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Epidermal Growth Factor and Interleukin-1ß Utilize Divergent Signaling Pathways to Synergistically Upregulate Cyclooxygenase-2 Gene Expression in Human Amnion-Derived WISH Cells¹

Department of Obstetrics and Gynecology (Division of Maternal-Fetal Medicine and Laboratory of Perinatal Research),³ Department of Internal Medicine (Division of Nephrology and Dorothy M. Davis Heart and Lung Research Institute),⁴ The Ohio State University, College of Medicine and Public Health, Columbus, Ohio 43210

In human parturition, uterotonic prostaglandins (PGs) arise predominantly via increased expression of cyclooxygenase-2 (COX-2 [also known as prostaglandin synthase 2]) within intrauterine tissues. Interleukin-1 (IL-1) and epidermal growth factor (EGF), both inducers of COX-2 transcription, are among numerous factors that accumulate within amniotic fluid with advancing gestation. It was previously demonstrated that EGF could potentiate IL-1ß-driven PGE₂ production in amnion and amnion-derived (WISH) cells. To define the mechanism for this observation, we hypothesized that EGF and IL-1ß might exhibit synergism in regulating COX-2 gene expression. In WISH cells, combined treatment with EGF and IL-1ß resulted in a greater-than-additive increase in COX-2 mRNA relative to challenge with either agent independently. Augmentation of IL-1ß-induced transactivation by EGF was not observed in cells harboring reporter plasmids bearing nuclear factor-kappa B (NFB) regulatory elements alone, but was evident when a fragment (–891/ +9) of the COX-2 gene 5'-promoter was present. Both agents transiently activated intermediates of multiple signaling pathways potentially involved in the regulation of COX-2 gene expression. The 26 S proteasome inhibitor, MG-132, selectively abrogated IL-1ß-driven NFB activation and COX-2 mRNA expression. Only pharmacologic blockade of the p38 mitogen-activated protein kinase eliminated COX-2 expression following EGF stimulation. We conclude that EGF and IL-1ß appear to signal through different signaling cascades leading to COX-2 gene expression. IL-1ß employs the NFB pathway predominantly, while the spectrum of EGF signaling is broader and includes p38 kinase. The synergism observed between IL-1ß and EGF does not rely on augmented NFB function, but rather, occurs through differential use of independent response elements within the COX-2 promoter.

¹ Supported in part by NIH grant RO1 HD35881 (D.A.K.) and The Ohio State University Perinatal Research and Development Fund. Portions of this work were presented at the 49th Annual Meeting of the Society for Gynecologic Investigation in Los Angeles, California, March 20–23, 2002, and the 51st Annual Meeting of the Society for Gynecologic Investigation in Houston, Texas, March 24–27, 2004.

² Correspondence: Douglas A. Kniss, Laboratory of Perinatal Research, Department of Obstetrics and Gynecology, The Ohio State University, 5th Floor Means Hall, 1654 Upham Drive, Columbus, OH 43210. FAX: 614 293 5728; kniss.1{at}osu.edu