 0.05). Addition of MPA lowered basal MMP-1 and MMP-3 outputs by 70%, whereas the TNF-␣-and IL-1␤-enhanced MMP-1 and MMP-3 levels were blunted by more than 50% (P Ͻ 0.05). SB203580 suppressed TNF-␣-and IL-1␤-induced MMP-1 and MMP-3 secretion by severalfold. Western blotting confirmed the ELISA results, and mRNA levels corresponded with MMP-1 and MMP-3 protein levels. MMP-1 and MMP-3 proteolytic activity was confirmed by substrate gel zymography. Conclusion