Effects and mechanisms of FR167653, a dual inhibitor of interleukin-1 and tumor necrosis factor, on adjuvant arthritis in rats

Effects and mechanisms of FR167653, 1-[7-(4-fluorophenyl)-1,2,3,4-tetrahydro-8-(4-pyridyl)pyrazolo[5,1-c][1,2,4] triazin-2-yl]-2-phenylethanedione sulfate monohydrate, a dual inhibitor of interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha), on rat adjuvant arthritis (AA) was investigated. Complete Freund's adjuvant was used to induce AA in rats. Secondary paw swelling of AA rats was measured, and polyarthritis index was scored. Synoviocytes were separated by the method of collagenase and DNase digestion. Synoviocytes proliferation was assayed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. TNF-alpha, IL-1 and interleukin-10 (IL-10) production of synoviocytes was measured with ELISA. The expression of IL-10 mRNA of synoviocytes was determined using RT-PCR. There were significant secondary inflammatory reactions in AA rats, which accompanied with the decrease of body and immune organs weight simultaneously. The administration of FR167653 (4, 12, 36 mg/kg, subcutaneously (s.c.)) inhibited the inflammatory response and restored the weight of body and immune organs of AA rats. Synoviocytes proliferation of AA rats significantly increased, and the levels of TNF-alpha and IL-1 in supernatants of synoviocytes in AA rats were also elevated compared with the sham group. The administration of FR167653 (4, 12, 36 mg/kg, s.c.) reduced the above changes significantly. In contrast to TNF-alpha and IL-1, IL-10 production and the level of its mRNA of synoviocytes in AA rats were apparently decreased. FR167653 (4, 12, 36 mg/kg, s.c.) markedly increased IL-10 in synoviocytes at protein and transcription level. The results indicated that FR167653 had a beneficial effect on rats AA due to modulating inflammatory cytokines production of synoviocytes, which played a crucial role in pathogenesis of this disease.