Analysis of the cytokine network among tumor necrosis factor interleukin-1β, interleukin-8, and interleukin-1 receptor antagonist in monosodium urate crystal-induced rabbit arthritis

In the present study, we analyzed the cytokine network among TNFα, IL- 1β, IL-8, and IL-1 receptor antagonist (IL-1Ra) in a rabbit experimental model of acute gout. The production of TNFα in synovial fluids reached the peak at 2 hours after the intra-articular injection of monosodium urate (MSU) crystals. The production of IL-1β and IL-8 reached the first peak at 2 hours and the second peak at 9 and 12 hours, respectively. The production of endogenous IL-1Ra reached the peak at 9 hours. The source of TNFα and the first phase of IL-8 was synovial cells, whereas infiltrating leukocytes were the source of the second phase of IL-8 and also of IL-1β and IL-1Ra. The production of TNFα was not altered by either anti-IL-8 IgG or IL-1Ra. The first IL-1 peak was reduced only with a combination of anti-TNFα mAb and anti-IL-8 IgG, whereas the second peak was significantly reduced by either inhibitor. The first IL-8 peak was not altered with anti-TNFα mAb or IL- 1Ra, whereas the second IL-8 peak was reduced with IL-1Ra. Anti-TNFα mAb or anti-IL-8 IgG significantly reduced the peak level of endogenous IL-1Ra. These cytokine inhibitors also attenuated the maximal leukocyte accumulation at 9 hours, but not the initial phase, which occurred within 2 hours. These results provide evidence that IL-8 and TNFα were responsible for the production of IL-1β and IL-1Ra, and that IL-1β was responsible for the second phase of IL-1β and IL-8 production. Our data also suggest that the initial and the maximal phases of leukocyte influx are differently regulated. Finally, the intravenous injection of colchicine inhibited neutrophil infiltration without affecting the production of TNFα or the first peak of IL-8, suggesting that colchicine inhibits MSU crystal-induced arthritis by directly inhibiting the migration of neutrophils.