FK506 attenuates developing and established joint inflammation and suppresses interleukin 6 and nitric oxide expression in bacterial cell wall induced polyarthritis

Objective, To determine the efficacy of therapeutic administration of FK506 (Tacrolimus) in suppressing developing and established joint inflammation, proinflammatory cytokine expression, and nitric oxide (NO) production in p eptidoglycan-polysaccharide (PG/PS) induced experimental polyarthritis in r ats. Methods. Chronic joint inflammation was induced by intraperitoneal injectio n of PG/PS, and joint inflammation was quantified using arthritis index and paw volume. Serum and joint levels of interleukin 6 (IL-6) were measured b y bioassay and Western blot analysis respectively, and serum levels of NO p roduction were determined by the Griess procedure and the expression of the inducible isoform of nitric oxide synthase (i-NOS) in the joints was deter mined by Western blot analysis. Results. Arthritis induced by PG/PS is biphasic, progressing through an ini tial acute phase and a remission phase, which is followed by a persistent c hronic phase. Daily administration of FK506 initiated during the remission phase significantly attenuated the onset and development of chronic joint i nflammation. We observed a significant reduction in joint inflammation and swelling, an apparent suppression of pannus development, and minimal erosiv e damage to the articular cartilage and subchondral bone. Fully established chronic joint inflammation was also ameliorated by daily administration of FK506. Joint swelling and inflammation was significantly reduced by 5 days posttreatment with FK506 and the erosive activity associated with the pann us appeared diminished. The elevated expression of IL-6 and NO characterist ic of chronic joint inflammation in the serum and in joint tissue was signi ficantly reduced by FK506 treatment. Conclusion, Therapeutic administration of FK506 has a profound antiinflamma tory effect on the development of the chronic, erosive arthritis induced by PG/PS. This attenuation in joint inflammation was associated with suppress ion of IL-6 and NO production systemically and locally in the joints. Our d ata suggest that FK506 may be effective in the treatment of chronic joint i nflammation associated with rheumatoid arthritis.