Lee, Yun, Sooranna, Suren R., Terzidou, Vasso, Christian, Mark, Brosens, Jan J., Huhtinen, Kaisa, Poutanen, Matti, Barton, Geraint, Johnson, Mark R. and Bennett, Phillip R. (2012) Interactions between inflammatory signals and the progesterone receptor in regulating gene expression in pregnant human uterine myocytes. Journal of Cellular and Molecular Medicine, 16 (10). pp. 2487-2503. jcmm0016-2487. doi:10.1111/j.1582-4934.2012.01567.x

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Abstract

The absence of a fall in circulating progesterone levels has led to the concept that human labour is associated with ‘functional progesterone withdrawal’ caused through changes in the expression or function of progesterone receptor (PR). At the time of labour, the human uterus is heavily infiltrated with inflammatory cells, which release cytokines to create a ‘myometrial inflammation’ via NF-κB activation. The negative interaction between NF-κB and PR, may represent a mechanism to account for ‘functional progesterone withdrawal’ at term. Conversely, PR may act to inhibit NF-κB function and so play a role in inhibition of myometrial inflammation during pregnancy. To model this inter-relationship, we have used small interfering (si) RNA-mediated knock-down of PR in human pregnant myocytes and whole genome microarray analysis to identify genes regulated through PR. We then activated myometrial inflammation using IL-1β stimulation to determine the role of PR in myometrial inflammation regulation. Through PR-knock-down, we found that PR regulates gene networks involved in myometrial quiescence and extracellular matrix integrity. Activation of myometrial inflammation was found to antagonize PR-induced gene expression, of genes normally upregulated via PR. We found that PR does not play a role in repression of pro-inflammatory gene networks induced by IL-1β and that only MMP10 was significantly regulated in opposite directions by IL-1β and PR. We conclude that progesterone acting through PR does not generally inhibit myometrial inflammation. Activation of myometrial inflammation does cause ‘functional progesterone withdrawal’ but only in the context of genes normally upregulated via PR.

Item Type:	Journal Article
Subjects:	R Medicine > RG Gynecology and obstetrics
Divisions:	Faculty of Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine > Reproductive Health ( - until July 2016) Faculty of Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine Faculty of Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH):	Progesterone -- Receptors, Pregnancy, Labor (Obstetrics), Parturition, NF-kappa B (DNA-binding protein), Uterus -- Contraction, Myometrium
Journal or Publication Title:	Journal of Cellular and Molecular Medicine
Publisher:	Wiley-Blackwell Publishing, Inc
ISSN:	1582-1838
Official Date:	October 2012
Dates:	Date Event October 2012 Published 26 September 2012 Available 20 February 2012 Accepted 31 October 2011 Updated
Date of first compliant deposit:	30 December 2015
Volume:	16
Number:	10
Number of Pages:	7
Page Range:	pp. 2487-2503
Article Number:	jcmm0016-2487
DOI:	10.1111/j.1582-4934.2012.01567.x
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
Funder:	National Institute for Health Research (Great Britain) (NIHR)

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