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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.

Original publication

DOI

10.1111/j.1365-2567.2008.02820.x

Type

Journal

Immunology

Publication Date

09/2008

Volume

125

Pages

59 - 69

Addresses

Strathclyde Institute for Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK.

Keywords

Hematopoietic Stem Cells, Cells, Cultured, Macrophages, Animals, Mice, Inbred BALB C, Mice, Leishmania donovani, Toxoplasmosis, Leishmaniasis, Visceral, Nitrites, Nitric Oxide, Norgestrel, Dexamethasone, Progesterone, Lipopolysaccharides, Receptors, Glucocorticoid, Receptors, Progesterone, Interleukin-12, Cell Survival, Macrophage Activation, Down-Regulation, Dose-Response Relationship, Drug, Male, Toll-Like Receptor 4