Interleukin-1-induced NF-kappaB recruitment to the oxytocin receptor gene inhibits RNA polymerase II-promoter interactions in cultured human myometrial cells.
The myometrial oxytocin receptor (OTR) is highly regulated during pregnancy, reaching maximal concentrations near term. These levels are then abruptly reduced in advanced labour and the post-partum period. Our goal was to examine the molecular basis for this reduction, using chromatin immunoprecipitation (ChIP). Interleukin-1alpha (IL1A) treatment of cultured human myometrial cells has previously been shown to reduce steady-state levels of OTR mRNA. We show further that IL1A reduced RNA polymerase II cross-linking to the otr promoter, as reflective of transcriptional inhibition. IL1A also increased the recruitment of nuclear factor kappaB (NF-kappaB) to a site 955 bp upstream from the transcriptional start site. Inhibition of NF-kappaB activation negated the effects of IL1A on polymerase II dissociation, indicating a causal relationship, at least in part, between recruitment of NF-kappaB and detachment of polymerase from the otherwise constitutively active otr promoter. IL1A treatment also resulted in increased histone H4 acetylation in the otr promoter region. Whereas NF-kappaB recruitment and histone acetylation are generally associated with activation of gene expression, our findings show that both processes can be involved in dissociation of RNA polymerase II from an active promoter. The results of these studies suggest that the elevation of IL1 in the myometrium occurring at the end of pregnancy initiates the process of down-regulation of OTRs in advanced labour, resulting in the desensitization of the myometrium to elevated levels of OT in the blood during lactation.
Soloff
Melvyn S
MS
Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, TX 77555-1062, USA. msoloff@utmb.edu
Izban
Michael G
MG
Cook
Dennis L
DL
Jeng
Yow-Jiun
YJ
Mifflin
Randy C
RC
D000107:Acetylation; D002478:Cells, Cultured; D015536:Down-Regulation; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D053582:Interleukin-1alpha / Q000378:metabolism*; D009215:Myometrium / Q000166:cytology / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D011247:Pregnancy; D011401:Promoter Regions, Genetic / Q000235:genetics; D012319:RNA Polymerase II / Q000378:metabolism*; D018045:Receptors, Oxytocin / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
D006657:Histones; D053582:Interleukin-1alpha; D016328:NF-kappa B; D018045:Receptors, Oxytocin; D012319:RNA Polymerase II