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