Open Access

REVIEW

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

Emma Lefrançais^1,2, Corinne Cayrol^1,2

1 Centre national de la recherche scientifique, Institut de pharmacologie et de biologie structurale, 205 route de Narbonne F-31077 Toulouse, France
2 Université de Toulouse, universite Paul Sabatier, institut de pharmacologie et de biologie structurale, F-31077 Toulouse, France

* Corresponding Author: C. Cayrol.

European Cytokine Network 2012, 23(4), 120-127. https://doi.org/10.1684/ecn.2012.0320

Accepted 29 October 2012;

Abstract

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.

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Keywords

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