The Biology of ST2: The International ST2 Consensus Panel

doi:10.1016/j.amjcard.2015.01.034

The American Journal of Cardiology

Volume 115, Issue 7, Supplement, 2 April 2015, Pages 3B-7B

https://doi.org/10.1016/j.amjcard.2015.01.034 Get rights and content

ST2 is a member of the interleukin 1 receptor family with 2 main isoforms: transmembrane or cellular (ST2L) and soluble or circulating (sST2) forms. ST2 is the receptor of the IL-33, which is an IL-1–like cytokine that can be secreted by living cells in response to cell damage. IL-33 exerts its cellular functions by binding a receptor complex composed of ST2L and IL-1R accessory protein. The IL-33/ST2 system is upregulated in cardiomyocytes and fibroblasts as response to mechanical stimulation or injury. The interaction between IL33 and ST2L has been demonstrated to be cardioprotective: in experimental models, this interaction reduces myocardial fibrosis, prevents cardiomyocyte hypertrophy, reduces apoptosis, and improves myocardial function. The beneficial effects of IL-33 are specifically through the ST2L receptor. sST2 avidly binds IL-33 which results in interruption of the interaction between IL-33/ST2L and consequently eliminates the antiremodeling effects; thus, sST2 is viewed as a decoy receptor. In recent years, knowledge about ST2 role in the pathophysiology of cardiovascular diseases has broadly expanded, with strong links to myocardial dysfunction, fibrosis, and remodeling. Beyond its myocardial role, the IL-33/ST2 system could have an additional role in the development and progression of atherosclerosis. In conclusion, IL-33/ST2L signaling is a mechanically activated, cardioprotective fibroblast–cardiomyocyte paracrine system, which may have therapeutic potential for beneficially regulating the myocardial response to overload and injury. In contrast, sST2 acts as a decoy receptor and, by sequestering IL-33, antagonizes the cardioprotective effects of IL-33/ST2L interaction.

Section snippets

ST2 Isoforms and Regulation

The gene named ST2 is placed on human chromosome 2q12 and is part of the larger IL-1 gene cluster (GenBank accession number AC007248). Four isoforms are the transcriptional product of the gene and 2 of them are the most important: a transmembrane receptor (ST2L or IL1RL1-b) and a truncated soluble receptor that can be detected circulating in serum (sST2 or IL1RL1-a; Figure 1). Alternative promoter splicing and 3′ processing of the same mRNA seem to be responsible for the production of sST2 and

ST2 and IL-33 Interaction

In 2005, IL-33 (also known as IL-1F11) was identified as the ligand of ST2.⁴ IL-33 is an IL-1–like cytokine that can be secreted by most cells in response to damage.¹⁰ IL-33 exerts its cellular functions by binding a receptor complex composed of ST2L and IL-1R accessory protein (IL-1RAcP). IL-1RAcP is essential for IL-33 signaling through ST2L by enhancing the affinity of IL-33 for ST2L.¹¹ The interaction of IL-33 and ST2L activates mitogen-activated protein kinases and several biochemical

ST2 in Inflammatory Diseases

Before recognition of a cardiovascular role for ST2, most knowledge about the marker had been related to inflammatory and immune processes, particularly regarding the regulation of mast cells and type 2 CD4 + T-helper cells, and the production of Th2-associated cytokines.⁹ IL-33/ST2 signaling participates in the immune response through the activation of Th2 effector cells and the release of Th2-related cytokines. Therefore, a role for IL-33/ST2 has been demonstrated in numerous diseases

ST2 in Response to Myocardial Stress

The IL-33/ST2 system is upregulated in response to myocardial stress. The evidence supporting it arises from experimental studies and furthermore has been confirmed in clinical studies. In the pioneering work of Weinberg et al,³ rat neonatal cardiomyocytes were subjected to cyclic strain; of thousands of gene transcripts analyzed, ST2 was the most highly induced transcript in response to biomechanical stress, and both soluble and membrane forms were induced. Analysis of rat neonatal

The IL-33/ST2L Signaling is Cardioprotective

The interaction between IL33 and ST2L has been demonstrated to be cardioprotective in experimental models; this interaction reduces myocardial fibrosis, prevents cardiomyocyte hypertrophy, reduces apoptosis, and improves myocardial function. In an experimental model, IL-33 markedly antagonized angiotensin II–induced and phenylephrine-induced cardiomyocyte hypertrophy,¹³ whereas in a model of mice subjected to overt pressure overload of ventricles by aortic banding, treatment with IL-33 reduced

sST2 as a Pathophysiological Mediator

In contrast to cardioprotective effects of IL33/ST2L signaling, through its action as a decoy receptor, excessive amounts of sST2 appear to block the beneficial effects of IL-33. Indeed, the sST2 protein reversed in a dose-dependent manner the antihypertrophic effect of IL-33 in cardiomyocytes stimulated with angiotensin II or phenylephrine.¹³ A decrease in free IL-33 protein was noted after preincubation with sST2-Fc. In the presence of hypoxia, IL-33 reduced apoptosis of cardiomyocytes, but

ST2 in Atherosclerosis

IL-33 and ST2 are expressed in the normal and atherosclerotic vasculature of murine and human cells and tissues. Given atherosclerosis is a Th1 immune response, IL-33/ST2L may have protective effects by inducing a Th1-to-Th2 switch of immune response. In a model of atherosclerosis development in ApoE^−/− mice on a high-fat diet, IL-33 treatment reduced atherosclerotic plaque size and macrophage and T-cell accumulation in the aortic sinus and induced Th2 cytokines and ox-low-density

ST2 Biology: Unanswered Questions and Future Directions

Although much has been learned about IL-33/ST2 biology and cardiovascular disease, a better understanding of the cardiac role played by the ST2 system is needed. Given that IL-33/ST2L/sST2 proteins have distinct functions in different cells within different biologic systems, more knowledge about regulation of these systems is required. The source(s) of circulating ST2 besides the heart need more firm identification; given the prognostic role of sST2 to presage onset of disease across a wide

Conclusions

ST2 is a member of the interleukin 1 receptor family with 2 main isoforms: transmembrane ST2L and circulating or soluble sST2; ST2 is the receptor of the IL-33, which is an IL-1–like cytokine that can be secreted by living cells in response to cell damage. The IL-33/ST2 system is upregulated in numerous cells relevant to the diagnosis of heart failure: it is found in cardiomyocytes and fibroblasts as response to mechanical stimulation or injury, and in experimental models, the interaction of

Author Disclosures

Domingo Pascual-Figal reports receiving grant support from Critical Diagnostics. James Januzzi reports receiving grant support and consulting income from Critical Diagnostics and Roche Diagnostics; grant support from Thermo Fisher and Singulex; consulting income from diaDexus, SphingoTec, and Novartis; and participates in clinical end points committees/data monitoring committees for Novartis, Amgen, Resmed, and Boeringer-Ingelheim.

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Highly sensitive and specific graphene oxide-based FRET aptasensor for quantitative detection of human soluble growth stimulating gene protein 2
2024, Talanta
Soluble growth stimulation expressed gene 2 (sST2) is a new generation biomarker in the diagnosis and prognosis of heart failure (HF). Here, the sST2-specific aptamers were selected from a random ssDNA library with the full length of 88 nucleotides (nt) via target-immobilized magnetic beads (MB)-based systematic evolution of ligands by exponential enrichment (SELEX) technology. After eight rounds of selection, six aptamers with the most enrichment were selected. Among, the aptamer L1 showed the high-affinity binding to sST2 with the lowest Kd value (77.3 ± 0.05 nM), which was chosen as the optimal aptamer for further molecular docking. Then, the aptamer L1 was used to construct a graphene oxide (GO) - based fluorescence resonance energy transfer (FRET) biosensor for sST2, which exhibits a linear detection range of 0.1–100 μg/ml and a detection limit of 3.7 ng/ml. The aptasensor was applied to detect sST2 in real samples, with a good correlation and agreement with the traditional enzyme-linked immunosorbent assay (ELISA) when quantitative analyzing the sST2 concentration in serum samples from HF patients. The results show that not only an efficient strategy for screening the practicable aptamer, but also a rapid and sensitive detection platform for sST2 were established.
Transient anti-cytokine autoantibodies superimpose the hyperinflammatory response in Kawasaki disease and multisystem inflammatory syndrome in children: a comparative cohort study on correlates of disease
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Children with SARS-CoV-2 related Multisystem Inflammatory Syndrome in Children (MIS-C) often present with clinical features that resemble Kawasaki disease (KD). Disease severity in adult COVID-19 is associated to the presence of anti-cytokine autoantibodies (ACAAs) against type I interferons. Similarly, ACAAs may be implicated in KD and MIS-C. Therefore, we explored the immunological response, presence of ACAAs and disease correlates in both disorders.
Eighteen inflammatory plasma protein levels and seven ACAAs were measured in KD (n = 216) and MIS-C (n = 56) longitudinally by Luminex and/or ELISA. Levels (up to 1 year post-onset) of these proteins were related to clinical data and compared with healthy paediatric controls.
ACAAs were found in both patient groups. The presence of ACAAs lagged behind the inflammatory plasma proteins and peaked in the subacute phase. ACAAs were mostly directed against IFN-γ (>80%) and were partially neutralising at best. KD presented with a higher variety of ACAAs than MIS-C. Increased levels of anti-IL-17A (P = 0·02) and anti-IL-22 (P = 0·01) were inversely associated with ICU admission in MIS-C. Except for CXCL10 in MIS-C (P = 0·002), inflammatory plasma proteins were elevated in both KD and MIS-C. Endothelial angiopoietin-2 levels were associated with coronary artery aneurysms in KD (P = 0·02); and sCD25 (P = 0·009), angiopoietin-2 (P = 0·001), soluble IL-33-receptor (ST2, P = 0·01) and CXCL10 (P = 0·02) with ICU admission in MIS-C.
Markers of endothelial activation (E-selectin, angiopoietin-2), and innate and adaptive immune responses (macrophages [CD163, G-CSF], neutrophils [lipocalin-2], and T cells [IFN-γ, CXCL10, IL-6, IL-17]), are upregulated in KD and MIS-C. ACAAs were detected in both diseases and, although only partly neutralising, their transient presence and increased levels in non-ICU patients may suggest a dampening role on inflammation.
The Kawasaki study is funded by the Dutch foundation Fonds Kind & Handicap and an anonymous donor. The sponsors had no role in the study design, analysis, or decision for publication.
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: Publication of this supplement was supported by funding from Critical Diagnostics, San Diego, CA.

: Statement of author disclosure: Please see the Author Disclosures section at end of this article.

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The Biology of ST2: The International ST2 Consensus Panel

Section snippets

ST2 Isoforms and Regulation

ST2 and IL-33 Interaction

ST2 in Inflammatory Diseases

ST2 in Response to Myocardial Stress

The IL-33/ST2L Signaling is Cardioprotective

sST2 as a Pathophysiological Mediator

ST2 in Atherosclerosis

ST2 Biology: Unanswered Questions and Future Directions

Conclusions

Author Disclosures

FEBS Lett

Immunity

J Biol Chem

J Biol Chem

Cytokine

J Am Coll Cardiol

J Am Coll Cardiol

Int J Biochem Cell Biol

JACC Hear Fail

J Am Coll Cardiol

J Mol Cell Cardiol