Inflammasome Activators Induce Interleukin-1α Secretion via Distinct Pathways with Differential Requirement for the Protease Function of Caspase-1

Through their capacity to sense danger signals and to generate active interleukin-1 beta (IL-1 beta), inflammasomes occupy a central role in the inflammatory response. In contrast to IL-1 beta, little is known about how IL-1 alpha is regulated. We found that all inflammasome activators also induced the secretion of IL-1 alpha, leading to the cosecretion of both IL-1 cytokines. Depending on the type of inflammasome activator, release of IL-1 alpha was inflammasome dependent or independent. Calcium influx induced by the opening of cation channels was sufficient for the inflammasome-independent IL-1 alpha secretion. In both cases, IL-1 alpha was released primarily in a processed form, resulting from intracellular cleavage by calpain-like proteases. Inflammasome-caspase-1-dependent release of IL-1 alpha and IL-1 beta was independent of caspase-1 catalytic activity, defining a mode of action for caspase-1. Because inflammasomes contribute to the pathology of numerous chronic inflammatory diseases such as gout and diabetes, IL-1 alpha antagonists may be beneficial in the treatment of these disorders.