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Paradoxical Stimulation of Cyclooxygenase-2 Expression by Glucocorticoids via a Cyclic AMP Response Element in Human Amnion Fibroblasts

School of Life Sciences (X.O.Z., Z.Y., C.M.G., J.N.L., K.S.), Fudan University, Shanghai 200433, People’s Republic of China; Shanghai First Maternity and Infant Health Hospital (X.T.N., Y.C.G.), Shanghai 20040, People’s Republic of China; and Department of Obstetrics and Gynecology (L.M.), University of Texas Health Science Center at San Antonio, Texas 78229

Address all correspondence and requests for reprints to: Kang Sun, M.D., Ph.D., School of Life Sciences, Fudan University, 220 Handan Road, Shanghai 200433, People’s Republic of China. E-mail: sungang{at}fudan.edu.cn.

Human amnion fibroblasts produce abundant prostaglandins toward the end of gestation, which is one of the major events leading to parturition. In marked contrast to its well-described antiinflammatory effect, glucocorticoids have been shown to up-regulate cyclooxygenase-2 (COX-2) expression in human amnion fibroblasts. The mechanisms underlying this paradoxical induction of COX-2 by glucocorticoids have not been resolved. Using cultured human amnion fibroblasts, we found that the induction of COX-2 mRNA expression by cortisol was a glucocorticoid receptor (GR)-dependent process requiring ongoing transcription. Upon transfection of a COX-2 promoter-driven reporter gene into the amnion fibroblasts, cortisol stimulated the COX-2 promoter activity. This was abolished by mutagenesis of a cAMP response element (CRE) at –53 to approximately –59bp as well as by cotransfection of a plasmid expressing dominant-negative CRE-binding protein (CREB). The phosphorylation level of CREB-1 was significantly increased by cortisol treatment of the amnion fibroblasts, whereas the effect was attenuated either by the protein kinase A inhibitor H89 or the p38 -MAPK inhibitor SB203580. The induction of the COX-2 promoter activity and the phosphorylation of CREB-1 were also blocked by the GR antagonist RU486. Chromatin immunoprecipitation (ChIP) assay revealed that the binding of CREB-1 to the CRE of the COX-2 promoter was increased by cortisol treatment of the amnion fibroblasts. In conclusion, cortisol, via binding to GR, stimulated COX-2 expression by increasing phosphorylated CREB-1 binding to the CRE of the COX-2 gene. Cortisol may phosphorylate CREB-1 by activating either protein kinase A or p38-MAPK in the amnion fibroblasts.

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Nuclear Receptors:   GR

Ligands:   Hydrocortisone  |  RU486