Abstract
Interleukin-33 (IL-33) is a IL-1 family member of cytokines exerting pleiotropic activities. In the steady-state, IL-33 is expressed in the nucleus of epithelial, endothelial, and fibroblast-like cells acting as a nuclear protein. In response to tissue damage, infections or necrosis IL-33 is released in the extracellular space, where it functions as an alarmin for the immune system. Its specific receptor ST2 is expressed by a variety of immune cell types, resulting in the stimulation of a wide range of immune reactions. Recent evidences suggest that different IL-33 isoforms exist, in virtue of proteolytic cleavage or alternative mRNA splicing, with potentially different biological activity and functions. Although initially studied in the context of allergy, infection, and inflammation, over the past decade IL-33 has gained much attention in cancer immunology. Increasing evidences indicate that IL-33 may have opposing functions, promoting, or dampening tumor immunity, depending on the tumor type, site of expression, and local concentration. In this review we will cover the biological functions of IL-33 on various immune cell subsets (e.g., T cells, NK, Treg cells, ILC2, eosinophils, neutrophils, basophils, mast cells, DCs, and macrophages) that affect anti-tumor immune responses in experimental and clinical cancers. We will also discuss the possible implications of diverse IL-33 mutations and isoforms in the anti-tumor activity of the cytokine and as possible clinical biomarkers.
Highlights
TO IL-33 BIOLOGYInterleukin-33 (IL-33) is a cytokine member of IL-1 family, including IL-1α, IL-1β, IL-18, and IL1Ra that are related to each other by receptor structure and signal transduction pathways
The current literature indicate that IL33 expression can be regulated during the progression of distinct types of cancers and that IL-33/ST2 signaling within the tumor microenvironment may differently contribute to tumorigenesis, promoting antitumor responses or mediating tumor growth or metastasis, depending on the nature of the malignant tissue
Further studies are needed to elucidate the role of this pathway at specific time points during cancer development as a possible diagnostic/prognostic marker for patients and to clarify whether IL-33/ST2 blockade may represent a valid approach for adjuvant therapies of established IL-33-dependent tumors
Summary
TO IL-33 BIOLOGYInterleukin-33 (IL-33) is a cytokine member of IL-1 family, including IL-1α, IL-1β, IL-18, and IL1Ra that are related to each other by receptor structure and signal transduction pathways. Recent studies have demonstrated the existence of several human full-length active mRNA splice variants dependent on both the cell type expressing IL-33 and the pathological condition and triggered by diverse stimulations during immune responses [12,13,14].
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