Distinct regulation of cyclooxygenase-2 by interleukin-1beta in normal and endometriotic stromal cells.
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-1beta in normal and endometriotic stroma. Ectopic endometriotic stromal cell is at least 100 times more sensitive to IL-1beta treatment, compared with its eutopic counterpart. Induction of COX-2 expression in normal endometrial stroma by IL-1beta is primary due to enhancement of COX-2 mRNA stability. In contrast, IL-1beta 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-1beta 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-1beta-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-1beta, which is consistently present in the peritoneal fluid of endometriosis patients. Distinct regulation of COX-2 gene by IL-1beta may play a critical role in pathophysiological processes such as cancer formation and endometriosis.
The Institute of Clinical Medicine, Department of Obstetrics and Gynecology, College of Medicine, National Cheng Kung University, 1 University Road, Tainan 70101, Taiwan, Republic of China.
Meng-Hsing
MH
Wu
Chu-An
CA
Wang
Chen-Chung
CC
Lin
Lei-Chin
LC
Chen
Wen-Chang
WC
Chang
Shaw-Jenq
SJ
Tsai
D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D051546:Cyclooxygenase 2; D004715:Endometriosis / Q000201:enzymology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D007527:Isoenzymes / Q000235:genetics*; D008565:Membrane Proteins; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D017472:Receptors, Interleukin-1 / Q000502:physiology; D017154:Stromal Cells / Q000201:enzymology*
D017362:Cyclic AMP Response Element-Binding Protein; D007375:Interleukin-1; D007527:Isoenzymes; D008565:Membrane Proteins; D017472:Receptors, Interleukin-1; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases