The Effect of Mechanical Stretch on Cyclooxygenase Type 2 Expression and Activator Protein-1 and Nuclear Factor-κB Activity in Human Amnion Cells

Abstract

Stretch of the uterus plays a role in parturition. Uterine stretch also leads to stretch of the fetal membranes, including the amnion, an important source of prostaglandin E2 (PGE2). We tested the hypothesis that stretch of the amnion leads to increased cyclooxygenase (COX)-2 expression and PGE2 synthesis and investigated the mechanisms involved. We obtained amnion from women undergoing term elective cesarean section and isolated amnion epithelial cells. These cells were subjected to 11% static stretch. Stretch increased COX-2 expression and PGE2 production. EMSA studies showed that stretch increased both activator protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB) DNA binding at 1 and 6 h. In contrast, IL-1beta increased both AP-1 and NF-kappaB DNA binding at 1 h only. Chromatin immunoprecipitation studies confirmed that stretch increased binding of NF-kappaB to the COX-2 promoter in vivo. Stretch had no effect on inhibitory-kappaBalpha (IkappaBalpha) levels at the early time points but caused a decrease at 4 h. IL-1beta stimulation decreased IkappaBalpha levels after 30 min. MG132, a proteasome inhibitor, inhibited only the second stretch-induced increase in NF-kappaB binding. This suggests that stretch initially activates NF-kappaB via a nonclassical pathway, which does not involve the inhibitory-kappa kinase-induced degradation of IkappaBalpha. The second peak of NF-kappaB activation may be mediated by the classical mechanism. Stretch of the amnion may contribute to increased expression of COX-2- and other AP-1- and NF-kappaB-regulated genes with the onset of labor in the human.

Mechano-Sensitive Transcriptional Factor Egr-1 Regulates Insulin-Like Growth Factor-1 Receptor Expression and Contributes to Neointima Formation in Vein Grafts

“…As shown in Figure I, mechanical stretch also significantly increased NF-B transcriptional activity (4.0Ϯ0.6-fold vs control; without mechanical stretch; nϭ4), consistent with other reports. 19,20 The effect of mechanical stretch on activation of both Egr-1 and NF-B is specific because mechanical stretch did not increase other transcriptional factor activity. Next, we examined if Egr-1 regulates IGF-1R expression in vein grafts when mechanical stretch is high.…”

Advances in the role of oxytocin receptors in human parturition

“…Increased PG synthesis occurs first in the region overlying the cervix where it is thought to mediate cervical ripening and dilation. Mechanical stretch of human amnion epithelial cells has been shown to lead to the activation of AP-1 and NF-κB systems and in turn, increase COX-2 and PG expression [47]. PGs have been shown to play a role in placental separation M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT [48], fetal membrane rupture by inducing matrix metalloproteinase (MMP) activity [49], and promoting myometrial contractility.…”

Role of heme oxygenase-1 in inflammatory response induced by mechanical stretch in synovial cells

“…Inflammatory mediators such as interleukin-1b (IL-1b), tumor necrosis factor-a (TNF-a), and prostaglandin E 2 (PGE 2 ) have been detected in synovial fluid samples from patients with joint disorders [4][5][6]. In addition, Mohan et al [7] reported that mechanical stretch induced the expression of cyclooxygenase-2 (COX-2) during the biochemical events involved in parturition, which resemble inflammatory reactions.…”