Progesterone acts via the nuclear glucocorticoid receptor to suppress IL-1 beta-Induced COX-2 expression in human term myometrial cells
Author(s)
Type
Journal Article
Abstract
Progesterone is widely used to prolong gestation in women at risk of preterm labour (PTL), and acts at least in part via the
inhibition of inflammatory cytokine-induced prostaglandin synthesis. This study investigates the mechanisms responsible
for this inhibition in human myometrial cells. We used reporter constructs to demonstrate that interleukin 1beta (IL-1b)
inhibits progesterone driven PRE activation via p65 activation and that IL-1b reduced progesterone driven gene expression
(FKBP5). Conversely, we found that the activity of a p65-driven NFkB reporter construct was reduced by overexpression of
progesterone receptor B (PRB) alone and that this was enhanced by the addition of MPA and that both MPA and
progesterone suppressed IL-1b-driven cyclo-oxygenase-2 (COX-2) expression. We found that over-expressed Halo-tagged
PRB, but not PRA, bound to p65 and that in IL-1b-treated cells, with no overexpression of either PR or p65, activated p65
bound to PR. However, we found that the ability of MPA to repress IL-1b-driven COX-2 expression was not enhanced by
overexpression of either PRB or PRA and that although the combined PR and GR antagonist Ru486 blocked the effects of
progesterone and MPA, the specific PR antagonist, Org31710, did not, suggesting that progesterone and MPA act via GR
and not PR. Knockdown using siRNA confirmed that both MPA and progesterone acted via GR and not PR or AR to repress
IL-1b-driven COX-2 expression. We conclude that progesterone acts via GR to repress IL-1b-driven COX-2 activation and that
although the interaction between p65 and PRB may be involved in the repression of progesterone driven gene expression it
does not seem to be responsible for progesterone repression of IL-1b-induced COX-2 expression.
inhibition of inflammatory cytokine-induced prostaglandin synthesis. This study investigates the mechanisms responsible
for this inhibition in human myometrial cells. We used reporter constructs to demonstrate that interleukin 1beta (IL-1b)
inhibits progesterone driven PRE activation via p65 activation and that IL-1b reduced progesterone driven gene expression
(FKBP5). Conversely, we found that the activity of a p65-driven NFkB reporter construct was reduced by overexpression of
progesterone receptor B (PRB) alone and that this was enhanced by the addition of MPA and that both MPA and
progesterone suppressed IL-1b-driven cyclo-oxygenase-2 (COX-2) expression. We found that over-expressed Halo-tagged
PRB, but not PRA, bound to p65 and that in IL-1b-treated cells, with no overexpression of either PR or p65, activated p65
bound to PR. However, we found that the ability of MPA to repress IL-1b-driven COX-2 expression was not enhanced by
overexpression of either PRB or PRA and that although the combined PR and GR antagonist Ru486 blocked the effects of
progesterone and MPA, the specific PR antagonist, Org31710, did not, suggesting that progesterone and MPA act via GR
and not PR. Knockdown using siRNA confirmed that both MPA and progesterone acted via GR and not PR or AR to repress
IL-1b-driven COX-2 expression. We conclude that progesterone acts via GR to repress IL-1b-driven COX-2 activation and that
although the interaction between p65 and PRB may be involved in the repression of progesterone driven gene expression it
does not seem to be responsible for progesterone repression of IL-1b-induced COX-2 expression.
Date Issued
2012-11-28
Date Acceptance
2012-10-22
Citation
PLoS ONE, 2012, 7 (11)
ISSN
1932-6203
Publisher
Public Library of Science (PLoS)
Journal / Book Title
PLoS ONE
Volume
7
Issue
11
Copyright Statement
© 2012 Lei et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited.
use, distribution, and reproduction in any medium, provided the original author and source are credited.
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000312601700037&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Subjects
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
PRETERM BIRTH
KAPPA-B
17-ALPHA-HYDROXYPROGESTERONE CAPROATE
HORMONAL SIGNALS
DOUBLE-BLIND
LABOR
PREGNANCY
PREVENTION
WOMEN
RISK
Publication Status
Published
Article Number
e50167
Date Publish Online
2012-11-28