Interleukin-1 (IL-1) family cytokines IL-1? and IL-1?, have emerged as principal mediators of multiple inflammatory diseases. Both bind to the interleukin-1 receptor (IL-1R) to induce a proinflammatory signaling cascade. Over the last decade, much progress has been made in defining the roles and regulation of IL-1? in multiple disease models. Studies from our lab and others have highlighted the contributions of Nod-like receptors (NLRs) and multi-protein complexes known as inflammasomes, and caspase-8 in the regulation of IL-1? production and inflammation. In stark contrast to IL-1?, and despite being the first major human pyrogen described, the regulation of IL-1? remains poorly understood. Notwithstanding the increasing appreciation of the contribution of IL-1? in the pathogenesis of many important human diseases, the factors that control functional IL-1? maturation remain completely obscure. Novel discoveries from our lab using a mouse model of cutaneous inflammatory disease (Ptpn6spin mutant mice) suggest that the inflammatory disease progresses in an inflammasome- and IL-1?-independent manner. Instead, inflammation in the Ptpn6spin model requires IL- 1? and is driven by receptor interacting protein kinase 1 (RIPK1). Except for these studies, our current understanding of the roles and regulation of IL-1? in inflammatory disease is severely limited. The central goal of this project is to identify the cellular and molecular mechanisms of IL-1? regulation and to provide critical information essential for understanding the function of IL-1?.
STATEMENT Inflammatory diseases have been directly linked to IL-1?. However, we have little understanding of how IL-1? activity is regulated to induce IL-1RI signaling. Understanding the exact function and mechanism of IL-1? regulation will help in development of specific therapies that target IL-1? and potentially leave the beneficial roles of IL-1? intact. This proposal will fill the major gap in our understanding of IL-1? biological activity and will provide new mechanistic insights into fundamental processes related to IL-1? function, and have the potential to identify novel therapeutic targets to treat debilitating inflammatory diseases in humans.
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