Analysis of the Cytokine Network Among Tumor Necrosis Factor Alpha, Interleukin-1-Beta, Interleukin-8, and Interleukin-1 Receptor Antagonist in Monosodium Urate Crystal-Induced Rabbit Arthritis

In the present study, we analyzed the cytokine network among TNF alpha, IL-1 beta, IL-8, and IL-1 receptor antagonist (IL-1Ra) in a rabbit experimental model of acute gout. The production of TNF alpha in synovial fluids reached the peak at 2 hours after the intra-articular injection of monosodium urate (MSU) crystals. The production of IL-1 beta 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 TNF alpha 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-1 beta and IL-1Ra. The production of TNF alpha was not altered by either anti-IL-8 IgG or IL-1Ra. The first IL-1 beta peak was reduced only with a combination of anti-TNF alpha 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-TNF alpha mAb or IL-1Ra, whereas the second IL-8 peak was reduced with IL-1Ra. Anti-TNF alpha 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 TNF alpha were responsible for the production of IL-1 beta and IL-1Ra, and that IL-1 beta was responsible for the second phase of IL-1 beta 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 TNF alpha or the first peak of IL-8, suggesting that colchicine inhibits MSU crystal-induced arthritis by directly inhibiting the migration of neutrophils. [References: 39]

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