Analysis of the Inflammatory Cytokine Network Among Tnf-Alpha, Il-1-Beta, Il-1 Receptor Antagonist, and Il-8 in Lps-Induced Rabbit Arthritis

We investigated the cytokine network in rabbit lipopolysaccharide (LPS)-induced arthritis, using inhibitors against homologous TNF alpha, IL-1 beta, and IL-8. Rabbits were intraarticularly injected with LPS (10 ng) and cytokine inhibitors (10 mu g each), and the concentrations of each cytokine in the synovial fluids were measured. Maximum levels of TNF alpha and IL-8 were detected at 2 hours after LPS-injection, whereas IL-1 beta and IL-1 receptor antagonist (IL-1Ra) were detected at 6 and 9 hours, respectively. By immunohistochemistry, synovial lining cells were positive for TNF alpha and IL-8, and infiltrating leukocytes were positive for IL-1 beta and IL-1Ra. The effects of cytokine inhibitors on the release of each cytokine were then investigated. The maximum levels of TNF alpha and IL-8 were not affected by blocking the activities of other cytokines. In contrast, the peak concentration of IL-1 beta was reduced by anti-TNF alpha monoclonal Ab (mAb), IL-1Ra or anti-IL-8 IgG. Peak concentrations of IL-l Ra were reduced by anti-TNF alpha mAb or anti-IL-8 IgG. Anti-TNF alpha mAb, IL-1Ra, and anti-IL-8 IgG reduced the recruitment of leukocytes into the joint cavity, and the effect of anti-IL-8 IgG was less than that of anti-TNF alpha mAb plus IL-1Ra. The initial phase of the leukocyte influx was not inhibited. These results provide new evidence that IL-8 as well as TNF alpha are the most proximal cytokines and induce subsequent production of IL-1 beta and IL-1Ra. The data also raise the possibility that factor(s) other than IL-8 may be involved in the leukocyte influx in LPS-induced arthritis. [References: 41]

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