Interleukin 33 is a guardian of barriers and a local alarmin

Nat Immunol. 2016 Feb;17(2):122-31. doi: 10.1038/ni.3370.


Interleukin 33 (IL-33) is a member of the IL-1 family of cytokines with a growing number of target cells and a plethora of biological functions. Although it has commonalities with other IL-1 cytokines, IL-33 exhibits some unique features. Here we review the biology of IL-33 and its receptor and develop a working model that describes two 'lives' for IL-33-one intracellular and one extracellular. Under healthy conditions, constitutively produced, intracellular IL-33 participates in maintaining barrier function by regulating gene expression as a nuclear protein. In parallel, nuclear IL-33 functions as a stored alarmin that is released when barriers are breached. Extracellular IL-33 coordinates immune defense and repair mechanisms while also initiating differentiation of helper T cells as the adaptive immune response is triggered.

Publication types

  • Review

MeSH terms

  • Alarmins / metabolism*
  • Animals
  • Gene Expression Regulation
  • Humans
  • Inflammation / genetics
  • Inflammation / immunology
  • Inflammation / metabolism
  • Interleukin-33 / chemistry
  • Interleukin-33 / genetics
  • Interleukin-33 / metabolism*
  • Protein Binding
  • Protein Transport
  • Receptors, Interleukin / genetics
  • Receptors, Interleukin / metabolism
  • Signal Transduction


  • Alarmins
  • Interleukin-33
  • Receptors, Interleukin