Nuclear factor-kappa B regulates inducible prostaglandin E synthase expression in human amnion mesenchymal cells.
The human amnion is a major intrauterine source of prostaglandin (PG) E(2), a potent mediator of uterine contractions and cervical ripening. During parturition, inflammatory cytokines promote PGE(2) production through increased prostaglandin-endoperoxide synthase-2 (PTGS2, also known as cyclooxygenase-2) expression. This is mediated, in part, through activation of the transcription factor nuclear factor kappa B (NFkappaB). Prostaglandin E synthase (PTGES, also known as microsomal PGE synthase-1) acts downstream of PTGS2 and is inducibly expressed in most systems. We hypothesized that NFkappaB might regulate cytokine-induced PTGES expression in amnion cells. With amnion mesenchymal cells, we found that proinflammatory cytokines coordinately upregulated PTGS2 and PTGES mRNA expression. In parallel, increased expression of the PTGS2 and PTGES proteins was observed. In comparison, the expression of two other PGE synthases (PTGES2 and PTGES3) was unmodified. PTGES induction was blocked both in the presence of pharmacological NFkappaB inhibitors and following adenovirus-mediated overexpression of a dominant-negative NFkappaB pathway protein. In cells transiently transfected with a luciferase reporter bearing a portion (-597/+33) of the human PTGES gene promoter, interleukin-1beta (IL1B) produced a moderate increase in luciferase activity; this effect was abrogated in the presence of an indirect NFkappaB inhibitor (MG-132). Finally, a kappaB-like regulatory element was identified that, when mutated, markedly attenuated IL1B-responsive PTGES promoter activity. In conclusion, our results support a role for NFkappaB in cytokine-induced PTGES expression in amnion mesenchymal cells in vitro. By coordinately regulating PTGS2 and PTGES, NFkappaB may contribute to an inducible PGE(2) biosynthesis pathway during human parturition.
Ackerman
William E
WE
Department of Obstetrics and Gynecology, Laboratory of Perinatal Research and Division of Maternal-Fetal Medicine, The Ohio State University, Columbus, OH 43210, USA. ackerman.72@osu.edu
Summerfield
Taryn L S
TL
Vandre
Dale D
DD
Robinson
John M
JM
Kniss
Douglas A
DA
D000650:Amnion / Q000166:cytology* / Q000378:metabolism*; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D000071876:Prostaglandin-E Synthases; D020218:Response Elements; D015398:Signal Transduction
D016207:Cytokines; D016328:NF-kappa B; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; C000605863:PTGES2 protein, human; C490849:PTGES3 protein, human; D000071876:Prostaglandin-E Synthases