Immunomodulating action of the 3-phenylcoumarin derivative 6,7-dihydroxy-3-[3′,4′-methylenedioxyphenyl]-coumarin in neutrophils from patients with rheumatoid arthritis and in rats with acute joint inflammation

• Published in: Inflammation research Vol. 69; no. 1; pp. 115 - 130
• Main Authors: Albiero, Lucinéia Reuse, de Andrade, Micássio Fernandes, Marchi, Larissa Fávaro, Landi-Librandi, Ana Paula, de Figueiredo-Rinhel, Andréa Silva Garcia, Carvalho, Camila Andressa, Kabeya, Luciana Mariko, de Oliveira, Renê Donizeti Ribeiro, Azzolini, Ana Elisa Caleiro Seixas, Pupo, Mônica Tallarico, da Silva Emery, Flávio, Lucisano-Valim, Yara Maria
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.01.2020; Springer Nature B.V
• Subjects: Allergology; Antigen-antibody complexes; Arthritis; Biomedical and Life Sciences; Biomedicine; Cell activation; Chemotaxis; Cholesterol; Coumarin; Cytotoxicity; Dermatology; Edema; Elastase; IL-1β; Immunology; Immunomodulators; Infiltration; Inflammation; Interleukin 6; Joints (anatomy); Lecithin; Leukocytes; Leukocytes (neutrophilic); Liposomes; Neurology; Neutrophils; Original Research Paper; Pharmacology/Toxicology; Phosphatidylcholine; Polydispersity; Reactive oxygen species; Remission; Rheumatoid arthritis; Rheumatology; Toxicity; Tumor necrosis factor-α; Zeta potential; Liposome; Inflammation; Neutrophil; Chemotaxis; Rheumatoid arthritis; 3-Phenylcoumarin
• ISSN: 1023-3830; 1420-908X
• DOI: 10.1007/s00011-019-01298-w

Objective To examine whether free (3-PD-5 free ) and/or liposomal (3-PD-5 lipo ) 6,7-dihydroxy-3-[3′,4′-methylenedioxyphenyl]-coumarin (3-PD-5) (1) modulate the effector functions of neutrophils from patients with rheumatoid arthritis under remission (i-RA) and with active disease (a-RA), in vitro; and (2) exert anti-inflammatory effect in a rat model of zymosan-induced acute joint inflammation. Methods and results Incorporation of 3-PD-5 into unilamellar liposomes of soya phosphatidylcholine and cholesterol was efficient (57.5 ± 7.9%) and yielded vesicles with low diameter (133.7 ± 18.4 nm), polydispersity index (0.39 ± 0.06), and zeta potential (− 1.22 ± 0.34 mV). 3-PD-5 free (1 µM) and 3-PD-5 lipo (3 µM) equally suppressed elastase release and reactive oxygen species generation in neutrophils from healthy subjects and i-RA and a-RA patients, stimulated with immune complexes. 3-PD-5 free (20 µM) suppressed the release of neutrophil extracellular traps and chemotaxis in vitro, without clear signs of cytotoxicity. 3-PD-5 lipo (1.5 mg/kg, i.p.) diminished joint edema and synovial infiltration of total leukocytes and neutrophils, without changing the synovial levels of TNF-α, IL-1β, and IL-6. Conclusion Altogether, the results reported herein indicate that 3-PD-5 is a promising modulator of the early stages of acute joint inflammation that can help to diminish not only excessive neutrophil infiltration in the synovia but also neutrophil activation and its outcomes in RA patients.