Regulation of inflammatory response by an inhibitory cytokine in a mode of inhiditory cybemetics

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We developed rabbit recombinant IL-lbeta and IL-lra, as well as antibodies against these cytokines. Using these materials and anti-rabbit TNFalpha, we investigated the role of IL-l and TNFalpha in the pathogenesis of LPS-arthritis in rabbits. In the LPS-induced arthritis leukocyte infiltration peaked at 9hrs while destruction of caltilagepeaked at 24 hrs of the inflammation. When 10mug of IL-lra was injected simultaneously with LPS,the resulting neutrophil infiltration was inhibited by 70%during a whole observation period until 48 hrs and destruction of caltilage was completely prevented. Anti-TNFalpha (100mug) antibody also inhibited neutrophil infiltration by 70% and completely preveted destruction of caltilage. A combination of these two inhibitory substances produced furher suppression of neutrophil-infiltration by more than 90% and complete abrogation of caltilage-destruction. In the LPS-arthritis, production of IL-l peaked at 6hr and its amount was 196.7 pg/joint and the most of the produced IL-l was beta in form. Production of TNFalpha peaked at 2hr and its amount was 12.5 ng/joints. To investigate the role of neutrophils in the desruction of caltilate, we made neutropenic rabbits using i.v.nitrogen mustard. LPS induced no caltilage destruction and no production of IL-lbeta in the neutropenic rabbits, while production of TNFalpha was unchanges in comparison with non-leukopenic rabbits. Injection of IL-lbeta (187 pg) into the leukopenic rabbits did not result in destruction of caltilage. Thus, both TNFalpha and IL-lbeta is the key mediators for induction of LPS-stimulated arthritis. But, these cytokines are not directly responsible for tissue damage. Next, we investigated a production which may involved in the destruction of caltilage and we found that neutrophil-derived superoxide anion and elastase is responsible for destruction of caltilage in this inflammation.