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Comparison of anti-arthritic properties of leflunomide with methotrexate and FK506: effect on T cell activation-induced inflammatory cytokine production in vitro and rat adjuvant-induced arthritis

Comparison of anti-arthritic properties of leflunomide with methotrexate and FK506: effect on T cell activation-induced inflammatory cytokine production in vitro and rat adjuvant-induced arthritis

Inflammation Research: Official Journal of the European Histamine Research Society . 53(10): 544-550

ISSN/ISBN: 1023-3830

PMID: 15597149

DOI: 10.1007/s00011-004-1294-9

To examine the effect of leflunomide (LEF) on T cell activation-induced inflammatory cytokine production in human peripheral blood mononuclear cells (PBMC) and rat established adjuvant-induced arthritis (AIA), and compare these effects with methotrexate (MTX) and FK506 (tacrolimus), focusing on improvement of joint function in AIA. Human PBMC were cultured with immobilized anti-CD3/CD28 monoclonal antibody to produce tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6. The active metabolite of LEF was used in in vitro study. AIA was induced in female Lewis rats. Paw swelling and grip strength were measured as indicators of arthritis and joint function, respectively. Rats were therapeutically administered LEF (3.2-32 mg/kg) from days 15-24 by oral administration. LEF inhibited anti-CD3/CD28 induced production of TNF-alpha, IL-1beta and IL-6, with IC50 values of 27, 21 and 21 microg/ml, respectively. LEF also suppressed mouse bone marrow cell MTT conversion, with an IC50 value of 15 microg/ml. LEF significantly inhibited paw swelling and loss of grip strength in established AIA at 10 and 32 mg/kg. The inhibition of paw swelling and grip strength loss by LEF was more potent than MTX. However, maximum recovery of grip strength loss by LEF (23.5%) was less potent compared to that with FK506 (57.8%). LEF inhibited anti-CD3/CD28 induced inflammatory cytokine production in human PBMC at concentrations showing deleterious effects on bone marrow cell proliferation. LEF is superior to MXT in improving arthritis and joint function in established AIA, but is inferior to FK506 in recovering joint function, probably due to its anti-proliferative actions.

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Accession: 011882438

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