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This Article Full Text Full Text (PDF) All Versions of this Article: 78/1/68    most recent biolreprod.107.061663v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Ackerman, W. E Articles by Kniss, D. A Search for Related Content PubMed PubMed Citation Articles by Ackerman, W. E, IV Articles by Kniss, D. A Agricola Articles by Ackerman, W. E Articles by Kniss, D. A

Nuclear Factor-Kappa B Regulates Inducible Prostaglandin E Synthase Expression in Human Amnion Mesenchymal Cells¹

Department of Obstetrics and Gynecology, Laboratory of Perinatal Research and Division of Maternal-Fetal Medicine,³ Department of Biomedical Engineering,⁴ and Department of Cell Biology and Physiology,⁵ The Ohio State University, Columbus, Ohio 43210

ABSTRACT

The human amnion is a major intrauterine source of prostaglandin (PG) E₂, a potent mediator of uterine contractions and cervical ripening. During parturition, inflammatory cytokines promote PGE₂ 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 PGE₂ biosynthesis pathway during human parturition.

cytokines, gene regulation, parturition, placenta, pregnancy

¹Supported by NIH grants F32 HD042910 and K08 HD049628 and The Ohio State University Perinatal Research and Development Fund. Portions of this study were presented in abstract form at the 53rd Annual Meeting of the Society for Gynecologic Investigation, March 22–25, 2006, Toronto, ON, Canada.

Correspondence: ²William E. Ackerman IV, Laboratory of Perinatal Research, Department of Obstetrics and Gynecology, The Ohio State University, 5th Floor Means Hall, 1654 Upham Dr., Columbus, OH 43210. FAX: 614 293 5728; e-mail: ackerman.72{at}osu.edu