ST2: A Key Player in Immune and Cardiac Health

ST2 is a biomarker and receptor protein involved in immune function and cardiovascular health. As a member of the interleukin-1 receptor family, it interacts with IL-33, influencing inflammation and tissue repair. Researchers recognize its diagnostic and prognostic potential, particularly in heart failure and inflammatory conditions.

Understanding ST2’s biological mechanisms and clinical significance offers insights into disease progression and treatment strategies.

Biology And Structure Of ST2

ST2, also known as interleukin-1 receptor-like 1 (IL1RL1), is encoded by the IL1RL1 gene on chromosome 2q12. Structurally, it features an extracellular immunoglobulin-like domain for ligand binding, a transmembrane region, and an intracellular Toll/interleukin-1 receptor (TIR) domain that facilitates downstream signaling. These components enable ST2 to function as a receptor for interleukin-33 (IL-33), a cytokine involved in immune regulation.

ST2 exists in distinct forms with specific biological roles. The transmembrane form, ST2L, mediates cellular responses upon IL-33 binding, triggering signaling cascades that regulate gene expression. The soluble form, sST2, circulates in the bloodstream, acting as a decoy receptor by sequestering IL-33 and modulating its effects. The balance between ST2L and sST2 is critical in IL-33 regulation.

Post-translational modifications refine ST2’s function. Glycosylation affects stability and ligand-binding affinity, while proteolytic cleavage of membrane-bound ST2 generates sST2. Enzymes such as ADAM metalloproteases regulate this process, contributing to the dynamic control of ST2 expression.

Isoforms And Receptor Variants

ST2 isoforms arise from alternative splicing of the IL1RL1 gene. The primary functional variants, ST2L and sST2, differ in structure and function. ST2L, the membrane-bound form, initiates intracellular signaling upon IL-33 binding. In contrast, sST2 lacks the transmembrane and intracellular domains, allowing it to circulate freely and modulate IL-33 availability.

Various stimuli, including mechanical stress and pro-inflammatory cytokines, regulate ST2 isoform expression. Pathological conditions often upregulate sST2, reducing IL-33 interaction with ST2L and altering immune responses. Epigenetic modifications, such as DNA methylation and histone acetylation, further influence IL1RL1 gene expression.

Additional ST2 variants, generated through alternative splicing, exhibit altered ligand-binding properties. Though expressed at lower levels, these variants may fine-tune ST2 signaling. Transcriptomic studies suggest tissue-specific expression patterns, indicating that different cell types preferentially produce distinct ST2 isoforms.

ST2 In The IL-33 Signaling Pathway

The ST2-IL-33 interaction triggers a signaling cascade that influences cellular responses. IL-33, stored in the nucleus of various cells, is released upon injury or stress. It binds to ST2L, inducing a conformational change that recruits the IL-1 receptor accessory protein (IL-1RAcP). This complex activates the MyD88-dependent pathway, stimulating kinases like IRAK1, IRAK4, and TRAF6, which, in turn, activate NF-κB and MAPK pathways to regulate gene transcription.

The signaling strength and duration are modulated by sST2, which binds IL-33 and prevents its interaction with ST2L, dampening the cascade. Under normal conditions, ST2L and sST2 maintain equilibrium, but an increase in sST2 can suppress IL-33 signaling.

Post-translational modifications further regulate ST2 function. Glycosylation enhances ligand binding, phosphorylation modulates intracellular interactions, and proteolytic cleavage generates sST2, adjusting IL-33 availability. These mechanisms ensure adaptable signaling in response to physiological changes.

Roles In Immune Regulation

ST2 influences both innate and adaptive immune responses through IL-33 interaction. Macrophages and dendritic cells expressing ST2 enhance antigen presentation and cytokine production upon IL-33 stimulation. Tissue-resident macrophages rely on ST2 signaling to resolve inflammation by shifting toward an anti-inflammatory phenotype.

T cells are also affected by ST2 signaling. Regulatory T cells (Tregs) upregulate ST2 in response to IL-33, enhancing their suppressive function in autoimmune diseases. Meanwhile, ST2 signaling in type 2 helper T cells (Th2) boosts IL-4, IL-5, and IL-13 production, key cytokines in allergic responses and parasitic defense. This dual role allows ST2 to fine-tune immune responses based on cellular context.

Association With Inflammatory Disorders

ST2 is implicated in inflammatory diseases due to its regulatory role in IL-33 signaling. Conditions such as rheumatoid arthritis, inflammatory bowel disease, and systemic lupus erythematosus show altered ST2 expression, often with elevated sST2 levels. This increase disrupts immune balance by preventing IL-33 from interacting with ST2L.

In rheumatoid arthritis, higher sST2 levels correlate with severe joint inflammation and erosion. Similarly, in ulcerative colitis and Crohn’s disease, abnormal sST2 expression is linked to heightened intestinal inflammation and mucosal damage.

Beyond autoimmune disorders, ST2 is associated with chronic low-grade inflammation in obesity and type 2 diabetes. IL-33/ST2 signaling influences adipose tissue inflammation, with ST2L promoting regulatory responses that mitigate harmful inflammatory cascades. However, excessive sST2 counteracts these effects, exacerbating insulin resistance and metabolic complications.

Given its role in inflammation, ST2 is being explored as a biomarker for disease severity and treatment response. Monitoring sST2 levels may help assess therapeutic efficacy in conditions where inflammation plays a central role.

Relevance In Cardiac Health

ST2 is a key biomarker in cardiovascular medicine, particularly in heart failure and myocardial remodeling. Elevated sST2 levels are associated with worse cardiac outcomes, including increased hospitalization and mortality risk. IL-33/ST2 signaling plays a role in cardiac stress responses, with IL-33 binding to ST2L promoting cardioprotective mechanisms such as reducing fibrosis and limiting hypertrophy. However, increased sST2 sequesters IL-33, preventing these protective effects and contributing to pathological remodeling.

Following a myocardial infarction, ST2 expression shifts in response to tissue damage. Patients with high sST2 levels post-heart attack exhibit greater myocardial fibrosis and a higher likelihood of heart failure. As a result, sST2 has been incorporated into cardiac risk stratification, complementing biomarkers like B-type natriuretic peptide (BNP) and troponins. Unlike BNP, which fluctuates with treatment, sST2 remains stable, making it a valuable tool for long-term risk assessment.

Research is investigating therapeutic strategies to modulate IL-33/ST2 signaling to protect cardiac function.

Measurement Methods In Clinical Settings

sST2 measurement is increasingly relevant for diagnosing and monitoring disease progression. Enzyme-linked immunosorbent assays (ELISA) are widely used for quantifying sST2 in blood samples, offering high sensitivity and specificity. Standardized ELISA kits ensure reproducibility across laboratories.

Newer technologies, including automated immunoassays and point-of-care testing platforms, aim to improve accessibility and turnaround times, particularly in emergency and critical care settings. Research is also exploring ST2 measurements in non-blood specimens, such as tissue biopsies and cerebrospinal fluid, to expand diagnostic applications.

As assay technologies advance, integrating ST2 testing into routine clinical workflows may enhance personalized treatment strategies for inflammatory and cardiovascular conditions.