title: Selective inhibition of extracellular oxidants liberated from human neutrophils--A new mechanism potentially involved in the anti-inflammatory activity of hydroxychloroquine.
abstract: Hydroxychloroquine is used in the therapy of rheumatoid arthritis or lupus erythematosus. Although these diseases are often accompanied by activation of neutrophils, there are still few data relating to the impact of hydroxychloroquine on these cells. We investigated the effect of orally administered hydroxychloroquine on neutrophil oxidative burst in rats with adjuvant arthritis. In human neutrophils, extra- and intracellular formation of oxidants, mobilisation of intracellular calcium and the phosphorylation of proteins regulating NADPH oxidase assembly were analysed. Administration of hydroxychloroquine decreased the concentration of oxidants in blood of arthritic rats. The inhibition was comparable with the reference drug methotrexate, yet it was not accompanied by a reduction in neutrophil count. When both drugs were co-applied, the effect became more pronounced. In isolated human neutrophils, treatment with hydroxychloroquine resulted in reduced mobilisation of intracellular calcium, diminished concentration of external oxidants and in decreased phosphorylation of Ca(2+)-dependent protein kinase C isoforms PKCα and PKCβII, which regulate activation of NADPH oxidase on plasma membrane. On the other hand, no reduction was observed in intracellular oxidants or in the phosphorylation of p40(phox) and PKCδ, two proteins directing the oxidase assembly to intracellular membranes. Hydroxychloroquine reduced neutrophil-derived oxidants potentially involved in tissue damage and protected those capable to suppress inflammation. The observed effects may represent a new mechanism involved in the anti-inflammatory activity of this drug.
authors.affiliation: Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, Dúbravská cesta 9, 841 04 Bratislava, Slovak Republic. Electronic address: Viera.Jancinova@savba.sk.
authors.forename: Viera
authors.initials: V
authors.lastname: Jančinová
authors.affiliation: Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, Dúbravská cesta 9, 841 04 Bratislava, Slovak Republic.
authors.forename: Silvia
authors.initials: S
authors.lastname: Pažoureková
authors.affiliation: Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, Dúbravská cesta 9, 841 04 Bratislava, Slovak Republic.
authors.forename: Marianna
authors.initials: M
authors.lastname: Lucová
authors.affiliation: Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, Dúbravská cesta 9, 841 04 Bratislava, Slovak Republic.
authors.forename: Tomáš
authors.initials: T
authors.lastname: Perečko
authors.affiliation: Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, Dúbravská cesta 9, 841 04 Bratislava, Slovak Republic.
authors.forename: Danica
authors.initials: D
authors.lastname: Mihalová
authors.affiliation: Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, Dúbravská cesta 9, 841 04 Bratislava, Slovak Republic.
authors.forename: Katarína
authors.initials: K
authors.lastname: Bauerová
authors.affiliation: Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, Dúbravská cesta 9, 841 04 Bratislava, Slovak Republic.
authors.forename: Radomír
authors.initials: R
authors.lastname: Nosáľ
authors.affiliation: Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, Dúbravská cesta 9, 841 04 Bratislava, Slovak Republic.
authors.forename: Katarína
authors.initials: K
authors.lastname: Drábiková
mesh_terms: D000328:Adult; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000473:pathology; D020013:Calcium Signaling / Q000187:drug effects; D005110:Extracellular Space / Q000378:metabolism*; D006801:Humans; D006886:Hydroxychloroquine / Q000494:pharmacology*; D066298:In Vitro Techniques; D007958:Leukocyte Count; D008297:Male; D008727:Methotrexate / Q000494:pharmacology; D008875:Middle Aged; D019255:NADPH Oxidases / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D016877:Oxidants / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D016897:Respiratory Burst / Q000187:drug effects; D055815:Young Adult
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D016877:Oxidants; D006886:Hydroxychloroquine; D019255:NADPH Oxidases; D011493:Protein Kinase C; D008727:Methotrexate
keywords: Adjuvant arthritis; Chemiluminescence; Hydroxychloroquine; Intracellular calcium; Neutrophil; Protein kinase C