ABSTRACT
BACKGROUND: At the development of graft versus host disease in genetically homogeneous population of (C57BI/6 x DBA/2) Fl mice two clinical phenotypes of SLE-like disease were revealed: lupus+ (immune complex glomerulonephritis and hemnolytic anemia) and lupus - (hemolytic anemia). The GvHD phenotypic heterogeneity is determined by the Th2-polarization: Th2 lymphocyte predominant activity, leads to the lupus+development, or prevalence activity of Th1 cells, leads to the lupus- development. OBJECTIVE: Our aim was to evaluate the possibility of using an experimental model of autoimmnune disease for studying and testing of epigenetic modifications, shifting Th1/Th2 balance in vivo. METHODS: Chronic GVHD was induced in B6D2F1 mice by the transplantation of 130x10(6) parental DBA/2 splenocytes. Anti-ds-DNA, total IgG and IgGI, IgG2a Abs were measured by ELISA. RESULTS: Six- to 8-week-old female DBA/2 and B6D2F1 mice were obtained from Biological Research Laboratory (Novosibirsk). It was established that regular moderate physical activity (unladed swimming) shifted Th1/Th2 balance towards Th1. This leads to a decrease in a population of recipients the lupus+ mice from 57 to 26% (p <0,001) with significantly reduced hypergammaglobulinemia (IgG from 2,8 to 2,0 mg/ml; p <0,047) and DNA antibodies titer from 0,18 to 0,12 OD (p =0,05). Administration of epigenetic modificator bisphenol A at low doses, which mimicking estrogen effects, enhances the proportion of lupus+ mice in experimental groups from 33 to 64% (p <0,001) and impairs their clinical status by the increasing the urine protein level from 2.8 to 4,2 mg/ml (p <0,001) in animals. CONCLUSION: Th1/Th2 - balance presumably is determined by the immune system epigenetic modification in experimental mice, formed on the previous stages of ontogeny and defines the direction of immune processes development in individual animal.
Subject(s)
Autoimmune Diseases/genetics , Autoimmunity/genetics , Epigenomics/methods , Graft vs Host Disease/genetics , T-Lymphocytes/immunology , Animals , Autoimmune Diseases/immunology , Disease Models, Animal , Enzyme-Linked Immunosorbent Assay , Female , Graft vs Host Disease/immunology , Immunoglobulins/immunology , Kidney Tubules/immunology , Kidney Tubules/metabolism , Kidney Tubules/pathology , Mice , Mice, Inbred C57BL , Mice, Inbred DBA , Spleen/immunology , Spleen/transplantationABSTRACT
Synthetic water-soluble phenolic antioxidant TS-13 exhibits pronounced anti-inflammatory properties in vivo and induces intracellular signal system Nrf2/ARE. At concentrations 150-1000 microM it inhibits nitric oxide (NO) production in mouse peritoneal macrophages. However, this compound at low concentrations (1-100 microM) paradoxically increases NO production and decreases activity of arginase. These results are indicative of an ambiguous role of NO and its metabolites in the mechanism of development of inflammatory reaction.
Subject(s)
Antioxidants/pharmacology , Arginine/metabolism , Macrophages/drug effects , NF-E2-Related Factor 2/metabolism , Thiosulfonic Acids/pharmacology , Animals , Antioxidants/chemical synthesis , Antioxidants/chemistry , Lipopolysaccharides/pharmacology , Macrophages/metabolism , Mice , Nitric Oxide/metabolism , Thiosulfonic Acids/chemical synthesis , Thiosulfonic Acids/chemistryABSTRACT
Known cytochrome P450-dependent oxygenase inhibitor ketoconazole (5-50 microM) blocked the murine macrophage-mediated modification of human low density lipoprotein (LDL) as measured by production of thiobarbituric acid-reactive substance, stimulation of [125I]LDL degradation in a fresh set of macrophages and LDL electrophoretic mobility, in a dose-dependent manner with complete inhibition at 30-40 microM. When resident macrophages were incubated with LDL in the presence of metyrapone, methoxsalen and alpha-naphthaflavone at concentrations that have been shown to inhibit the cytochrome P450-dependent oxygenases, there was no change in LDL modification. Induction of benzo[alpha]pyrene hydroxylase activity in macrophages by 24 h incubation with benzo[alpha]pyrene was accompanied by a 1.5-fold increase of LDL modification which has been leveled down by ketoconazole as well as methoxsalen and alpha-naphthaflavone. Furthermore, ketoconazole effectively diminished cell-free LDL oxidation induced by iron, but not copper ions, and reduced the spontaneous and zymosan-stimulated lucigenin-amplified chemiluminescence of macrophages. The data allow us to suggest that ketoconazole inhibits LDL oxidation by acting as an iron chelator and/or inhibitor of prooxidant forms of iron-containing enzymes.
