Potent anti-inflammatory effects of honokiol in human fetal membranes and myometrium

Abstract

BackgroundPreterm birth is the most prominent complication attributing to poor pregnancy and neonatal outcome. Infection is most commonly implicated in preterm birth; it initiates a cascade of inflammatory events that leads to the rupture of fetal membranes and spontaneous uterine contractions. Anti-inflammatory agents may thus be a therapeutic approach to prevent the premature rupture of fetal membranes and block contractions. In non-gestational tissues, the polyphenol honokiol has been shown to possess potent anti-inflammatory properties. PurposeThe aim of this study was to investigate the effect of honokiol on pro-inflammatory mediators in human gestational tissues. MethodsFetal membranes, myometrium and freshly isolated amnion cells and primary myometrial cells were treated with honokiol in the absence or presence of the products lipopolysaccharide (LPS) and fibroblast-stimulating lipopeptide-1 (fsl-1), the viral dsRNA analogue polyinosinic:polycytidylic acid (poly(I:C)) or the pro-inflammatory cytokines TNF or IL1B. A luciferase assay was used to determine the effect of honokiol on nuclear factor kappa B (NF-κB) RelA transcriptional activity. ResultsHonokiol significantly decreased pro-inflammatory cytokine (IL1A, IL6) and chemokine (CXCL8, CXCL1, CCL2) mRNA expression and secretion from fetal membranes (amnion and choriodecidua) and myometrium stimulated with LPS, fsl-1 or poly(I:C). In amnion cells, honokiol also significantly decreased the expression and secretion of the extracellular matrix degrading enzyme MMP9. Moreover, in myometrium, honokiol significantly suppressed the expression of the contraction associated protein PTGFR, the secretion of the uterotonic prostaglandins PGE2 and PGF2α, and blocked TNF-induced myometrial cell contractility. Finally, honokiol significantly suppressed IL1B- and TNF-induced NF-κB RelA transcriptional activity in primary amnion and myometrial cells. ConclusionsHonokiol reduced the expression of pro-inflammatory and pro-labour mediators in human amnion, choriodecidua and myometrium and that this may be facilitated through the suppression of NF-κB activation. These results indicate that the polyphenol honokiol may be a potent therapeutic for the prevention of preterm birth.