title: Troglitazone regulates peroxisome proliferator-activated receptors and inducible nitric oxide synthase in murine ovarian macrophages.
abstract: Peroxisome proliferator-activated receptor-gamma (PPARG) and PPAR-alpha (PPARA) control metabolic processes in many cell types and act as anti-inflammatory regulators in macrophages. PPAR-activating ligands include thiazolidinediones (TZDs), such as troglitazone, once frequently used to treat insulin resistance as well as symptoms of polycystic ovary syndrome (PCOS). Since macrophages within the ovary mediate optimal follicle development, TZD actions to improve PCOS symptoms are likely to be partly mediated through these specifically localized immune cells. In mouse ovary, PPARG protein was expressed in granulosa cells and in isolated cells localized to theca, stroma, and corpora lutea, consistent with EMR1+ macrophages. Isolation of immune cells (EMR1+ or H2+) showed that Pparg and Ppara were expressed in ovarian macrophages at much higher levels than in peritoneal macrophages. Ovulatory human chorionic gonadotropin downregulated expression of Pparg and Ppara in EMR1+ ovarian macrophages, but no hormonal responsiveness was observed in H2+ cells. Downstream anti-inflammatory effects of PPARG activation were analyzed by in vitro treatment of isolated macrophages with troglitazone. Interleukin-1 beta (Il1b) expression was not altered, and tumor necrosis factor-alpha (Tnf) expression was affected in peritoneal macrophages only. In ovarian macrophages, inducible nitric oxide synthase (Nos2), an important proinflammatory enzyme that regulates ovulation, was significantly reduced by troglitazone treatment, an effect that was restricted to cells from the preovulatory ovary. Thus, expression of PPARs within ovarian macrophages is hormonally regulated, reflecting the changing roles of these cells during the ovulatory cycle. Additionally, ovarian macrophages respond directly to troglitazone to downregulate expression of proinflammatory Nos2, providing mechanistic information about ovarian effects of TZD treatment.
authors.affiliation: Research Centre for Reproductive Health, Department of Obstetrics and Gynaecology, University of Adelaide, Queen Elizabeth Hospital, Woodville, South Australia 5011, Australia.
authors.forename: Cadence E
authors.initials: CE
authors.lastname: Minge
authors.forename: Natalie K
authors.initials: NK
authors.lastname: Ryan
authors.forename: Kylie H
authors.initials: KH
authors.lastname: Van Der   Hoek
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Robker
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Norman
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002135:Calcium-Binding Proteins; D002839:Chromans / Q000494:pharmacology*; D005260:Female; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D052247:Nitric Oxide Synthase Type II / Q000187:drug effects* / Q000378:metabolism; D010053:Ovary / Q000187:drug effects* / Q000378:metabolism; D010060:Ovulation / Q000378:metabolism; D047493:PPAR alpha / Q000187:drug effects / Q000378:metabolism; D047495:PPAR gamma / Q000187:drug effects* / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled; D020133:Reverse Transcriptase Polymerase Chain Reaction; D045162:Thiazolidinediones / Q000494:pharmacology*; D000077288:Troglitazone; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C000634132:Adgre1 protein, mouse; D002135:Calcium-Binding Proteins; D002839:Chromans; D007375:Interleukin-1; D047493:PPAR alpha; D047495:PPAR gamma; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D052247:Nitric Oxide Synthase Type II; D000077288:Troglitazone