Differential effects of FK506 and methotrexate on inflammatory cytokine levels in rat adjuvant-induced arthritis
Magari, K.; Miyata, S.; Nishigaki, F.; Ohkubo, Y.; Mutoh, S.; Goto, T.
Journal of Rheumatology 30(10): 2193-2200
2003
ISSN/ISBN: 0315-162X PMID: 14528517 Document Number: 556679
Objective: To investigate the effects of prophylactic and therapeutic treatments with FK506 (tacrolimus), an immunosuppressive drug that specifically inhibits T cell activation, and methotrexate (MTX) on inflammatory cytokines, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6 levels in rat adjuvant-induced arthritis (AIA). Methods: AIA was induced in female Lewis rats. Arthritis was assessed by hindpaw swelling. TNF-alpha, IL-1beta, and IL-6 levels in paw extracts were determined by ELISA. To assess the effects on cytokine levels, rats were treated prophylactically with FK506 (3 mg/kg) or MTX (0.1 mg/kg) from day 1 to day 17, and therapeutically with FK506 (5 mg/kg) or MTX (1 mg/kg) from day 15 to day 17 (3-day treatment) or day 15 to 20 (6-day treatment) by oral administration. Results: TNF-alpha, IL-1beta, and IL-6 levels in paw tissue were found to significantly increase between day 15 and day 21 after adjuvant injection, when the arthritis was in a developed stage. Prophylactic treatment with FK506 and MTX suppressed arthritis and reduced the levels of those inflammatory cytokines. FK506 caused a marked reduction of TNF-alpha and IL-1beta levels in paw tissue even in short-term (3-day) therapeutic treatment. It reduced all levels of TNF-alpha, IL-1beta, and IL-6 in paws in 6-day therapeutic treatment. In contrast, therapeutic treatment with MTX affected neither TNF-alpha or IL-6 levels in paws. MTX reduced IL-1beta levels only in the 6-day treatment. Conclusion: FK506 is more effective than MTX in reducing elevated levels of inflammatory cytokines TNF-alpha IL-1beta, and IL-6 in established stages of AIA. Our findings suggest that inhibition of T cell activation results in a rapid reduction of inflammatory cytokine levels even after the arthritis is established in AIA.