Interleukin-33 (IL33) cytokine is a member of the Interleukin-1 family. It can be classified as an alarmin because it is released into the extracellular space during cell damage. It acts as an endogenous danger signal (Liew et al. 2010).]
The gene product is biologically active (full-length IL33). Its potency has been reported to increase significantly (up to 30x) after cleavage at the N-terminus by inflammatory proteases such as Cathepsin G (CTSG) and Neutrophil elastase (ELANE) (Lefrançais et al. 2012, Lefrançais et al. 2014) but others have suggested that processing inactivates IL33 (Cayrol & Girard 2009). IL33 can act as an extracellular ligand and an intracellular signaling molecule (Martin et al. 2013, 2016). Full-length IL33 has a nuclear localization sequence and can translocate to the nucleus, where it binds heterochromatin (Moussion et al. 2008, Carriere et al. 2007, Roussel et al. 2008, Kuchler et al. 2008, Sundlisaeter et al. 2012, Baekkevold et al. 2003). IL33 that has undergone proteolytic processing is unable to translocate to the nucleus (Martin et al. 2013, Ali et al. 2010).
Binding of extracellular IL33 to its receptor Interleukin-1 receptor-like 1 (IL1RL1, suppression of tumorigenicity 2, ST2) initiates several cellular signaling pathways. Cell injury or death are the dominant mechanisms by which IL33 reaches the extracellular environment, IL33 is not actively secreted by cells (Martin et al. 2016, Kaczmarek et al. 2013, Vancamelbeke et al. 2017). Because IL33 is expressed constitutively by endothelial and epithelial cells it is immediately available to the extracellular microenvironment after cell injury and necrosis (Lefrançais et al. 2012). Increases in extracellular ATP or mechanical stress correlate with increased IL33 secretion by mast cells or cardiomyocytes, respectively (Shimokawa et al. 2017, Kakkar et al. 2012, Zhao et al. 2012, Sanada et al. 2007, Chen et al. 2015).
Soluble IL1RL1 (IL1RL1 Isoform C, ST2V) (Iwahana et al. 2005, Tominaga et al. 1999) shares the extracellular components of IL1RL1, including the ligand binding domain, but lacks the transmembrane and intracellular components of IL1RL1 (Kakkar et al. 2008, Iwahana et al. 1999). The IL33-IL1RL1 complex recruits a co-receptor, most commonly IL1 receptor accessory protein (IL1RAP, IL-1RAcP) (Schmitz et al. 2005, Lingel et al. 2009, Palmer et al. 2008, Liu et al. 2013).