Inhibition of interleukin-6 and nitric oxide expression with tacrolimus attenuates chronic joint inflammation in experimental polyarthritis

The immunosuppressive drug, Tacrolimus(FK506), attenuates the development of chronic polyarthritis induced by the administration of an aqueous suspension of peptidoglycan/polysaccharide(PG/PS, single i. p. injection of 25ug PG/PG/g-body weight administered on day 0) isolated from group A Streptococcalbauteria into female LEW/N rats. Joint histopathology was correlated with expression of tumor necrosis factor(TNF), interleukin-1(IL-1), interleukin-6(IL-6), and nitric oxide(NO), during the development of chronic joint inflammation The onset of chronic joint pathology characterized synovitis and articular cartilage and bone erosion is preceded by increases in TNF and IL-1 on day 17, followed by increases IL-6 and NO on day 18 TNF and IL-1 diminish to control values by day 22. IL-6 and NO remained elevated concurrent with the progression of joint inflammation. Administration of Tacrolimus(0.4mg/kg/day) on day 10 before the development of chronic phase of joint inflammation suppressed the expression of IL-6 and NO, but not TNF or IL-1 and attenuated the development joint pathology, by suppressing pannus development and bone and cartilage erosion. These observations suggest that expression of TNF and IL-1 may trigger the onset of chronic joint inflammation, and sustained expression of IL-6 and/or NO may be required for development and persistence of chronic joint inflammation. The inhibition of IL-6 and NO by Tacrolimus may explain its efficacy on ameliorating PG/PS-induced chronic joint inflammation Tacrolimus may have therapeutic value in the treatment of pint inflammation associated with human rheumatoid arthritis.