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

Inflamm Res. 2012 May;61(5):445-54. doi: 10.1007/s00011-011-0431-5. Epub 2012 Jan 14.

Abstract

Objective and design: 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.

Materials: Human, mouse, and rat peripheral blood mononuclear cells (PBMCs) were used. Lewis rats and DBA/1J mice were used for animal models.

Treatment: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Publication types

  • Comparative Study

MeSH terms

  • Administration, Oral
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use*
  • Arthritis, Experimental / drug therapy*
  • Collagen Type II / immunology
  • Cytokines / biosynthesis
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / therapeutic use*
  • Humans
  • Interleukin-6 / biosynthesis
  • Isoxazoles / administration & dosage
  • Isoxazoles / therapeutic use*
  • Leflunomide
  • Lipopolysaccharides / pharmacology
  • Lymphocyte Activation / drug effects
  • MAP Kinase Kinase 1 / antagonists & inhibitors*
  • MAP Kinase Kinase 2 / antagonists & inhibitors*
  • Mice
  • Mice, Inbred ICR
  • Pyridones / therapeutic use*
  • Pyrimidinones / therapeutic use*
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Collagen Type II
  • Cytokines
  • Enzyme Inhibitors
  • Interleukin-6
  • Isoxazoles
  • Lipopolysaccharides
  • Pyridones
  • Pyrimidinones
  • trametinib
  • MAP Kinase Kinase 1
  • MAP Kinase Kinase 2
  • Leflunomide