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Title: Molecular mechanisms of progesterone withdrawal in human uterine smooth muscle cells
Author: Lei, Kaiyu
ISNI:       0000 0004 2706 1807
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2011
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Progesterone administration reduces the risk of preterm labour in high-risk women with singleton pregnancies but has no effect in women with a multiple pregnancy. However, it should be noted that it is not clear why progesterone is effective in the singleton pregnancies and in addition stretch-induced preterm labour is an attractive but not fully proven explanation. The data from my studies showed that progesterone did not inhibit stretch-induced MAPK activation or gene expression possibly explaining why progesterone is ineffective in the prevention of preterm labour in multiple pregnancies. Although stretch did reduce PR expression in a NF-κB-dependent manner, this was not sufficient to inhibit progesterone action, suggesting that it is not responsible for the functional progesterone withdrawal observed with the onset of human labour. Progesterone is thought to reduce the risk of preterm labour by inhibiting inflammatory cytokine-induced increases in prostaglandin synthesis. Initially, I demonstrated that IL-1β inhibited progesterone-driven PRE activation via p65. Conversely, p65-driven NF-κB reporter construct activity was reduced by overexpression of PR-B and this was enhanced by the addition of MPA. Both MPA and progesterone repression of IL-1β-driven COX-2 expression was lost by knockdown of GR. Subsequently, a series of in vitro studies suggested that progesterone acted via progesterone-induced and GR-mediated MKP-1 activation to repress IL-1β-driven COX-2 and that although the interaction between p65 and PR-B might be involved in the repression of progesterone-driven gene expression, it did not seem to be responsible for progesterone repression of IL-1β-induced COX-2 expression. Finally, the cDNA microarray analysis showed that the PR and GR regulated distinct gene networks and cellular functions in the absence or presence of ligand. However, the ability of progesterone to modulate gene expression can be mediated via both PR and GR. These data broaden our view of progesterone action and suggest alternative roles for PR and GR in human parturition.
Supervisor: Johnson, Mark ; Sooranna, Dev ; Bennett, Phillip Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral