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

Imperial College London (A.R.M., T.M.L., P.R.B.), Parturition Research Group, Institute of Reproductive and Developmental Biology, Hammersmith Hospital Campus, London W12 ONN, United Kingdom; and Department of Obstetrics and Gynaecology (S.R.S., M.R.J.), Imperial College, Chelsea Westminster Hospital, London SW10 9NH, United Kingdom

Address all correspondence and requests for reprints to: Dr. A. Mohan, Parturition Research Group, Institute of Reproductive and Developmental Biology, Hammersmith Hospital Campus, Du Cane Road, London W12 ONN, United Kingdom. E-mail: a.mohan{at}imperial.ac.uk.

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-B (NF-B) DNA binding at 1 and 6 h. In contrast, IL-1ß increased both AP-1 and NF-B DNA binding at 1 h only. Chromatin immunoprecipitation studies confirmed that stretch increased binding of NF-B to the COX-2 promoter in vivo. Stretch had no effect on inhibitory-B (IB) levels at the early time points but caused a decrease at 4 h. IL-1ß stimulation decreased IB levels after 30 min. MG132, a proteasome inhibitor, inhibited only the second stretch-induced increase in NF-B binding. This suggests that stretch initially activates NF-B via a nonclassical pathway, which does not involve the inhibitory- kinase-induced degradation of IB. The second peak of NF-B 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-B-regulated genes with the onset of labor in the human.

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