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 1beta (IL 1beta) inflammasomes occupy a central role in the inflammatory response. In contrast to IL 1beta little is known about how IL 1alpha is regulated. We found that all inflammasome activators also induced the secretion of IL 1alpha leading to the cosecretion of both IL 1 cytokines. Depending on the type of inflammasome activator release of IL 1alpha was inflammasome dependent or independent. Calcium influx induced by the opening of cation channels was sufficient for the inflammasome independent IL 1alpha secretion. In both cases IL 1alpha was released primarily in a processed form resulting from intracellular cleavage by calpain like proteases. Inflammasome caspase 1 dependent release of IL 1alpha and IL 1beta 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 1alpha antagonists may be beneficial in the treatment of these disorders.