title: 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.affiliation: Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland. ogross@lrz.tu-muenchen.de
authors.forename: Olaf
authors.initials: O
authors.lastname: Gross
authors.forename: Amir S
authors.initials: AS
authors.lastname: Yazdi
authors.forename: Christina J
authors.initials: CJ
authors.lastname: Thomas
authors.forename: Mark
authors.initials: M
authors.lastname: Masin
authors.forename: Leonhard X
authors.initials: LX
authors.lastname: Heinz
authors.forename: Greta
authors.initials: G
authors.lastname: Guarda
authors.forename: Manfredo
authors.initials: M
authors.lastname: Quadroni
authors.forename: Stefan K
authors.initials: SK
authors.lastname: Drexler
authors.forename: Jurg
authors.initials: J
authors.lastname: Tschopp
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling / Q000276:immunology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism*; D016923:Cell Death / Q000276:immunology; D004268:DNA-Binding Proteins; D005260:Female; D006801:Humans; D058847:Inflammasomes / Q000276:immunology* / Q000378:metabolism; D053582:Interleukin-1alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000378:metabolism; D053583:Interleukin-1beta / Q000096:biosynthesis; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000378:metabolism; D010538:Peritonitis / Q000276:immunology; D011499:Protein Processing, Post-Translational; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C540422:Aim2 protein, mouse; D051017:Apoptosis Regulatory Proteins; D015220:Calcium Channels; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D058847:Inflammasomes; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; C512299:Ipaf protein, mouse; C529636:NALP1 protein, mouse; D009687:Nuclear Proteins; D017472:Receptors, Interleukin-1; D020170:Caspase 1