Abstract
Preterm premature rupture of membranes is a leading cause of preterm births. Cytokine induced matrix metalloproteinase1 and interleukin 8 production from amnion mesenchymal cells may contribute to fetal membrane weakening and rupture. Progestins inhibit inflammation induced fetal membrane weakening but their effect on the inflammatory response of amnion mesenchymal cells is unknown. This study was designed to determine the role of progesterone receptor membrane component 1 and the glucocorticoid receptor in mediating the effects of progestins on interleukin-1β induced matrix metalloproteinase 1 and interleukin-8 expression in human amnion mesenchymal cells. Primary amnion mesenchymal cells harvested from human fetal membranes were passaged once and treated with vehicle, progesterone or medroxyprogesterone acetate at 10–6 M for 1 h followed by stimulation with interleukin-1β at 1 ng/ml for 24 h. Medroxyprogesterone acetate but not progesterone inhibited interleukin-1β-induced interlukin-8 and matrix metalloproteinase 1 mRNA expression. In subsequent dose response studies, medroxyprogesterone acetate, but not progesterone, at doses of 10–6–10–8 M inhibited interleukin-1β induced interleukin-8 and matrix metalloproteinase 1 mRNA expression. We further demonstrated that inhibition of glucocorticoid receptor expression, but not progesterone receptor membrane component 1 knockdown with small interfering RNA transfection, resulted in a reversal in medroxyprogesterone acetate’s (10–7 M) inhibition of interleukin-1β- induced matrix metalloproteinase 1 mRNA expression and interleukin-8 mRNA expression and protein expression. Our findings demonstrate that medroxyprogesterone acetate exerts its anti-inflammatory effect primarily through the glucocorticoid receptor in human amnion mesenchymal cells. Modulation of glucocorticoid receptor signaling pathways maybe a useful therapeutic strategy for preventing inflammation induced fetal membrane weakening leading to preterm premature rupture of membranes.
Highlights
Preterm birth (PTB) remains a major public health problem in the United States
When glucocorticoid receptor (GR) was primarily expressed in the cytoplasm there was no evidence of co-localization with progesterone receptor membrane component 1 (PGRMC1) (Figure 1G)
Our findings demonstrate that medroxyprogesterone acetate (MPA) but not P4 inhibit IL1βinduced matrix metalloproteinase 1 (MMP1) mRNA expression and interleukin 8 (IL8) mRNA levels and secreted protein levels through GR and not through PGRMC1 in amnion mesenchymal cells
Summary
Preterm birth (PTB) remains a major public health problem in the United States. Despite a slight decline in PTB rates from 2007 to 2014, rates have continued to increase in non-hispanic black women (Martin et al, 2017). Preterm premature rupture of membranes contributes significantly to perinatal morbidity and mortality, from adverse effects of prematurity and expectant management, increasing the risks of perinatal infections, placental abruption, umbilical cord prolapse, neonatal respiratory morbidity and adverse neurodevelopmental outcomes (Hadi et al, 1994; Lewis et al, 2007; Lee et al, 2010; Storness-Bliss et al, 2012; Korzeniewski et al, 2014; Ekin et al, 2015). The pathophysiology of PPROM involves the remodeling in fetal membranes of the extracellular matrix (ECM) in response to inflammation (Kumar et al, 2006). This inflammation induced ECM remodeling leads to fetal membrane weakening and rupture. Inflammatory cytokines induce MMP1 expression and activity in amnion mesenchymal cells which contributes to collagen degradation in the amnion leading to fetal membrane weakening and PPROM. Evidence suggesting that MMP1 plays a key role in PPROM include: elevated levels of MMP1 have been detected in the amniotic fluid of PPROM patients in both the presence and absence of infection (Maymon et al, 2000), a single nucleotide polymorphism in the promoter region of the MMP1 gene is associated with an increased risk of PPROM and changes in DNA methylation in the promotor region of the MMP1 gene have been associated with an increased risk of PPROM (Wang et al, 2008)
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