Interleukin-1β Processing Is Dependent on a Calcium-mediated Interaction with Calmodulin

J Biol Chem. 2015 Dec 25;290(52):31151-61. doi: 10.1074/jbc.M115.680694. Epub 2015 Nov 11.


The secretion of IL-1β is a central event in the initiation of inflammation. Unlike most other cytokines, the secretion of IL-1β requires two signals: one signal to induce the intracellular up-regulation of pro-IL-1β and a second signal to drive secretion of the bioactive molecule. The release of pro-IL-1β is a complex process involving proteolytic cleavage by caspase-1. However, the exact mechanism of secretion is poorly understood. Here we sought to identify novel proteins involved in IL-1β secretion and intracellular processing to gain further insights into the mechanism of IL-1 release. A human proteome microarray containing 19,951 unique proteins was used to identify proteins that bind human recombinant pro-IL-1β. Probes with a signal-to-noise ratio of >3 were defined as biologically relevant. In these analyses, calmodulin was identified as a particularly strong hit, with a signal-to-noise ratio of ∼ 11. Using an ELISA-based protein-binding assay, the interaction of recombinant calmodulin with pro-IL-1β, but not mature IL-1β, was confirmed and shown to be calcium-dependent. Finally, using small molecule inhibitors, it was demonstrated that both calcium and calmodulin were required for nigericin-induced IL-1β secretion in THP-1 cells and primary human monocytes. Together, these data suggest that, following calcium influx into the cell, pro-IL-1β interacts with calmodulin and that this interaction is important for IL-1β processing and release.

Keywords: IL-1; IL-1β; calcium; calmodulin (CaM); caspase 1 (CASP1); inflammasome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcium / metabolism*
  • Calcium Signaling / physiology*
  • Calmodulin / genetics
  • Calmodulin / metabolism*
  • Cell Line, Tumor
  • Female
  • Humans
  • Interleukin-1beta / genetics
  • Interleukin-1beta / metabolism*
  • Male
  • Monocytes / cytology
  • Monocytes / metabolism*
  • Protein Array Analysis
  • Protein Precursors / genetics
  • Protein Precursors / metabolism*
  • Proteolysis*
  • Proteomics


  • Calmodulin
  • IL1B protein, human
  • Interleukin-1beta
  • Protein Precursors
  • Calcium