The IL-33/ST2 pathway: therapeutic target and novel biomarker

Interleukin-33 (IL-33) is a recently discovered member of the IL-1 family of cytokines.The receptor for IL-33, ST2, is present in multiple isoforms, including a membrane-bound form (ST2L), which together with the interleukin-1 (IL-1) receptor accessory protein forms the transmembrane IL-33 receptor, and a soluble form (sST2), which may act as a decoy receptor for IL-33.ST2L was originally investigated as a cell-surface marker for a subclass of T-cell leukocytes, the type II T-helper (Th2) cell. More recently, ST2L has been shown to participate in activation of antigen-primed Th2 cells.ST2 has been implicated in numerous inflammatory conditions such as asthma, fibroproliferative diseases, autoimmune diseases, including rheumatoid arthritis, and septic shock.The intracellular signalling cascade of IL-33 might share many of the features of canonical Toll-like receptor/IL-1-receptor superfamily signalling. Furthermore, IL-33 may also exhibit direct nuclear targeting.Soluble ST2 has emerged as a novel cardiac biomarker. Elevated serum sST2 levels identify heart failure or myocardial infarction patients with higher mortality. As a potential diagnostic assay, elevated serum sST2 levels identify high-risk patients presenting with shortness of breath.The IL-33/ST2 system appears to participate in cardiac protection. IL-33 produced by fibroblasts may dampen the maladaptive pro-hypertrophic and pro-fibrotic response of the myocardium to biomechanical overload.IL-33 might also be protective against atherosclerosis. Administration of IL-33 to mice that are prone to atherosclerotic vascular disease can abrogate plaque build-up in the vessel wall.Although the IL-33/ST2L signalling cascade may provide targets for therapeutic intervention, consideration must be given to its apparent diverse roles.