Immunity
Volume 36, Issue 3, 23 March 2012, Pages 388-400
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Article
Inflammasome Activators Induce Interleukin-1α Secretion via Distinct Pathways with Differential Requirement for the Protease Function of Caspase-1

https://doi.org/10.1016/j.immuni.2012.01.018Get rights and content
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Summary

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

Highlights

► IL-1α is cosecreted with IL-1β upon inflammasome activation ► IL-1α secretion can be inflammasome dependent or independent ► Caspase-1 has a protease activity-independent function that controls IL-1 secretion ► Osmotic stress and TRP channel-activity induce inflammasome activation

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These authors contributed equally to this work