ABSTRACT
Tissue damage in autoimmune diseases involves excessive production of reactive oxygen species (ROS) triggered by immune complexes (IC) and neutrophil (PMN) interactions via receptors for the Fc portion of IgG (FcgammaR) and complement receptors (CR). Modulation of both the effector potential of these receptors and ROS generation may be relevant to the maintenance of body homeostasis. In the present study, the modulatory effect of four flavonols (myricetin, quercetin, kaempferol, galangin) on rabbit PMN oxidative metabolism, specifically stimulated via FcgammaR, CR or both classes of receptors, was evaluated by luminol- and lucigenin-dependent chemiluminescence assays. Results showed that flavonol inhibitory effect was not dependent on the cell membrane receptor class stimulated but related to the lipophilicity of the compounds (their apparent partition coefficient values were obtained by high-performance liquid chromatography), and was also inversely related to the number of hydroxyl groups in the flavonol B ring and the ROS-scavenger activity (assessed by the luminol--H2O2--horseradish peroxidase reaction). Under the experimental conditions the flavonols tested were not toxic to PMNs (evaluated by lactate dehydrogenase release and trypan blue exclusion) and did not interfere with IC-induced phagocytosis (evaluated by transmission electron microscopy). Our results suggested that inhibition of IC-stimulated PMNs effector functions by the flavonols tested herein was the result of cooperation of different cellular mechanisms.
Subject(s)
Benzene Derivatives/pharmacology , Flavonols/pharmacology , Immunologic Factors/chemistry , Neutrophils/drug effects , Neutrophils/metabolism , Receptors, Complement/metabolism , Receptors, Fc/metabolism , Acridines/chemistry , Animals , Antigen-Antibody Complex/immunology , Antigen-Antibody Complex/metabolism , Benzene Derivatives/chemistry , Benzene Derivatives/metabolism , Complement System Proteins/metabolism , Flavonoids/chemistry , Flavonoids/metabolism , Flavonoids/pharmacology , Flavonols/chemistry , Flavonols/metabolism , Free Radical Scavengers/chemistry , Free Radical Scavengers/metabolism , Free Radical Scavengers/pharmacology , Hydrophobic and Hydrophilic Interactions , Hydroxylation , Immune Complex Diseases/drug therapy , Immune Complex Diseases/metabolism , Immunologic Factors/metabolism , Kaempferols/chemistry , Kaempferols/metabolism , Kaempferols/pharmacology , Luminescent Measurements , Luminol/chemistry , Molecular Structure , Neutrophils/immunology , Oxidation-Reduction/drug effects , Phagocytosis/drug effects , Phagocytosis/immunology , Quercetin/chemistry , Quercetin/metabolism , Quercetin/pharmacology , Rabbits , Receptors, Complement/immunology , Receptors, Fc/immunology , Structure-Activity RelationshipABSTRACT
Treatment with cyclosporin A (CsA) improves proteinuria and reduces renal cellular infiltration in chronic serum sickness (CSS). We examined if these effects were associated with a reduced renal expression of CD54 and its ligands, interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha) and MHC class II molecules. We studied two groups of rats in which CSS was induced by daily injections of ovalbumin (OVA): a group treated with CsA (OVA.CsA group, n = 11) and a group that received no treatment (OVA.CSS group, n = 11). An additional group of five rats (control group) received only phosphate buffer. Immunostaining techniques were used to follow CSS and to study the expression of CD54, CD18, CD11b/c, IFN-gamma, TNF-alpha and MHC class molecules. Proteinuria (mg/24 h) was reduced from 248.2 +/- 73.1 (OVA.CCS group) to 14.5 +/- 13.1 with CsA treatment (P < 0.0001). The renal expression of CD54 and its ligands (CD18 and CD11b/c) was reduced by 50% to 75%. Correspondingly, there was a 60% to 85% reduction in the number of infiltrating leucocytes. The number of cells expressing TNF-alpha, IFN-gamma and MHC II molecules was also reduced. CsA reduces expression of CD54 and its ligands. This effect is associated with a reduction of cellular infiltration, IFN-gamma, TNF-alpha-producing cells and with MHC II expression in the kidney. These findings suggest that expression of adhesion molecules plays a critical role in CSS and underline the importance of cellular immunity in this experimental model.