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This Article Full Text Full Text (PDF) All Versions of this Article: 78/1/193    most recent biolreprod.107.063990v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Guo, C. Articles by Sun, K. Search for Related Content PubMed PubMed Citation Articles by Guo, C. Articles by Sun, K. Agricola Articles by Guo, C. Articles by Sun, K.

Paradox of Glucocorticoid-Induced Cytosolic Phospholipase A2 Group IVA Messenger RNA Expression Involves Glucocorticoid Receptor Binding to the Promoter in Human Amnion Fibroblasts¹

School of Life Sciences,³ Fudan University, Shanghai 200433, People's Republic of China Maternal and Fetal Care Hospital of Changning District,⁴ Shanghai 200051, People's Republic of China Department of Obstetrics and Gynecology,⁵ No. 401 Hospital, Qingdao 266100, People's Republic of China Department of Obstetrics and Gynecology,⁶ College of Medicine, University of Cincinnati, Cincinnati, Ohio 45267

ABSTRACT

Glucocorticoids (GCs) are well-known anti-inflammatory drugs inhibiting prostaglandin production. Paradoxically, GCs are reported to stimulate cytosolic phosphoplipase A2 group IVA (PLA2G4A) and prostaglandin-endoperoxide synthase 2 (PTGS2) expression in human amnion fibroblasts. This study was designed to examine the molecular mechanisms underlying glucocorticoid-induced PLA2G4A expression in human amnion fibroblasts. Our data showed that cortisol (0.011 µM) increased PLA2G4A mRNA level in a dose-dependent manner in human amnion fibroblasts, which was blocked by glucocorticoid receptor antagonist RU486 (1 µM) as well as by the mRNA transcription inhibitor 5,6-dichlorobenzimidazole riboside (DRB; 75 µM). Concurrently, cortisol (0.011 µM) decreased rather than increased proinflammatory cytokine mRNA levels, including interleukin 1 beta (IL1B), interleukin 6 (IL6), and tumor necrosis factor alpha (TNF), in a dose-dependent manner in human amnion fibroblasts. Chromatin immunoprecipitation assay revealed that glucocorticoid receptor was bound to PLA2G4A promoter in human amnion fibroblasts upon cortisol stimulation. This was confirmed by electrophoretic mobility shift assay showing that nuclear protein extracted from human amnion fibroblasts upon cortisol stimulation could bind the synthesized oligonucleotide sequence corresponding to PLA2G4A promoter region from –95 bp to –65 bp bearing the putative glucocorticoid response element. This binding was super shifted by glucocorticoid receptor antibody. In conclusion, we demonstrated in this study that cortisol increased PLA2G4A mRNA level via GR-dependent ongoing transcription in human amnion fibroblasts by activating the binding of GR to PLA2G4A promoter directly, and this effect appeared unlikely to be secondary to the effect of cortisol on the expression of proinflammatory cytokines in human amnion fibroblasts.

amnion, cortisol, glucocorticoid receptor, parturition, PLA2G4A, placenta, pregnancy, prostaglandin

¹Supported by the National Natural Science Foundation of China (30470655 and 30570680), the Ministry of Education of China (20050246015), and National Institutes of Health RO1 HD31514-10.

Correspondence: ²Kang Sun, School of Life Sciences, Fudan University, 220 Handan Rd., Shanghai 200433, China. FAX: 86 21 65490496; e-mail: sunkang2000{at}yahoo.com