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Title: Immunomodulatory effects of progesterone on TLR3 and TLR4 mediated signalling in macrophages and dendritic cells
Author: Kreem, Shrook Abdulla
ISNI:       0000 0004 2744 7451
Awarding Body: University of Strathclyde
Current Institution: University of Strathclyde
Date of Award: 2013
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Sexual dimorphism in the immune response is at least in part related to the effects of sex hormones. The current studies investigate the ability of progesterone to manipulate signalling events in macrophages and dendritic cells following TLR3 or TLR4 ligation. Progesterone can mediate its action by binding both progesterone and glucocorticoid receptors. To differentiate these effects, norgestrel, a synthetic progesterone specific receptor agonist and dexamethasone a glucocorticoid receptor agonist were utilised. Progesterone and norgestrel, but not dexmethasone increased poly-riboinosinic-ribocytidylic acid (polyI:C), a TLR3 agonist, induced interferon regulatory factor 3 (IRF3) phosphorylation in BMDCs, suggesting that it may be mediated by progesterone receptor. Subsequent experiments, showed inhibitory effects of both progesterone and norgestrel on numerous elements downstream in the TLR3 and TLR4 signalling pathways, specifically at the transcriptional level represented by inhib ition of polyI:C-induced p65 and IRF3 nuclear translocation. Progesterone also inhibited LPS-induced IRF3 nuclear translocation. Progesterone and norgestrel inhibited LPS- and polyI:C-induced ISRE DNA-binding activity and may contribute to modulation of specific target gene promoters bearingISRE consensus elements including IL-12, IL-27 and IFNβ. The effects of progesterone were evident at the level of transcription. Thus, polyI:C-induced IL-12p35, EBI3 and IFNβ mRNAexpression were inhibited by progesterone and norgestrel and LPS-induced IFNβ mRNA expression was inhibited by progesterone. Progesterone inhibited LPS- and polyI:C-induced IL-6, but not norgestrel. However, IL-12p70 production was reduced by both progesterone and norgestrel following LPS and polyI:C stimulation. These results indicate that progesterone selectively functions as an immunomodulatory agent through both progesterone and glucocorticoid receptors. Progesterone potentially has a greater ability to affect TLR3 rather than TLR4 signalling. These results could have therapeutic implications for control of the innate immune response, inflammation and infectious diseases.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available