title: The influence of aging and estradiol to progesterone ratio on rat macrophage phenotypic profile and NO and TNF-α production.
abstract: The phenotype and function of tissue macrophages substantially depend on the cellular milieu and biological effector molecules, such as steroid hormones, to which they are exposed. Furthermore, in female rats, aging is associated with the altered macrophage functioning and the increased estrogen level is followed by a decrease in that of progesterone. Therefore, the present study aimed to investigate the influence of estradiol/progesterone balance on rat macrophage function and phenotype throughout whole adult lifespan. We ovariectomized rats at the late prepubertal age or at the very end of reproductive lifespan, and examined the expression of ED2 (CD163, a marker of mature resident macrophages related to secretion of inflammatory mediators) on peritoneal macrophages and their ability to produce TNF-α and NO upon LPS-stimulation at different age points. In addition, to delineate direct and indirect effects of estrogen, we assessed the in vitro influence of different concentrations of 17β-estradiol on LPS-induced macrophage TNF-α and NO production. Results showed that: (a) the low frequency of ED2(high) cells amongst peritoneal macrophages of aged rats was accompanied with the reduced TNF-α, but not NO production; (b) estradiol level gradually increased following ovariectomy; (c) macrophage ED2 expression and TNF-α production were dependent on estradiol/progesterone balance and they changed in the same direction; (d) changes in estradiol/progesterone balance differentially affected macrophages TNF-α and NO production; and (e) estradiol exerted pro-inflammatory and anti-inflammatory effects on macrophages in vivo and in vitro, respectively. Overall, our study discloses that estradiol/progesterone balance contributes to the fine-tuning of rat macrophage secretory capacity, and adds to a better understanding of the ovarian steroid hormone role in the regulation of macrophage function, and its significance for the age-associated changes in innate immunity.
authors.affiliation: Institute of Virology, Vaccines and Sera, "Torlak", Immunology Research Center "Branislav Janković", Vojvode Stepe 458, 11152 Belgrade, Serbia. Electronic address: miradim@sezampro.rs.
authors.forename: Mirjana
authors.initials: M
authors.lastname: Dimitrijević
authors.forename: Stanislava
authors.initials: S
authors.lastname: Stanojević
authors.forename: Nataša
authors.initials: N
authors.lastname: Kuštrimović
authors.forename: Katarina
authors.initials: K
authors.lastname: Mitić
authors.forename: Vesna
authors.initials: V
authors.lastname: Vujić
authors.forename: Iva
authors.initials: I
authors.lastname: Aleksić
authors.forename: Katarina
authors.initials: K
authors.lastname: Radojević
authors.forename: Gordana
authors.initials: G
authors.lastname: Leposavić
mesh_terms: D000375:Aging / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D004958:Estradiol / Q000008:administration & dosage / Q000378:metabolism*; D005260:Female; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis; D010052:Ovariectomy; D010641:Phenotype; D011374:Progesterone / Q000378:metabolism*; D051381:Rats; D011956:Receptors, Cell Surface / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D000098902:CD163 Antigen
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000098902:CD163 Antigen; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D011956:Receptors, Cell Surface; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D011374:Progesterone; D004958:Estradiol
keywords: Aging; Estradiol/progesterone balance; Macrophages; NO; Rat; TNF-α