ABSTRACT Interleukin-1 (IL-1) family cytokines IL-1α and IL-1β, 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-1β 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-1β production and inflammation. In stark contrast to IL-1β, and despite being the first major human pyrogen described, the regulation of IL-1α remains poorly understood. Notwithstanding the increasing appreciation of the contribution of IL-1α in the pathogenesis of many important human diseases, the factors that control functional IL-1α 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-1β-independent manner. Instead, inflammation in the Ptpn6spin model requires IL- 1α and is driven by receptor interacting protein kinase 1 (RIPK1). Except for these studies, our current understanding of the roles and regulation of IL-1α in inflammatory disease is severely limited. The central goal of this project is to identify the cellular and molecular mechanisms of IL-1α regulation and to provide critical information essential for understanding the function of IL-1α.