Differential effects of FK506 and methotrexate on inflammatory cytokine levels in rat adjuvant-induced arthritis.

Abstract

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)-a, 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-a, 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-a, 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-a and IL-1beta levels in paw tissue even in short-term (3-day) therapeutic treatment. It reduced all levels of TNF-a, IL-1beta, and IL-6 in paws in 6-day therapeutic treatment. In contrast, therapeutic treatment with MTX affected neither TNF-a 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-a, 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.

• Authors: Katsue Magari, Susumu Miyata, Fusako Nishigaki, Yoshitaka Ohkubo, Seitaro Mutoh, Toshio Goto
• Journal: The Journal of rheumatology (J Rheumatol) Vol. 30 Issue 10 Pg. 2193-200 (Oct 2003) ISSN: 0315-162X [Print] Canada
• PMID: 14528517 (Publication Type: Journal Article)

Chemical References

• Cytokines
• Immunosuppressive Agents
• Interleukin-1
• Interleukin-6
• Tumor Necrosis Factor-alpha
• Tacrolimus
• Methotrexate

Topics

• Animals
• Arthritis, Experimental (drug therapy, metabolism, pathology)
• Cytokines (metabolism)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Edema (drug therapy, pathology)
• Enzyme-Linked Immunosorbent Assay
• Female
• Hindlimb (drug effects, metabolism, pathology)
• Immunosuppressive Agents (administration & dosage, therapeutic use)
• Interleukin-1 (metabolism)
• Interleukin-6 (metabolism)
• Methotrexate (administration & dosage, therapeutic use)
• Rats
• Rats, Inbred Lew
• Tacrolimus (administration & dosage, therapeutic use)
• Tumor Necrosis Factor-alpha (analysis)