Intracellular interleukin-1 receptor 2 binding prevents cleavage and activity of interleukin-1α, controlling necrosis-induced sterile inflammation

Immunity. 2013 Feb 21;38(2):285-95. doi: 10.1016/j.immuni.2013.01.008. Epub 2013 Feb 7.


Necrosis can induce profound inflammation or be clinically silent. However, the mechanisms underlying such tissue specificity are unknown. Interleukin-1α (IL-1α) is a key danger signal released upon necrosis that exerts effects on both innate and adaptive immunity and is considered to be constitutively active. In contrast, we have shown that necrosis-induced IL-1α activity is tightly controlled in a cell type-specific manner. Most cell types examined expressed a cytosolic IL-1 receptor 2 (IL-1R2) whose binding to pro-IL-1α inhibited its cytokine activity. In cell types exhibiting a silent necrotic phenotype, IL-1R2 remained associated with pro-IL-1α. Cell types possessing inflammatory necrotic phenotypes either lacked IL-1R2 or had activated caspase-1 before necrosis, which degraded and dissociated IL-1R2 from pro-IL-1α. Full IL-1α activity required cleavage by calpain after necrosis, which increased its affinity for IL-1 receptor 1. Thus, we report a cell type-dependent process that fundamentally governs IL-1α activity postnecrosis and the mechanism allowing conditional release of this blockade.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calpain / genetics
  • Calpain / immunology
  • Caspase 1 / genetics
  • Caspase 1 / immunology
  • Cell Line
  • Gene Expression Regulation
  • Humans
  • Inflammation / genetics
  • Inflammation / immunology
  • Inflammation / metabolism*
  • Interleukin-1alpha / genetics*
  • Interleukin-1alpha / immunology
  • Interleukin-1alpha / metabolism
  • Mice
  • Necrosis / genetics
  • Necrosis / immunology
  • Necrosis / metabolism*
  • Organ Specificity
  • Protein Binding
  • Protein Precursors / genetics*
  • Protein Precursors / immunology
  • Protein Precursors / metabolism
  • Proteolysis
  • Receptors, Interleukin-1 Type II / genetics*
  • Receptors, Interleukin-1 Type II / immunology
  • Receptors, Interleukin-1 Type II / metabolism
  • Signal Transduction


  • IL1R2 protein, human
  • Interleukin-1alpha
  • Protein Precursors
  • Receptors, Interleukin-1 Type II
  • Calpain
  • Caspase 1