Objective-To determine if progesterone (P), 17-α-hydroxyprogesterone (17OHP) and 17-α hydroxyprogesterone caproate (17OHPC) modulate the Toll-like receptor (TLR) pathway in the response of decidua to lipopolysaccharide.Study Design-Cultured human decidual cells were incubated under control conditions, lipopolysaccharide alone, or pretreatment with each of the three progestins. Relative expression of 113 genes in the TLR pathway was determined using microarray.Results-We failed to demonstrate a suppression of TLR gene pathway expression in human decidual cells in response to lipopolysaccharide when pretreated with progestins. Pretreatment with each progestin prior to lipopolysaccharide resulted in a relative increase in the expression of the proapoptotic molecule, CASP8. There were no differences among the progestins.Conclusions-Our data do not support suppression of TLR pathways as a mechanism for the benefit of 17OHPC. Increased CASP8 gene expression raises the possibility that progestins "prime" the decidual cell to respond with a NFκB-mediated inflammatory response.
Intra-amniotic infection leads to preterm labor and is associated with the local release of inflammatory cytokines by fetal membranes, resulting in the production of uterotonic prostaglandins. Oxytocin, however, also plays a key role in the initiation of labor. Short-term exposure of myometrium to interleukin (IL)-1 enhances oxytocin signaling and contractility. With intrauterine infection, however, myometrium is exposed to inflammatory cytokines for prolonged periods. The present study was conducted to demonstrate that myometrial oxytocin signaling is significantly impaired following prolonged exposure to IL-1. Myometrial cells were treated with IL-1 for 24 h. Oxytocin-stimulated inositol trisphosphate (IP(3)) production was measured in tritiated myoinositol-loaded myometrial cells. Arachidonic acid (AA) release was measured in tritiated AA-loaded myometrial cells. Increases in intracellular calcium were measure with fluo-3. Prostaglandin (PG) F(2alpha) and 6-keto-PGF(1alpha) were measured by ELISA assay. Prolonged exposure of myometrial cells to IL-1 resulted in a significant reduction in oxytocin-mediated signaling as measured by IP(3) production and AA release, as well as a decrease in intracellular calcium. Prolonged exposure of myometrial cells to IL-1, however, resulted in enhanced PG release. Oxytocin may not contribute significantly to the labor-inducing action of IL-1 in the setting of preterm labor with prolonged infection.
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