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

Immunity. 2012 Mar 23;36(3):388-400. doi: 10.1016/j.immuni.2012.01.018.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*
  • Inflammasomes / metabolism
  • Interleukin-1alpha / antagonists & inhibitors
  • Interleukin-1alpha / biosynthesis*
  • Interleukin-1alpha / 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


  • 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