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Regulation of the Human Oxytocin Receptor by Nuclear Factor-B and CCAAT/Enhancer-Binding Protein-ß

Imperial College London (V.T., Y.L., T.L., M.J., P.R.B.), Parturition Research Group, Institute of Reproductive and Developmental Biology, London W12 ONN, United Kingdom; and Department of Biological Sciences and Leicester Warwick Medical School (S.T.), University of Warwick, Coventry CV4 7AL, United Kingdom

Address all correspondence and requests for reprints to: Dr. V. Terzidou, Parturition Research Group, Institute of Reproductive and Developmental Biology, Hammersmith Hospital Campus, Du Cane Road, East Acton, London W12 ONN, United Kingdom. E-mail: v.terzidou{at}imperial.ac.uk.

Context: Increased myometrial sensitivity to oxytocin at term is mediated through increased oxytocin receptor (OTR) expression. OTR promoter contains putative transcription factor-binding sites for activating protein-1 (AP-1), CCAAT/enhancer-binding protein (C/EBP), and nuclear factor-B (NF-B), which may be activated by IL-1ß, whose concentrations increase with labor.

Objective: The objective of this study was to examine the effect of IL-1ß on OTR expression and the roles of AP-1, C/EBP, and NF-B in OTR promoter function.

Results: IL-1ß induces an increase in OTR mRNA concentrations and OTR ligand binding in myometrial cells, which is maximal at 4 h and decreased after 20 h. IL-1ß activates the transcription factors AP-1 C/EBPß, and NF-B. Using computer-based analysis and EMSA studies, we have identified three AP-1, nine C/EBP, and three NF-B DNA-binding sites in the OTR promoter. In transient transfection studies, OTR promoter activity was increased by C/EBPß and NF-B, but not by AP-1. C/EBPß and NF-B together had a synergistic action in the induction of OTR promoter activity. Site-directed mutagenesis of each individual C/EBP and NF-B site had no effect on the ability of C/EBPß, NF-B, or their combination to activate OTR promoter. However, mutation of both NF-B sites inhibited promoter activation by NF-B alone, but not that by the combination of C/EBPß and NF-B. Deletion studies showed that a region between –851 and –656 of the OTR confers responsiveness to the combination of C/EBPß and NF-B.

Conclusion: IL-1ß has a biphasic effect on OTR expression in myometrial cells, and C/EBP and NF-B play synergistic roles in OTR promoter activation.

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