Effects of vitamin K 2 combined with methotrexate against mitogen‐activated peripheral blood mononuclear cells of healthy subjects and rheumatoid arthritis patients

• Published in: Fundamental & clinical pharmacology Vol. 35; no. 5; pp. 832 - 842
• Main Authors: Xu, Wencheng, Wu, Hongguang, Tahara, Koichiro, Chen, Shuhe, Wang, Xiaoqin, Tanaka, Sachiko, Sugiyama, Kentaro, Sawada, Tetsuji, Hirano, Toshihiko
• Format: Journal Article
• Language: English
• Published: England 01.10.2021
• Subjects: Adult; Aged; Aged, 80 and over; Antirheumatic Agents - administration & dosage; Antirheumatic Agents - pharmacology; Antirheumatic Agents - therapeutic use; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - metabolism; Drug Therapy, Combination; Female; Healthy Volunteers; Humans; Inhibitory Concentration 50; Leukocytes, Mononuclear - drug effects; Male; Methotrexate - administration & dosage; Methotrexate - pharmacology; Methotrexate - therapeutic use; Middle Aged; Vitamin K 2 - administration & dosage; Vitamin K 2 - pharmacology; Vitamin K 2 - therapeutic use; Young Adult; peripheral blood mononuclear cells; methotrexate; immunosuppressive pharmacodynamics; rheumatoid arthritis; vitamin K2
• ISSN: 0767-3981; 1472-8206
• DOI: 10.1111/fcp.12676

Methotrexate (MTX) is used as anchor drug for patients with early and established rheumatoid arthritis (RA). Vitamin K administration was also reported to be associated with decreased disease activity in RA. Immunosuppressive pharmacodynamics of vitamin K combined with MTX was investigated. Mitogen-activated peripheral blood mononuclear cells (PBMCs) were used to evaluate immunosuppressive pharmacodynamics of drugs in vitro. Vitamin K alone dose-dependently suppressed T cell mitogen-activated proliferation of PBMCs of both healthy subjects and RA patients. 446.5 and 2232.5 ng/mL vitamin K significantly decreased the IC values of MTX on the proliferation of PBMCs of RA patients, with little influences on the pharmacodynamics of MTX in the healthy PBMCs. 4465 ng/mL vitamin K potentiated the pharmacodynamics of MTX in both RA patients and healthy PBMCs. The additional effects of vitamin K to potentiate the suppressive effects of MTX seemed not to be related to the regulation of CD4 CD25 T cells or CD4 CD25 Foxp3 Treg cells. MTX alone at 100 ng/mL significantly decreased the percentage of CD4 T cells in PBMCs of healthy subjects (p < 0.001) with a slight influence in that of RA patients (not significant) and the combination did not show synergistic inhibitory effect. Vitamin K alone tended to suppress the secretion of IL-17, IFN-γ, and TNF-α from the activated PBMCs of RA patients with smaller influences on the cytokine productions from healthy PBMCs. These additional effects of vitamin K were also observed in combination with MTX. The above information may partially elucidate the potentiation effects of vitamin K on the immunosuppressive efficacy of MTX.