Leflunomide protects from T-cell-mediated liver injury in mice through inhibition of nuclear factor kappaB.

Abstract

Leflunomide is a novel immunosuppressive and anti-inflammatory agent for the treatment of autoimmune disease. The aim of this study was to investigate whether leflunomide protects from liver injury induced by concanavalin A (Con A), a T-cell-dependent model of liver damage. BALB/c mice were injected with 25 mg/kg Con A in the presence or absence of 30 mg/kg leflunomide. Liver injury was assessed biochemically and histologically. Levels of circulating cytokines and expressions of cytokine messenger RNA (mRNA) in the liver and the spleen were determined. Treatment with leflunomide markedly reduced serum transaminase activities and the numbers of dead liver cells. Leflunomide significantly inhibited increases in plasma tumor necrosis factor alpha (TNF-alpha) and interleukin 2 concentrations, and also reduced TNF-alpha mRNA expression in the liver after administration of Con A. These findings were supported by the results in which leflunomide administration decreased the number of T lymphocytes infiltrating the liver as well as inhibiting their production of TNF-alpha. Activation of nuclear factor kappaB (NF-kappaB), which regulates TNF-alpha production, was inhibited in the liver of mice treated with leflunomide, resulting in a reduction of TNF-alpha production from lymphocytes infiltrating the liver. In conclusion, leflunomide is capable of regulating T-cell-mediated liver injury in vivo and that this event may depend on the decrease of TNF-alpha production in the liver through inhibition of NF-kappaB activation caused by leflunomide.

• Authors: Motoaki Imose, Masahito Nagaki, Kiminori Kimura, Shinji Takai, Motohiro Imao, Takafumi Naiki, Yosuke Osawa, Takahiko Asano, Hideki Hayashi, Hisataka Moriwaki
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 40 Issue 5 Pg. 1160-9 (Nov 2004) ISSN: 0270-9139 [Print] United States
• PMID: 15455409 (Publication Type: Journal Article)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Caspase Inhibitors
• Cytokines
• Interleukin-2
• Isoxazoles
• NF-kappa B
• RNA, Messenger
• Tumor Necrosis Factor-alpha
• Concanavalin A
• Interferon-gamma
• Mitogen-Activated Protein Kinases
• Leflunomide

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Caspase Inhibitors
• Cells, Cultured
• Concanavalin A (immunology)
• Cytokines (genetics, metabolism)
• Enzyme Activation (drug effects)
• Hepatitis (immunology, pathology, physiopathology, prevention & control)
• Interferon-gamma (blood)
• Interleukin-2 (blood)
• Isoxazoles (pharmacology)
• Leflunomide
• Liver (metabolism, pathology)
• Mice
• Mice, Inbred BALB C
• Mitogen-Activated Protein Kinases (metabolism)
• NF-kappa B (antagonists & inhibitors)
• RNA, Messenger (metabolism)
• T-Lymphocytes (immunology, metabolism, pathology)
• Tumor Necrosis Factor-alpha (biosynthesis, metabolism)