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This version published online on October 13, 2004
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2004-1612
A more recent version of this article appeared on January 1, 2005
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Submitted on August 12, 2004
Accepted on October 7, 2004

Distinct Regulation of Cyclooxygenase-2 by Interleukin-1{beta} in Normal and Endometriotic Stromal Cells

Meng-Hsing Wu, Chu-An Wang, Chen-Chung Lin, Lei-Chin Chen, Wen-Chang Chang, and Shaw-Jenq Tsai*

The Institute of Clinical Medicine, Department of Obstetrics and Gynecology, The Institute of Molecular Medicine, Department of Physiology, and Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan, Republic of China

Aberrant production of cyclooxygenase-2 (COX-2) plays pivotal roles in many pathological processes including tumorigenesis and endometriosis though the underlying mechanism remains obscure. Herein we report evidence to demonstrate that COX-2 is distinctly regulated by interleukin-1{beta} (IL-1{beta}) in normal and endometriotic stroma. Ectopic endometriotic stromal cell is, at least, 100 times more sensitive to IL-1{beta} treatment compared with its eutopic counterpart. Induction of COX-2 expression in normal endometrial stroma by IL-1{beta} is primary due to enhancement of COX-2 mRNA stability. In contrast, IL-1{beta} not only increased COX-2 mRNA stability but also up-regulated COX-2 promoter activity in ectopic endometriotic stroma. Induction of COX-2 promoter activity by IL-1{beta} is mediated via mitogen-activated protein kinase-dependent phosphorylation of cAMP-responding element binding protein (CREB). Promoter activity and electrophoretic motility shift assays demonstrate that a CRE site located at -571/-564 of COX-2 promoter is critical for IL-1{beta}-induced COX-2 gene expression. Our results indicate that elevation of COX-2 expression in endometriotic tissues may result from increased sensitivity to proinflammatory cytokines such as IL-1{beta}, which is consistently present in the peritoneal fluid of endometriosis patients. Distinct regulation of COX-2 gene by IL-1{beta} may play critical role in pathophysiological process such as cancer formation and endometriosis.
Key words: COX-2 • Endometriosis • IL-1{beta} • PGE2 • Transcriptional regulation




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