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

Key Points 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. The recent discovery of the ST2 receptor ligand — interleukin-33 — has provided new insight into the importance of ST2 signalling as a mediator of inflammation. Now, an additional role for this pathway as a novel cardioprotective paracrine system is emerging. Here, Kakkar and Lee review these roles and discuss the therapeutic potential of targeting this pathway to treat associated diseases such as asthma, rheumatoid arthritis, atherosclerosis and heart failure. For many years, the interleukin-1 receptor family member ST2 was an orphan receptor that was studied in the context of inflammatory and autoimmune disease. However, in 2005, a new cytokine — interleukin-