title: Flavonols modulate the effector functions of healthy individuals' immune complex-stimulated neutrophils: a therapeutic perspective for rheumatoid arthritis.
abstract: Rheumatoid arthritis (RA) patients usually exhibit immune complex (IC) deposition and increased neutrophil activation in the joint. In this study, we assessed how four flavonols (galangin, kaempferol, quercetin, and myricetin) modulate the effector functions of healthy individuals' and active RA patients' IC-stimulated neutrophils. We measured superoxide anion and total reactive oxygen species production using lucigenin (CL-luc)- and luminol (CL-lum)-enhanced chemiluminescence assays, respectively. Galangin, kaempferol, and quercetin inhibited CL-lum to the same degree (mean IC50=2.5 μM). At 2.5 μM, quercetin and galangin suppressed nearly 65% CL-lum of active RA patients' neutrophils. Quercetin inhibited CL-luc the most effectively (IC50=1.71±0.36 μM). The four flavonols diminished myeloperoxidase activity, but they did not decrease NADPH oxidase activity, phagocytosis, microbial killing, or cell viability of neutrophils. The ability of the flavonols to scavenge hypochlorous acid and chloramines, but not H2O2, depended on the hydroxylation degree of the flavonol B-ring. Therefore, at physiologically relevant concentrations, the flavonols partially inhibited the oxidative metabolism of IC-stimulated neutrophils without affecting the other investigated effector functions. Using these compounds to modulate IC-mediated neutrophil activation is a promising safe therapeutic strategy to control inflammation in active RA patients.
authors.affiliation: Departamento de Física e Química, Faculdade de Ciências Farmacêuticas de Ribeirão Preto da Universidade de São Paulo, Avenida do Café s/n, Ribeirão Preto, SP 14040-903, Brazil; Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo, Avenida Bandeirantes 3900, Ribeirão Preto, SP 14049-900, Brazil.
authors.forename: Everton O L
authors.initials: EO
authors.lastname: Santos
authors.affiliation: Departamento de Física e Química, Faculdade de Ciências Farmacêuticas de Ribeirão Preto da Universidade de São Paulo, Avenida do Café s/n, Ribeirão Preto, SP 14040-903, Brazil.
authors.forename: Luciana M
authors.initials: LM
authors.lastname: Kabeya
authors.affiliation: Departamento de Física e Química, Faculdade de Ciências Farmacêuticas de Ribeirão Preto da Universidade de São Paulo, Avenida do Café s/n, Ribeirão Preto, SP 14040-903, Brazil.
authors.forename: Andréa S G
authors.initials: AS
authors.lastname: Figueiredo-Rinhel
authors.affiliation: Departamento de Física e Química, Faculdade de Ciências Farmacêuticas de Ribeirão Preto da Universidade de São Paulo, Avenida do Café s/n, Ribeirão Preto, SP 14040-903, Brazil.
authors.forename: Larissa F
authors.initials: LF
authors.lastname: Marchi
authors.affiliation: Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo, Avenida Bandeirantes 3900, Ribeirão Preto, SP 14049-900, Brazil.
authors.forename: Micássio F
authors.initials: MF
authors.lastname: Andrade
authors.affiliation: Departamento de Física e Química, Faculdade de Ciências Farmacêuticas de Ribeirão Preto da Universidade de São Paulo, Avenida do Café s/n, Ribeirão Preto, SP 14040-903, Brazil.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Piatesi
authors.affiliation: Departamento de Física e Química, Faculdade de Ciências Farmacêuticas de Ribeirão Preto da Universidade de São Paulo, Avenida do Café s/n, Ribeirão Preto, SP 14040-903, Brazil.
authors.forename: Adriana B
authors.initials: AB
authors.lastname: Paoliello-Paschoalato
authors.affiliation: Departamento de Física e Química, Faculdade de Ciências Farmacêuticas de Ribeirão Preto da Universidade de São Paulo, Avenida do Café s/n, Ribeirão Preto, SP 14040-903, Brazil.
authors.forename: Ana Elisa C S
authors.initials: AE
authors.lastname: Azzolini
authors.affiliation: Departamento de Física e Química, Faculdade de Ciências Farmacêuticas de Ribeirão Preto da Universidade de São Paulo, Avenida do Café s/n, Ribeirão Preto, SP 14040-903, Brazil. Electronic address: yaluva@usp.br.
authors.forename: Yara M
authors.initials: YM
authors.lastname: Lucisano-Valim
mesh_terms: D000328:Adult; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology*; D000936:Antigen-Antibody Complex / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D015550:Cell Degranulation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D044949:Kaempferols / Q000737:chemistry / Q000494:pharmacology*; D008875:Middle Aged; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology; D010084:Oxidation-Reduction / Q000187:drug effects; D009195:Peroxidase / Q000378:metabolism; D011794:Quercetin / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000893:Anti-Inflammatory Agents; D000936:Antigen-Antibody Complex; D005419:Flavonoids; D044949:Kaempferols; D017382:Reactive Oxygen Species; C037032:galangin; C006552:kaempferol; C040015:myricetin; D011794:Quercetin; D009195:Peroxidase
keywords: Flavonols; Immune complex; Neutrophils; Phagocytosis; Reactive oxygen species; Rheumatoid arthritis