Interleukin-33 and ST2 Signaling in Tumor Microenvironment

Abstract

Interleukin-33 (IL-33) is one of the members of the IL-1 family of cytokines and a ligand of ST2 and IL-1 receptor accessory protein (IL-1RAcP) that is known to affect Th2 inflammatory response with partial effects on Th1 responses. This cytokine is released by epithelial and smooth muscle cells of the airway system during their injury by several environmental stimuli, such as allergens, viruses, helminths, and pollutants. IL-33 is an alarmin that acts as an endogenous danger signal, and it has been known to affect various types of cells, such as mast cells, basophils, eosinophils, T cells, and specific subsets of innate lymphoid cells (ILCs). In recent findings, this cytokine is believed to have a critical role in several types of cancers, such as lung cancer, liver cancer, and head and neck squamous cell cancer. The expression of IL-33/ST2 in cancer tissues shows a close association with tumor growth and tumor progression in several types of cancer, suggesting the IL-33/ST2 pathway as a potential target for therapy.

Keywords: ST2; cancer; interleukin-33; tumor microenvironment; tumorigenesis.

FIG. 1.

The activation of precursor IL-33. (A) It is believed that IL-33 precursor protein undergoes a certain maturation process to acquire activity, but the rigorous cleavage site is still controversial. First, IL-33 was believed to be activated by the cleavage of caspase-1 at Ser 111 (Schmitz and others, 2005). Commercially available IL-33 recombinant proteins are expressed as Ile113-Thr270. The other site, Ser 117, was also proposed following the study with PR3 protease (Bae and others, 2012). The short splice variant of IL-33, which lacks exon 3 (Arg74-Gly116), is also a biologically active form. (B) IL-33 can be released by several stimuli under certain circumstances, and this can be both precursor form and mature form and even undergoes a degradation process. IL-33, interleukin-33.

FIG. 2.

Cellular targets of IL-33. Stromal, epithelial, and endothelial cells secrete IL-33 after tissue damage or mechanical stress. Secreted IL-33 stimulates several subsets of both lymphoid and myeloid lineages of immune cells.