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The Mitogen-Activated Protein Kinase Dependent Expression of Prostaglandin H Synthase-2 and Interleukin-8 Messenger Ribonucleic Acid by Myometrial Cells: The Differential Effect of Stretch and Interleukin-1ß

Department of Maternal Fetal Medicine (S.R.S., N.E., M.R.J.), Imperial College Parturition Research Group, Imperial College School of Medicine, Chelsea and Westminster Hospital, London SW10 9NH, United Kingdom; and Institute of Reproductive and Developmental Biology (J.A.Z.L., V.T., P.R.B.), Hammersmith Hospital Campus, London W12 0NN, United Kingdom

Address all correspondence and requests for reprints to: Dr. M. R. Johnson, Imperial College Parturition Research Group, Department of Maternal Fetal Medicine, Imperial College School of Medicine, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, United Kingdom. E-mail: mark.johnson{at}imperial.ac.uk.

Infection and uterine stretch are the common causes of preterm labor. IL-1ß plays a key role in infection-induced preterm labor and increases prostaglandin H synthase 2 (PGHS-2) and IL-8 expression. We have shown that mechanical stretch of uterine myocytes in vitro up-regulates the expression of PGHS-2 and IL-8. In this study, we tested the hypotheses that both IL-1ß and mechanical stretch increase the myometrial expression of PGHS-2 and IL-8 via MAPK activation and that their effects are synergistic. MAPK activation was assessed in myocytes obtained from pregnant women undergoing cesarean section before the onset of labor after exposure to IL-1ß and stretch either alone or in combination. Specific inhibitors of ERK, p38, and c-Jun N-terminal kinase were used to define the role of each in the increased expression of PGHS-2 and IL-8 mRNA. We found that both IL-1ß and stretch activated all three MAPK subtypes but that they had no synergistic effect. The inhibitor studies showed that stretch-induced increases in both PGHS-2 and IL-8 mRNA expression were ERK1/2 and p38 dependent and that IL-1ß-induced increases of PGHS-2 mRNA expression were also ERK1/2 and p38 dependent, but those of IL-8 were dependent only on ERK1/2 activation. These data show that exposure of human uterine myocytes to both stretch and IL-1ß activates the MAPK system, which is responsible for the increase in PGHS-2 and IL-8 mRNA expression. We found no evidence of a synergistic effect of IL-1ß and stretch on myometrial expression of PGHS-2 and IL-8 mRNA.

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