NEUTROPHIL ACCUMULATION AND ACTIVATION BY HOMOLOGOUS IL-8 IN RABBITS - IL-8 INDUCES DESTRUCTION OF CARTILAGE AND PRODUCTION OF IL-1 AND IL-1 RECEPTOR ANTAGONIST IN-VIVO

Whether or not IL-8 attracts T lymphocytes and activates neutrophils in vivo remains unclear. Most studies on function of IL-8 in vivo have been done on human IL-8 in heterologous animals. To elucidate the role of IL-8 in vivo, we injected homologous IL-8 into rabbit knee joints and investigated the inflammatory response. Injection of 10 mu g of rabbit IL-8 induced a massive accumulation of neutrophils. IL-8 attracts T lymphocytes in vitro; however, rabbit IL-8 induced no appreciable lymphocyte accumulation in rabbits. Although human IL-8 was reported not to induce cartilage destruction when injected into heterologous animals, we observed that rabbit IL-8 did provoke a release of neutrophil elastase, leading to cartilage destruction, when injected into rabbits. An inhibitor against neutrophil elastase (ONO-5046) prevented destruction of the cartilage. Injection of rabbit IL-8 induced bioactive and immunoreactive IL-1 beta and IL-1 receptor antagonist (IL-1Ra) in the joint cavity. Immunohistochemistry showed that IL-1 beta and IL-1Ra positive cells were infiltrating leukocytes. In neutrophil-depleted rabbits, rabbit IL-8 induced far lesser concentrations of IL-1 beta and IL-1Ra and no cartilage destruction compared with findings in normal rabbits. Thus, the infiltrating neutrophils are the main producers of these cytokines and are responsible for the cartilage destruction. In addition to neutrophil chemotactic activity, IL-8 proved to have a neutrophil-activating capability in vivo, with respect to release of neutrophil elastase and induction of IL-1 beta and IL-1 Ra.