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The Journal of Clinical Endocrinology & Metabolism Vol. 87, No. 7 3263-3273
Copyright © 2002 by The Endocrine Society

Other Original Articles

Interleukin-1ß Elevates Cyclooxygenase-2 Protein Level and Enzyme Activity via Increasing Its mRNA Stability in Human Endometrial Stromal Cells: An Effect Mediated by Extracellularly Regulated Kinases 1 and 2

Mitsutoshi Tamura, Siby Sebastian, Sijun Yang, Bilgin Gurates, Zongjuan Fang and Serdar E. Bulun

Departments of Obstetrics and Gynecology and Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois 60612

Address all correspondence and requests for reprints to: Serdar E. Bulun, M.D., Departments of Obstetrics and Gynecology and Molecular Genetics, University of Illinois at Chicago, 820 South Wood Street, M/C 808, Chicago, Illinois 60612. E-mail: . sbulun{at}uic.edu

Abstract

We investigated the regulation of PG production in human endometrial stromal cells (ESC) by IL-1ß. We found that cyclooxygenase-2 (COX-2) mRNA and protein levels and PGE2 production in ESC were significantly increased by IL-1ß. COX-2 mRNA, protein, and PGE2 levels in IL-1ß-treated ESC were decreased by a PKA inhibitor, a nuclear factor (NF-{kappa}B) inhibitor, and an ERK1/2 inhibitor, but not by a p38 MAPK inhibitor or a PKC inhibitor, suggesting the possible involvement of PKA, NF-{kappa}B, and/or the ERK1/2 signaling pathway(s) in IL-1ß-mediated COX-2 gene induction in ESC. We then transiently transfected deletion mutants of the COX-2 promoter fused to the luciferase reporter gene and variants of -360/+56 bp promoter construct carrying different site-directed mutations of selected cis-acting elements. We determined that a NF-{kappa}B site (-222/-213 bp), a nuclear factor for IL-6 expression site (NF-IL6, -132/-124 bp), and a cAMP response element (-59/-52 bp) were essential for the baseline COX-2 gene promoter regulation. The addition of IL-1ß, however, did not affect the activity of these COX-2 promoter constructs. To investigate the potential effects of IL-1ß on COX-2 mRNA stability, ESC were treated with actinomycin D, a general transcription inhibitor, in the absence or presence of IL-1ß. We found that 1) IL-1ß significantly increased COX-2 mRNA stability; 2) continuous transcription was not required to sustain the IL-1ß-induced COX-2 mRNA levels; and 3) COX-2 mRNA was highly unstable in the absence of IL-1ß. Additionally, we found that the ERK1/2 signaling pathway was essential for stabilizing COX-2 mRNA. We conclude that levels of COX-2 mRNA, protein, and enzyme activity in ESC are controlled by various signaling pathways, including PKA, ERK1/2, and NF-{kappa}B. Moreover, posttranscriptional mRNA stability is an important mechanism for IL-1ß-induced elevation of COX-2 expression in ESC.




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