ST2L

ST2L is the membrane-bound isoform of the interleukin-1 receptor family member IL1RL1 and serves as a receptor for interleukin-33 (IL-33). The IL1RL1 gene in humans encodes ST2, which exists in two main isoforms produced by alternative splicing: a transmembrane form, ST2L, and a soluble form, sST2. ST2L forms a signaling complex with IL-33 and the IL-1 receptor accessory protein (IL-1RAcP) to activate downstream pathways, including NF-κB and MAP kinases, thereby promoting type 2 immune responses. IL-33 is considered an alarmin released by damaged or stressed cells, linking tissue injury to immune activation.

ST2L expression is found on several immune cells, such as Th2 cells, mast cells, eosinophils, basophils, and group 2 innate lymphoid cells, and it is also present in cardiovascular tissues. The soluble receptor sST2 arises from alternative splicing and proteolytic cleavage and acts as a decoy receptor, binding IL-33 and limiting ST2L signaling. This decoy activity modulates the magnitude and duration of IL-33–driven responses.

Clinical relevance is centered on the IL-33/ST2 axis, which participates in allergic diseases like asthma and atopic dermatitis, as well as fibrosis and tissue repair. In the cardiovascular system, ST2 signaling influences cardiac remodeling and hypertrophy. Circulating sST2 serves as a prognostic biomarker in heart failure and myocardial infarction, with higher levels associated with worse outcomes. Genetic variation in IL1RL1 can affect ST2 expression and IL-33 signaling, though clinical effects are context-dependent.