Suppressive effect of an orally active MEK1/2 inhibitor in two different animal models for rheumatoid arthritis: a comparison with leflunomide.

摘要

To examine the effects of a mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2-inhibitor, JTP-74057, on inflammatory arthritis development, and compare its anti-arthritic effect with leflunomide.Human, mouse, and rat peripheral blood mononuclear cells (PBMCs) were used. Lewis rats and DBA/1J mice were used for animal models.JTP-74057 was tested between 0.1-100?nM in in-vitro studies. JTP-74057 (0.01-0.3?mg/kg) and leflunomide (2-10?mg/kg) were administered orally in vivo.PBMCs were stimulated with lipopolysaccharide. Adjuvant-induced arthritis (AIA) and type II collagen-induced arthritis (CIA) was induced in Lewis rats or DBA1/J mice, respectively.JTP-74057 blocked tumor necrosis factor-α and interleukin-6 production from PBMCs. AIA and CIA development were suppressed almost completely by 0.1?mg/kg of JTP-74057 or 10?mg/kg of leflunomide. In the CIA, JTP-74057, but not leflunomide, suppressed collagen-reactive T-cell proliferation ex vivo, whereas leflunomide, but not JTP-74057, suppressed anti-collagen antibody production.JTP-74057 exerts potent anti-arthritic effects with a different profile from leflunomide, suggesting that JTP-74057 may be useful as a new therapeutic reagent in the treatment of rheumatoid arthritis.