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Toll-like receptor-4-mediated macrophage activation is differentially regulated by progesterone via the glucocorticoid and progesterone receptors

Jones, L.A. and Anthony, J. and Henriquez, F.L. and Lyons, R. and Nickdel, M.B. and Carter, K.C. and Alexander, J. and Roberts, C.W. (2008) Toll-like receptor-4-mediated macrophage activation is differentially regulated by progesterone via the glucocorticoid and progesterone receptors. Immunology, 125 (1). pp. 59-69. ISSN 0019-2805

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Abstract

Macrophage function has been demonstrated to be subject to modulation by progesterone. However, as this steroid hormone can act through the glucocorticoid receptor as well as the progesterone receptor, the mechanism of action has not been precisely characterized. To determine the mode of action, we compared the ability of progesterone, norgestrel (a synthetic progesterone-receptor-specific agonist) and dexamethasone (a synthetic glucocorticoid receptor agonist) to modulate macrophage function following stimulation of the Toll-like receptor-4 (TLR-4) ligand lipopolysaccharide (LPS). The results demonstrate that following stimulation of TLR-4 with LPS and cotreatment with either progesterone or dexamethasone, but not norgestrel, there is a significant reduction in nitric oxide (NO) production, indicating that this progesterone-mediated effect is through ligation of the glucocorticoid receptor. In contrast, LPS-induced interleukin-12 (IL-12) production could be downregulated by all three steroids, indicating that ligation by progesterone of either the glucocorticoid or the progesterone receptors or both could mediate this effect. While progesterone downmodulated NO-mediated killing of Leishmania donovani by activated macrophages in vitro, most probably via the glucocorticoid receptor, it had little effect on Toxoplasma gondii growth in these cells. This would suggest that progesterone-mediated increased susceptibility to T. gondii during pregnancy is more likely to be related to the ability of the hormone to downregulate IL-12 production and a type-1 response utilizing the progesterone as well as the glucocorticoid receptors.

Item type: Article
ID code: 10374
Keywords: leishmania donovani, macrophage, nitric oxide, progesterone, toll-like receptor, toxoplasma gondii, Pharmacy and materia medica, Immunology, Immunology and Allergy, Pharmacology, Toxicology and Pharmaceutics(all)
Subjects: Medicine > Pharmacy and materia medica
Department: Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences
Unknown Department
Faculty of Engineering > Naval Architecture and Marine Engineering
Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences > Immunology
Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences > Centre for Biophotonics
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    Depositing user: Strathprints Administrator
    Date Deposited: 22 Jun 2010 14:31
    Last modified: 04 Apr 2014 12:08
    URI: http://strathprints.strath.ac.uk/id/eprint/10374

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