ST2, short for growth stimulation expressed gene 2 (ST2), also known as Suppression of Tumorigenicity 2, is a member of the interleukin-1 receptor family and was formerly known as IL1RL-1. As a new biomarker, it forms a signaling pathway with IL-33 and plays a crucial role in cardiovascular disease.
ST2 subtypes and distribution
ST2 can be divided into four different isoforms: soluble ST2 (sST2 or IL1RL1-a), membrane-bound receptor ST2 (ST2L or IL1RL1-b), ST2V, and ST2LV. sST2 and ST2L are the two most predominant isoforms. ST2L is expressed in colonocytes, endothelial cells, and various hematopoietic cells, such as basophils, CD4+ T lymphocytes, eosinophils, and macrophages. sST2 is primarily secreted by cardiomyocytes, endothelial cells, and various immune cells, such as proinflammatory T cells, macrophages, and mast cells. It is also expressed in several human tissues.
(Data source: Chen J, et al. Front Cardiovasc Med. 2022)
ST2 structure:
ST2 is a transmembrane protein. The gene encoding ST2 is located on human chromosome 2q12. The extracellular domain of ST2 contains three IgG-like domains (D1, D2, and D3). These three domains are involved in the interaction with IL-33. The connection between the D3 domain of ST2 and the D1D2 module is flexible, allowing ST2 to undergo conformational changes upon IL-33 binding, thereby enhancing binding stability.
(Data source: Fields JK, et al. Front Immunol. 2019)
Signal transduction regulation of ST2 and IL-33
IL-33 binds to ST2L, promoting its heterodimerization with the IL-1 receptor accessory protein (IL-1RAcP), which is required for activation of downstream signaling. IL-1RAcP acts as a co-receptor, assisting IL-33-induced signaling. ST2L activation leads to the recruitment of multiple signaling molecules, including MyD88, IRAK4, and TRAF6. These molecules are involved in the activation of multiple downstream signaling pathways, including NF-κB, p38, ERK, and JNK. The activity of the ST2L signaling pathway is regulated by various mechanisms. sST2 can act as a decoy receptor, capturing IL-33 and blocking its binding to ST2L, thereby reducing the inflammatory response. Modulating the ST2L signaling pathway provides a potential target for the treatment of related diseases. Using sST2 or antibodies targeting ST2L, modulating ST2L activity can be used to treat diseases.
(Data source: He PY, et al. Cytokine Growth Factor Rev. 2024)
ST2 and cardiovascular disease
ST2 plays a crucial role in cardiovascular diseases such as heart failure, coronary artery atherosclerotic heart disease (CAHD), type 2 diabetes mellitus (T2DM), and hypertension. The binding of IL-33 to ST2L plays a central role in immune responses, homeostasis, and the recovery of damaged (myocardial) tissue. This binding reduces apoptosis in cells exposed to ischemia and inflammation, reduces myocardial fibrosis, and promotes cardiomyocyte hypertrophy, thereby maintaining ventricular function and prolonging patient survival. Conversely, the soluble receptor sST2 is released from both fibroblasts and vascular structures. It competitively binds to IL-33 and prevents IL-33 from binding to ST2L, thereby blocking the receptor and preventing its cardioprotective effects. Consequently, increased sST2 expression and release can promote apoptosis, fibrosis, hypertrophy, myocardial remodeling, and the progression of heart failure. When the heart is subjected to mechanical stress, sST2 levels are significantly elevated, further increasing cardiac damage. Therefore, sST2 plays a crucial role in the diagnosis, treatment, and risk assessment of patients with heart disease. It, like natriuretic peptides (NT-proBNP and BNP), is a biomarker for heart failure.
(Data source: Homsak E, et al. Clin Chim Acta. 2020)
sST2 is a predictor of new heart failure events in people at high risk of heart failure; for patients with both heart failure symptoms and elevated BNP/NT-proBNP, sST2 can further assist in the diagnosis of acute heart failure: when sST2 is <35 ng/mL, it indicates that the possibility of acute heart failure is low, and other confounding factors should be considered; when sST2 is between 35-70 ng/mL, it is common in acute heart failure, but the severity of the disease is mild, and it is mild to moderate heart failure; when sST2 is >70 ng/mL, it indicates that the possibility of acute heart failure is high.
(Data source: Aleksova A, et al. J Clin Med. 2019)
sST2 reflects a persistent and long-term progression, indicating the degree of myocardial fibrosis and is crucial for risk stratification and prognosis assessment in patients with heart failure. When combined with BNP/NT-proBNP, it can enhance risk assessment for hospitalized patients with acute heart failure and the long-term management of chronic heart failure, significantly impacting the treatment and prognosis of both acute and chronic heart failure.
