Interactions between inflammatory signals and the progesterone receptor in regulating gene expression in pregnant human uterine myocytes

Journal of Cellular and Molecular Medicine

Yun Lee³  Suren R. Sooranna³  Vasso Terzidou³  Mark Christian³  Jan Brosens³  Kaisa Huhtinen²  Matti Poutanen²  Geraint Barton¹  Mark R. Johnson³ 

[1] Department of Bioinformatics, Imperial College London, London, UK;Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland;Parturition Research Group, Imperial College London, Institute of Reproductive and Developmental Biology, London, UK

关键词: labour;    parturition;    progesterone;    PR;    inflammation;    NF‐kappaB;   

DOI  :  10.1111/j.1582-4934.2012.01567.x

来源: Wiley

【 摘 要 】

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.

【 授权许可】

Unknown   
© 2012 The Authors Journal of Cellular and Molecular Medicine © 2012 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd