title: 17β-Estradiol influences in vitro response of aged rat splenic conventional dendritic cells to TLR4 and TLR7/8 agonists in an agonist specific manner.
abstract: This study was undertaken considering that, despite the broad use of the unopposed estrogen replacement therapy in elderly women, data on estrogen influence on the functional capacity of dendritic cells (DCs), and consequently immune response are limited. We examined the influence of 17β-estradiol on phenotype, cytokine secretory profile, and allostimulatory and polarizing capacity of splenic (OX62+) conventional DCs from 26-month-old (aged) Albino Oxford rats matured in vitro in the presence of LPS, a TLR4 agonist, and R848, a TLR7/8 agonist. In the presence of 17β-estradiol, DCs from aged rats exhibited an impaired ability to mature upon stimulation with LPS, as shown by the lower surface density of MHC II and costimulatory CD80 and CD86 molecules. 17β-Estradiol alone enhanced CD40 expression in OX62+ DCs without affecting the expression of other costimulatory molecules, thereby confirming that the expression of this molecule is regulated independently from the regulation of other costimulatory molecules. However, although R848 upregulated the expression of MHC II and CD80 and CD40 costimulatory molecules on DCs, 17β-estradiol diminished the effect of this TLR agonist only on MHC II expression. In conjunction, the previous findings suggest that LPS and R848 elicit changes in the expression of costimulatory molecules via triggering differential intracellular signaling pathways. Furthermore, 17β-estradiol diminished the stimulatory influence of both LPS- and R848-matured OX62+ DCs on allogeneic CD4+ T lymphocyte proliferation in a mixed lymphocyte reaction (MLR). Moreover, as shown in MLR, the exposure to 17β-estradiol during LPS- and R848-induced maturation diminished Th1- and enhanced Th17-driving capacity and reduced Th1-driving capacity of OX62+ DCs, respectively. This suggests that LPS and R848 affect not only the surface phenotype, but also functional characteristics of OX62+ DCs triggering distinct intracellular signaling pathways. Collectively, the findings indicate that estrogen directly acting on OX62+ DCs, may affect CD4+ lymphocyte-dependent immune response in aged female rats.
authors.affiliation: Department of Microbiology and Immunology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia.
authors.forename: Zorica
authors.initials: Z
authors.lastname: Stojić-Vukanić
authors.affiliation: Department of Physiology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia.
authors.forename: Mirjana
authors.initials: M
authors.lastname: Nacka-Aleksić
authors.affiliation: Department of Microbiology and Immunology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia.
authors.forename: Biljana
authors.initials: B
authors.lastname: Bufan
authors.affiliation: Immunology Research Center "Branislav Janković", Institute of Virology, Vaccines and Sera "Torlak", Belgrade, Serbia.
authors.forename: Ivan
authors.initials: I
authors.lastname: Pilipović
authors.affiliation: Department of Microbiology and Immunology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia.
authors.forename: Nevena
authors.initials: N
authors.lastname: Arsenović-Ranin
authors.affiliation: Department of Physiology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia.
authors.forename: Jasmina
authors.initials: J
authors.lastname: Djikić
authors.affiliation: Immunology Research Center "Branislav Janković", Institute of Virology, Vaccines and Sera "Torlak", Belgrade, Serbia.
authors.forename: Duško
authors.initials: D
authors.lastname: Kosec
authors.affiliation: Department of Physiology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia. Electronic address: Gordana.Leposavic@pharmacy.bg.ac.rs.
authors.forename: Gordana
authors.initials: G
authors.lastname: Leposavić
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D019013:CD40 Antigens / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D004958:Estradiol / Q000172:deficiency / Q000494:pharmacology*; D015914:Estrogen Replacement Therapy; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D007959:Lymphocyte Culture Test, Mixed; D051381:Rats; D011919:Rats, Inbred Strains; D013154:Spleen / Q000187:drug effects* / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000819:agonists*; D051199:Toll-Like Receptor 7 / Q000819:agonists*
chemical_list: D000943:Antigens, Differentiation; D019013:CD40 Antigens; D007093:Imidazoles; D008070:Lipopolysaccharides; C459465:OX-62 antigen, rat; D051197:Toll-Like Receptor 4; D051199:Toll-Like Receptor 7; D004958:Estradiol; C402365:resiquimod
keywords: 17β-Estradiol; Aging; Conventional dendritic cells; Cytokines; Rat; Th polarization