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

ABSTRACT: The secretion of IL-1? is a central event in the initiation of inflammation. Unlike most other cytokines, the secretion of IL-1? requires two signals: one signal to induce the intracellular up-regulation of pro-IL-1? and a second signal to drive secretion of the bioactive molecule. The release of pro-IL-1? 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-1? 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-1?. 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-1?, but not mature IL-1?, 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-1? secretion in THP-1 cells and primary human monocytes. Together, these data suggest that, following calcium influx into the cell, pro-IL-1? interacts with calmodulin and that this interaction is important for IL-1? processing and release.

SUBMITTER: Ainscough JS 

PROVIDER: S-EPMC4692238 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature