Progestins Inhibit Interleukin-1β-Induced Matrix Metalloproteinase 1 and Interleukin 8 Expression via the Glucocorticoid Receptor in Primary Human Amnion Mesenchymal Cells

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.

Progesterone Suppresses Uterine Contraction by Reducing Odontogenic Porphyromonas gingivalis Induced Chronic Inflammation in Mice

“…Various studies using human amniotic tissue and cells (chorionic villus cells, amnion cells, etc.) have also reported the anti-inflammatory effects of P4 [ 35 , 36 ]. These findings are consistent with our results.…”

“…These findings are consistent with our results. The mechanism by which P4 suppresses inflammation is mediated by receptors such as the classical progesterone receptor, membrane receptor, and glucocorticoid receptor [ 35 , 36 ]. Since we only examined the fetal membrane tissue in this study, it would be necessary to investigate the anti-inflammatory effects of P4 at the cellular level in future studies.…”

Progesterone as an Anti-Inflammatory Drug and Immunomodulator: New Aspects in Hormonal Regulation of the Inflammation

“…Similarly, MPA, unlike NET-A, decreased the expression of the proinflammatory IL-6, IL-8, and RANTES genes, as well as the level of IL-6 and IL-8 proteins. Marinello et al also demonstrated an anti-inflammatory GR-mediated action of MPA [ 75 ]. In primary human amnion mesenchymal cells, MPA had an anti-inflammatory effect via the inhibition of IL-1β-induced MMP-1 and IL-8 expression.…”

“…In primary human amnion mesenchymal cells, MPA had an anti-inflammatory effect via the inhibition of IL-1β-induced MMP-1 and IL-8 expression. This effect of MPA was blocked with the inhibition of glucocorticoid receptor expression by small interfering RNA transfection [ 75 ].…”