Inflammasome activators induce interleukin-1α secretion via distinct pathways with differential requirement for the protease function of caspase-1.

Abstract	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.
Authors	Olaf Gross, Amir S Yazdi, Christina J Thomas, Mark Masin, Leonhard X Heinz, Greta Guarda, Manfredo Quadroni, Stefan K Drexler, Jurg Tschopp
Journal	Immunity (Immunity) Vol. 36 Issue 3 Pg. 388-400 (Mar 23 2012) ISSN: 1097-4180 [Electronic] United States
PMID	22444631 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright	Copyright Â© 2012 Elsevier Inc. All rights reserved.
Chemical References	Adaptor Proteins, Signal Transducing Aim2 protein, mouse Apoptosis Regulatory Proteins Calcium Channels Calcium-Binding Proteins DNA-Binding Proteins Inflammasomes Interleukin-1alpha Interleukin-1beta Ipaf protein, mouse NALP1 protein, mouse Nuclear Proteins Receptors, Interleukin-1 Caspase 1
Topics	Adaptor Proteins, Signal Transducing (metabolism) Animals Apoptosis Regulatory Proteins (metabolism) Calcium Channels (metabolism) Calcium Signaling (immunology) Calcium-Binding Proteins (metabolism) Caspase 1 (metabolism) Cell Death (immunology) DNA-Binding Proteins Female Humans Inflammasomes (immunology, metabolism) Interleukin-1alpha (antagonists & inhibitors, biosynthesis, metabolism) Interleukin-1beta (biosynthesis) Male Mice Mice, 129 Strain Mice, Inbred BALB C Mice, Inbred C57BL Mice, Knockout Nuclear Proteins (metabolism) Peritonitis (immunology) Protein Processing, Post-Translational Receptors, Interleukin-1 (metabolism) Signal Transduction (immunology)

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