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Distinct Regulation of Cyclooxygenase-2 by Interleukin-1ß in Normal and Endometriotic Stromal Cells

The Institute of Clinical Medicine (M.-H.W.), The Institute of Molecular Medicine (C.-A.W., S.-J.T.), and Departments of Obstetrics and Gynecology (M.-H.W.), Physiology (C.-C.L., S.-J.T.), and Pharmacology (L.-C.C., W.-C.C.), College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan, Republic of China

Address all correspondence and requests for reprints to: Shaw-Jenq Tsai, Ph.D., Department of Physiology, College of Medicine, National Cheng Kung University, 1 University Road, Tainan 70101, Taiwan, Republic of China. E-mail: seantsai{at}mail.ncku.edu.tw.

Aberrant production of cyclooxygenase-2 (COX-2) plays pivotal roles in many pathological processes including tumorigenesis and endometriosis, although the underlying mechanism remains obscure. Herein we report evidence to demonstrate that COX-2 is distinctly regulated by IL-1ß in normal and endometriotic stroma. Ectopic endometriotic stromal cell is at least 100 times more sensitive to IL-1ß treatment, compared with its eutopic counterpart. Induction of COX-2 expression in normal endometrial stroma by IL-1ß is primary due to enhancement of COX-2 mRNA stability. In contrast, IL-1ß not only increases COX-2 mRNA stability but also up-regulates COX-2 promoter activity in ectopic endometriotic stroma. Induction of COX-2 promoter activity by IL-1ß is mediated via MAPK-dependent phosphorylation of cAMP-responding element binding protein. Promoter activity and EMSAs demonstrate that a cAMP response element site located at –571/–564 of COX-2 promoter is critical for IL-1ß-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-1ß, which is consistently present in the peritoneal fluid of endometriosis patients. Distinct regulation of COX-2 gene by IL-1ß may play a critical role in pathophysiological processes such as cancer formation and endometriosis.

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