The three cytokines IL-1β, IL-18, and IL-1α share related but distinct secretory routes

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Interleukin (IL)-1 family cytokines potently regulate inflammation, with the majority of the IL-1 family proteins being secreted from immune cells via unconventional pathways. In many cases, secretion of IL-1 cytokines appears to be closely coupled to cell death, yet the secretory mechanisms involved remain poorly understood. Here, we studied the secretion of the three best-characterized members of the IL-1 superfamily, IL-1α, IL-1β, and IL-18, in a range of conditions and cell types, including murine bone marrow-derived and peritoneal macrophages, human monocyte-derived macrophages, HeLa cells, and mouse embryonic fibroblasts. We discovered that IL-1β and IL-18 share a common secretory pathway that depends upon membrane permeability and can operate in the absence of complete cell lysis and cell death. We also found that the pathway regulating the trafficking of IL-1α is distinct from the pathway regulating IL-1β and IL-18. Although the release of IL-1α could also be dissociated from cell death, it was independent of the effects of the membrane-stabilizing agent punicalagin, which inhibited both IL-1β and IL-18 release. These results reveal that in addition to their role as danger signals released from dead cells, IL-1 family cytokines can be secreted in the absence of cell death. We propose that models used in the study of IL-1 release should be considered context-dependently.


  • Victor S Tapia
  • Michael J D Daniels
  • Pablo Palazón-Riquelme
  • Matthew Dewhurst
  • Nadia M Luheshi
  • Jack Rivers-Auty
  • Jack Green
  • Elena Redondo-Castro
  • Philipp Kaldis
  • Gloria Lopez-Castejon
  • David Brough
External organisations
  • National University of Singapore
  • A*Star Institute of Molecular and Cell Biology (IMCB)
Original languageEnglish
Pages (from-to)8325-8335
JournalJournal of Biological Chemistry
Issue number21
Publication statusPublished - 2019 May 24
Publication categoryResearch
Externally publishedYes

Bibliographic note

© 2019 Tapia et al.