Mechanisms of IL-33 processing and secretion: differences and similarities between IL-1 family members

Eur Cytokine Netw. Oct-Dec 2012;23(4):120-7. doi: 10.1684/ecn.2012.0320.


Interleukin-33 (IL-33) is the latest member of the IL-1 family that has become very attractive since the discovery of its major target cells, the innate lymphoid cells type 2 (ILC2), involved in the initiation of the type 2 immune response (secretion of IL-5 and IL-13) during parasitic infection and allergic diseases such as asthma. IL-33 is a chromatin-associated protein as it possesses in its N-terminus, a chromatin-binding domain, and is constitutively expressed in the nuclei of endothelial cells and in epithelial cells of tissues exposed to the environment. It is however, essential for IL-33 to be extracellularly released to bind to its receptor ST2 through the C-terminus portion of the protein in order to induce the inflammatory and type 2 responses. Like other IL-1 family members, IL-33 does not possess any signal peptide and may be released through unconventional secretory mechanisms or following cell damage and necrosis. It was initially believed that IL-33, like IL-1β and IL-18, requires processing by caspase-1 to be released, and for biological activity. On the contrary, full length IL-33 is biologically active, and processing by caspases results rather in IL-33 inactivation. Moreover, it has been recently shown that the bioactivity of IL-33 can be increased by inflammatory proteases secreted in the microenvironment, similarly to IL-1α, IL-1β and IL-18. This review will summarize recent progress on how IL-33 is released and processed compared with the other IL-1 family members, and how the immune cells recruited to the site of injury can regulate the disease-associated function of IL-33.

Keywords: IL-1 family; IL-33; caspase-1; inflammatory proteases; neutrophil serine proteases.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Humans
  • Interleukin-1 / metabolism*
  • Protein Processing, Post-Translational*
  • Signal Transduction


  • Interleukin-1