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Endocrinology Vol. 142, No. 4 1380-1385
Copyright © 2001 by The Endocrine Society

ARTICLES

Transcriptional Regulation of Oxytocin Receptor by Interleukin-1ß and Interleukin-6

Birgit Schmid, Susan Wong and B. F. Mitchell

Perinatal Research Center, Department of Obstetrics and Gynecology, HMRC 220, University of Alberta, Edmonton, Alberta, Canada T6G 2S2

Address all correspondence and requests for reprints to: Dr. B. F. Mitchell, Perinatal Research Center, Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Alberta, Canada T6G 252.

The up-regulation of oxytocin (OT) receptors in late pregnancy results principally from increased synthesis of messenger RNA. The 5'-flanking region of the human OT receptor gene contains several putative binding sites for nuclear factor-interleukin-6 (NF-IL6), also known as CAAT/enhancer binding protein-ß. This trans-acting factor modulates the expression of genes involved in acute inflammatory responses. Proinflammatory cytokines, such as IL-1ß or IL-6, have been implicated as mediators in both preterm and term labor, particularly in association with intrauterine infection. We hypothesized that IL-1ß and IL-6 induce OT receptor gene expression in human myometrial cells, and this is mediated by NF-IL6 and cognate response elements in the 5'-flanking region of the OT receptor gene. Contrary to the hypothesis, both IL-1ß and IL-6 treatment resulted in a significant decrease in OT receptor messenger RNA measured by ribonuclease protection analysis. Using electrophoretic mobility shift assay, we have shown that NF-IL6 is present at low levels that appear to be increased after treatment with either IL-1ß or IL-6. Using deletion analysis and functional transfection studies in HeLa cells, we demonstrated that the OT receptor gene promoter displays constitutive basal activity and is negatively regulated by both IL-1ß and IL-6. This suppressive ability of IL-1ß and IL-6 depends on the -1203/-722 region of the OT receptor promoter, which contains binding sites for NF-IL6, acute phase response element, and NF-{kappa}B. Our findings suggest a role for IL-1ß and IL-6 in the transcriptional regulation of the human OT receptor gene.




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