Anti-cytokine therapy for acute and chronic inflammatory diseases has entered clinical medicine. The main targets for anti-cytokine-based therapies are tumor necrosis factor (TNF) and interleukin-1 (IL-1), pleiotropic, proinflammatory cytokines. The IL-1 receptor antagonist (IL-1Ra) has been approved by the FDA for the treatment of rheumatoid arthritis. Other inhibitors of the IL-1 beta are in Phase II trials for various diseases. IL-18, a member of the IL-1 family and closely related to IL-1 beta, also appears to be a target for therapeutic intervention in disease. Specific inhibitors of ICE reduce the release and hence the biological activity of both IL-1 and IL-18. We have demonstrated that IL-18 has broad effects similar to those of IL-1 beta such as inducing the synthesis of other pro-inflammatory cytokines, the family of chemokines, activation of neutrophils, and upregulation of Fas ligand and endothelial adhesion molecules. Therefore, the host likely mounts various strategies to limit the biological activities of IL-18. We isolated and cloned a novel IL-18 inhibitor, the IL-18 binding protein (IL-18BP), which binds and neutralizes IL-18; the IL-18BP is a constitutively expressed and secreted inhibitor of IL-18 activity. Another member of the IL-1 family is the IL-1 homologue 4 (IL-1H4), which is structurally related to IL-18, binds to IL-18 receptor alpha chain, which is the ligand binding chain of the IL-18 receptor complex. However, IL-1H4 exhibits no agonist activities. Although likely to be the """"""""receptor antagonist"""""""" for IL-18, recombinant IL-1H4 exhibits no receptor antagonist activities for IL-18. We propose to study the function of IL-1 H4 and assess its role in disease as a naturally occurring inhibitor of IL-18 activity. Preliminary data indicate that IL-1H4 binds to the IL-18BP and that this complex recruits the signaling beta chain of the IL-18 receptor complex, thereby depriving the cell of the beta chain for signal transduction. As such, IL-1H4 appears to function as a """"""""decoy"""""""" cytokine. The proposed studies are intended to show that IL-1H4 plays a role in disease via this novel mechanism using animal models of inflammatory disease. Human IL-1H4 appears to reduce the activities of mouse IL-18, therefore, we will generate transgenic mice overexpressing human IL-1H4 and challenge these mice using IL-18-dependent models of disease. These studies may have implications for the use of IL-1H4 to treat IL-18-related diseases.
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