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The Interleukin 1beta-Induced Expression of Human Prostaglandin F_2alpha Receptor Messenger RNA in Human Myometrial-Derived ULTR Cells Requires the Transcription Factor, NFkappaB¹

Departments of Obstetrics & Gynecology,³ Pediatrics,⁴ Physiology,⁵ Perinatal Research Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2S2

ABSTRACT

Themolecular mechanisms that regulate the expression of genes involved in parturition are poorly understood. The mRNA expression of the prostaglandin F_2alpha receptor (PTGFR), a uterine activating gene, is increased at labor and is required for uterine contractile activity in numerous animal models, although the signaling pathways responsible for this increased expression have not been identified. Proinflammatory cytokines have been proposed to regulate the expression of the uterine activating genes via activation of the nuclear transcription factor, NFkappaB, and initiate labor. However, it is uncertain whether uterine PTGFR is regulated this way. In this report, we demonstrate for the first time that treatment of immortalized human myometrial-derived ULTR cells with the proinflammatory cytokine IL1beta causes an increase in PTGFR mRNA levels. Furthermore, IL1beta treatment increased the nuclear levels of the RELA subunit of NFkappaB and increased binding of RELA to the NFkappaB DNA-binding site. Inhibition of NFkappaB activation with either the proteasome inhibitor MG132 or phenethyl caffeiate reducedPTGFRmRNA levels, which indicates that this transcription factor is important for basal transcription. Furthermore, this inhibition prevented IL1beta induction ofPTGFRmRNA, which confirms that NFkappaB is required for the IL1beta-induced increase inPTGFR. These results are consistent with the proposal that proinflammatory cytokines directly regulate uterine activation genes and that the transcription factor NFkappaB is involved in both basal and IL1beta-stimulated transcription of thePTGFRgene.

cytokines, gene regulation, parturition, signal transduction, uterus

² Correspondence: FAX: 780 492 1308; dzaragoz{at}ualberta.ca

¹ Supported by the Canadian Institutes for Health Research (The Institute for Human Development, Child and Youth Health) and the CIHR Group for Perinatal Health and Disease.