Suppression Of Tumorigenicity 2 Research Articles

ST2L promotes VEGFA-mediated angiogenesis in gastric cancer by activating TRAF6/PI3K/Akt/NF-κB pathway via IL-33

Suppression of Tumorigenicity 2 (ST2) is a member of the interleukin-1 receptor/ Toll-like receptor superfamily, and its specific ligand is Interleukin-33 (IL-33). IL-33/ ST2 signaling has been implicated in numerous inflammatory and allergic diseases, as well as in promoting malignant behavior of tumor cells and angiogenesis. However, the precise role of ST2 in gastric cancer angiogenesis remains incompletely elucidated. We observed a significant correlation between high expression of ST2 in gastric cancer tissues and poor prognosis, along with various clinicopathological features. In vitro experiments demonstrated that the IL-33/ ST2 axis activates the PI3K/AKT/NF-κB signaling pathway through TRAF6, thereby promoting VEGFA-mediated tumor angiogenesis; meanwhile sST2 acts as a decoy receptor to regulate the IL-33/ST2L axis. Consistent findings were also observed in subcutaneous xenograft tumor models in nude mice. Furthermore, we investigated the molecular mechanism by which IL-33 promotes ST2L expression in GC cells via upregulation of transcription factors YY1 and GATA2 through intracellular signaling pathways.

Proteomic biomarkers and pathway analysis for progression to heart failure in three epidemiological representative cohorts.

Biomarkers associated with asymptomatic ventricular dysfunction might improve risk stratification and identify pathways leading to heart failure (HF). We explored the association between proteomic biomarkers and left ventricular hypertrophy (LVH), diastolic dysfunction (DD) and incident HF in three population-based cohorts. A chip was used to measure 92 protein biomarkers in blood samples from >1500 Malmö Preventive Project (MPP) participants, of whom 514 had LVH (34%), 462 had DD (32.4%) and, over a median follow-up of 13 (11-14) years, 130 developed HF (7.7%). Findings were confirmed in the STANISLAS (n > 1500, 238 participants with LVH, 76 with DD) and HOMAGE case-control (562 cases of incident HF, 871 controls) cohorts. In multivariable logistic or Cox regression analyses adjusted for age, sex and cardiovascular risk factors, N-terminal pro-B-type natriuretic peptide (NT-proBNP) was associated with LVH, DD and incident HF in all cohorts: MPP (LVH odds ratio [OR] [95% confidence interval] 1.48 [1.28-1.71]; DD OR 1.71 [1.53-1.92]; HF HR 1.98 [1.66-2.36]); STANISLAS (LVH OR 1.20 [1.02-1.41]; DD OR 1.46 [1.12-1.90]); HOMAGE (HF HR 1.85 [1.62-2.12]). Galectin-4, growth differentiation factor 15 and suppression of tumorigenicity-2 were associated with incident HF in MPP and HOMAGE. A pathway enrichment analysis suggested that inflammation and viral infection were related to incident HF. In conclusion, our study reinforces the role of NT-proBNP as a key biomarker for asymptomatic cardiac dysfunction and incident HF, consistent with its established use in clinical practice. This underscores the value of NT-proBNP for identifying patients at high risk for HF, and provides insights into pathways leading to HF and potential therapeutic targets.

Prognostic significance of suppressor of tumorigenicity 2, endothelin-1, macrophage migration inhibitory factor, interleukin-6 and C-reactive protein in patients with acute myocardial infarction with ST-segment elevation and reduced glomerular filtration

Acute myocardial infarction with ST‑segment elevation (STEMI) is one of the most severe forms of cardiovascular disease, requiring immediate diagnosis and treatment. Prognostic biomarkers play a crucial role in risk stratification and guiding therapeutic strategies in STEMI patients, particularly those with reduced glomerular filtration rate (GFR). Objective — to evaluate the prognostic significance of suppressor of tumorigenicity 2 (ST2), endothelin­1 (ET­1), macrophage migration inhibitory factor (MIF), interleukin­6 (IL­6), and C­reactive protein (CRP) in STEMI patients with reduced GFR compared to those with normal GFR for improved risk stratification and management. Materials and methods. This study was conducted on a cohort of 762 patients diagnosed with STEMI. The mean age of the patients was (60.5±10.5) years, with 74.7% being male. The glomerular filtration rate was calculated using the CKD­EPI 2021 formula. Patients were categorized into two groups: 246 with GFR <60 ml/min/1.73m2 and 516 with GFR ≥60 ml/min/1.73m2. Biomarker levels (ST2, ET­1, MIF, IL­6, CRP) were measured using enzyme­linked immunosorbent assay (ELISA) kits. Results. In patients with reduced GFR, ST2 and CRP levels were significantly higher than in patients with normal GFR (39.48 [26.49—80.71] and 33.78 [21.14—59.66] ng/ml, respectively, p=0.026 and 48 [36—96] and 24 [6—48] mg/l, p=0.015). The levels of MIF and IL‑6 were also increased in patients with reduced GFR, but the differences in these parameters were not statistically significant. No significant difference was recorded in ET‑1 levels between the groups. The analysis of ROC curves for ST2 revealed moderate prognostic accuracy in predicting survival in patients with reduced GFR (AUC=0.659; p=0.016). Conclusions. The results indicate the importance of ST2 as a prognostic marker in STEMI patients with reduced GFR. The use of these biomarkers in clinical practice can improve risk stratification and management in this patient group. Further research is warranted to develop individualized treatment approaches that consider the risks of cardiovascular events and renal dysfunction in STEMI patients.

Association of fibrotic markers with diastolic function after STEMI

Galectin-3 and Suppression of tumorigenicity-2 (ST2) are known markers of cardiac fibrosis. We investigated the prognostic value of fibrotic markers for the development of diastolic dysfunction and long-term outcome in patients suffering an ST-elevated myocardial infarction (STEMI). We analyzed 236 patients from the GIPS-III cohort with available echocardiographic studies and plasma measurements at hospitalization and after 4 months follow-up. Adjusted logistic mixed effects modelling revealed no association between the occurrence of diastolic dysfunction over time with abnormal plasma levels of galectin-3 and ST2. We observed no differences regarding survival outcome at follow-up of 5 years between patients with normal versus abnormal values in both galectin-3 (P = 0.75), and ST2 (P = 0.85). In conclusion, galectin-3 and sST2 were not associated with the development of diastolic dysfunction in non-diabetic patients that presented with a STEMI.

Pericardial Fluid Accumulates microRNAs That Regulate Heart Fibrosis after Myocardial Infarction.

Pericardial fluid (PF) has been suggested as a reservoir of molecular targets that can be modulated for efficient repair after myocardial infarction (MI). Here, we set out to address the content of this biofluid after MI, namely in terms of microRNAs (miRs) that are important modulators of the cardiac pathological response. PF was collected during coronary artery bypass grafting (CABG) from two MI cohorts, patients with non-ST-segment elevation MI (NSTEMI) and patients with ST-segment elevation MI (STEMI), and a control group composed of patients with stable angina and without previous history of MI. The PF miR content was analyzed by small RNA sequencing, and its biological effect was assessed on human cardiac fibroblasts. PF accumulates fibrotic and inflammatory molecules in STEMI patients, namely causing the soluble suppression of tumorigenicity 2 (ST-2), which inversely correlates with the left ventricle ejection fraction. Although the PF of the three patient groups induce similar levels of fibroblast-to-myofibroblast activation in vitro, RNA sequencing revealed that PF from STEMI patients is particularly enriched not only in pro-fibrotic miRs but also anti-fibrotic miRs. Among those, miR-22-3p was herein found to inhibit TGF-β-induced human cardiac fibroblast activation in vitro. PF constitutes an attractive source for screening diagnostic/prognostic miRs and for unveiling novel therapeutic targets in cardiac fibrosis.

Intestinal IL-33 promotes microbiota-derived trimethylamine N -oxide synthesis and drives metabolic dysfunction-associated steatotic liver disease progression by exerting dual regulation on HIF-1α.

Gut microbiota plays a prominent role in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). IL-33 is highly expressed at mucosal barrier sites and regulates intestinal homeostasis. Herein, we aimed to investigate the role and mechanism of intestinal IL-33 in MASLD. In both humans and mice with MASLD, hepatic expression of IL-33 and its receptor suppression of tumorigenicity 2 (ST2) showed no significant change compared to controls, while serum soluble ST2 levels in humans, as well as intestinal IL-33 and ST2 expression in mice were significantly increased in MASLD. Deletion of global or intestinal IL-33 in mice alleviated metabolic disorders, inflammation, and fibrosis associated with MASLD by reducing intestinal barrier permeability and rectifying gut microbiota dysbiosis. Transplantation of gut microbiota from IL-33 deficiency mice prevented MASLD progression in wild-type mice. Moreover, IL-33 deficiency resulted in a decrease in the abundance of trimethylamine N -oxide-producing bacteria. Inhibition of trimethylamine N -oxide synthesis by 3,3-dimethyl-1-butanol mitigated hepatic oxidative stress in mice with MASLD. Nuclear IL-33 bound to hypoxia-inducible factor-1α and suppressed its activation, directly damaging the integrity of the intestinal barrier. Extracellular IL-33 destroyed the balance of intestinal Th1/Th17 and facilitated Th1 differentiation through the ST2- Hif1a - Tbx21 axis. Knockout of ST2 resulted in a diminished MASLD phenotype resembling that observed in IL-33 deficiency mice. Intestinal IL-33 enhanced gut microbiota-derived trimethylamine N -oxide synthesis and aggravated MASLD progression through dual regulation on hypoxia-inducible factor-1α. Targeting IL-33 and its associated microbiota may provide a potential therapeutic strategy for managing MASLD.

Repeated Infusions of Bone-Marrow-Derived Mesenchymal Stem Cells over 8 Weeks for Steroid-Refractory Chronic Graft-versus-Host Disease: A Prospective, Phase I/II Clinical Study.

Chronic graft-versus-host disease (cGVHD) is a long-term complication of allogeneic hematopoietic stem cell transplantation associated with poor quality of life and increased morbidity and mortality. Currently, there are several approved treatments for patients who do not respond to steroids, such as ruxolitinib. Nevertheless, a significant proportion of patients fail second-line treatment, indicating the need for novel approaches. Mesenchymal stem cells (MSCs) have been considered a potential treatment approach for steroid-refractory cGVHD. To evaluate the safety and efficacy of repeated infusions of MSCs, we administered intravenous MSCs every two weeks to ten patients with severe steroid-refractory cGVHD in a prospective phase I clinical trial. Each patient received a total of four doses, with each dose containing 1 × 106 cells/kg body weight from the same donor and same passage. Patients were assessed for their response to treatment using the 2014 National Institutes of Health (NIH) response criteria during each visit. Ten patients with diverse organ involvement were enrolled, collectively undergoing 40 infusions as planned. Remarkably, the MSC infusions were well tolerated without severe adverse events. Eight weeks after the initial MSC infusion, all ten patients showed partial responses characterized by the amelioration of clinical symptoms and enhancement of their quality of life. The overall response rate was 60%, with a complete response rate of 20% and a partial response (PR) rate of 40% at the last follow-up. Overall survival was 80%, with a median follow-up of 381 days. Two patients died due to relapse of their primary disease. Immunological analyses revealed a reduction in inflammatory markers, including Suppression of Tumorigenicity 2 (ST2), C-X-C motif chemokine ligand (CXCL)10, and Secreted phosphoprotein 1(SPP1), following the MSC treatment. Repeated MSC infusions proved to be both feasible and safe, and they may be an effective salvage therapy in patients with steroid-refractory cGVHD. Further large-scale clinical studies with long-term follow-up are needed in the future to determine the role of MSCs in cGVHD.

Does the ST2 Level in Pediatric Heart Failure Patients Correlate with Cardiovascular Events and Mortality?

The suppression of tumorigenicity 2 (ST2) is a receptor member belonging to the interleukin-1 (IL-1) family. The ligand and soluble versions are its two isoforms. The IL-33-ST2L ligand complex's development provides protection against heart fibrosis and hypertrophy. Investigations on heart failure in adults have demonstrated that it does not change by age, body mass index (BMI), creatinine, hemoglobin, and albumin levels, in contrast to NT pro BNP. In adult heart failure patients, it has been demonstrated to be an independent predictor of mortality and cardiovascular events. The most recent guideline recommends using it as class 2b in the diagnosis of adult heart failure. Studies on ST2 in children are rare. The purpose of this study is to assess the prognostic value of ST2 for cardiovascular events in young individuals suffering from heart failure. This study included pediatric patients (0-18 years old) with congenital heart disease or cardiomyopathy who needed medical care, as well as surgical or interventional treatment. Height, weight, gender, saturation, heart failure classification (Ross or NYHA), medications, the electrocardiogram, echocardiography, pro BNP, and sST2 values of the patients, as well as any hospitalization, lower respiratory tract infection, organ dysfunction, or need for angiography or surgery during follow-up data on arrhythmia and death were gathered during a 1-year follow-up. The SPSS software version 25 application was used to carry out the statistical analysis. This study included 59 patients, of whom 27 (46.6%) were male. The average age of the patients was 55.5 months (1-228 months) and the average body weight was 16 kg (2.6-90 kg). Major cardiovascular events occurred in 45 of 59 patients (76.3%). Twenty-four patients experienced one MACE, while twenty-one patients experienced multiple MACEs. Pro BNP and sST2 levels were similar in the groups that developed MACE compared to those that did not. Pro BNP was discovered to be significantly higher in patients with hospitalization, growth retardation, lower respiratory tract infection, and organ failure, however, when assessing each situation (p = 0.001, p = 0.011, p = 0.001, p = 0.007, respectively). Soluble ST2 was found to be higher in patients with growth retardation than in those without (p = 0.037). Although the soluble ST2 level failed to demonstrate a correlation with pro BNP, it did show a positive correlation (r = 0.437) with the Ross score. When compared to other groups, it was discovered to be higher in patients with valvular insufficiency type heart disease. In this study, higher sST2 levels were discovered, particularly in the group with valve insufficiency and children with growth retardation. It was associated with the Ross score, but not with the pro BNP level. Although it increases in correlation with clinical heart failure, its predictive value for MACE is low. Similarly, pro BNP is not proven to be predictive; nonetheless, its high levels in patients with hospitalization, growth retardation, lower respiratory tract infection, and organ failure demonstrate that pro BNP may increase for a variety of causes. Long-term studies with more patients are needed for ST2 to be suitable for clinical use in pediatric patients.

Biomarkers in a phase 1b study of investigational microbiome therapeutic SER-155 in adults undergoing allogeneic hematopoietic cell transplantation (allo-HCT).

6554 Background: Acute graft- versus-host disease (aGvHD) is a life-threatening complication following allo-HCT. Microbiome dysfunction and associated GI barrier disruption may contribute to aGvHD via activation of inflammatory immune responses. Circulating biomarkers in the peri-transplant period are correlated with risk of severe aGvHD, including suppression of tumorigenicity 2 (ST2), regenerating islet-derived 3-alpha (Reg3a) and inflammatory cytokines (IL6, IFNϒγ & TNFα). SER-155 is an investigational cultivated oral microbiome therapeutic designed to restructure the GI microbiome, improve GI barrier integrity and reduce GI inflammation and is being assessed in a 2-part Phase 1b study in adults undergoing allo-HCT. We present preliminary safety, GvHD, PK, and exploratory biomarker data from the completed open-label Cohort 1 through Day 100 post-HCT. Methods: Adult recipients of allo-HCT were eligible. HCT conditioning and aGvHD prophylaxis were per investigator discretion. Patients received 2 courses of SER-155 (pre-HCT and post-neutrophil engraftment, each comprised of 4 days of microbiome conditioning with oral vancomycin followed by 10 days oral SER-155. The primary endpoint was safety. Strain engraftment (PK) and biomarkers were assessed in stool and plasma samples. Results: Fifteen adults enrolled; 13 received at least 1 course of study drug (median age 67; 54% male), and 11 underwent allo-HCT. Following each course, the majority of the 16 SER-155 strains were detected in stool. Treatment-emergent adverse events (AEs) were reported in all patients with GI AEs the most common. No serious AEs (SAEs) were deemed related to SER-155. Most SAEs and AEs of special interest (ie, BSIs, invasive or GI infections) occurred between HCT and the 2nd SER-155 course. There were no deaths before Day 100. No BSIs were attributable to SER-155 strains. The rate of grade 2-4 aGvHD based on MAGIC criteria through Day 100 was 45.5%; no severe grade 3-4 aGvHD was observed. Median levels of plasma biomarkers REG3α, ST2 and inflammatory cytokines were not elevated relative to a reference range (Table). Conclusions: In this small open-label cohort, SER-155 was generally well-tolerated through Day 100 without drug-related SAEs and no severe aGvHD. Plasma biomarkers were not elevated at HCT Day 0 or neutrophil recovery. These preliminary observations align with the design and preclinical evaluation of SER-155. Clinical trial information: NCT04995653 . [Table: see text]

Association of suPAR, ST2, and galectin-3 with eGFR decline and mortality in patients with advanced heart failure with reduced ejection fraction.

Patients with heart failure with reduced ejection fraction (HFrEF) are at risk for chronic kidney disease (CKD). Elevated levels of circulating biomarkers soluble urokinase plasminogen activator receptor (suPAR), galectin-3, soluble suppression of tumorigenicity 2 (ST2), and N-terminal prohormone B-type natriuretic peptide (NT-proBNP) are associated with CKD progression and mortality. The predictive value of these biomarkers in a population with HFrEF and kidney disease is relatively unknown. We sought to determine whether these biomarkers were associated with longitudinal trajectory of estimated glomerular filtration rate (eGFR) in HFrEF and assess their association with mortality using a joint model to account for competing risks of ventricular assist device (VAD) implantation and heart transplantation. We included participants from the Registry Evaluation of Vital Information for Ventricular Assist Devices in Ambulatory Life with repeated eGFR measures over 2 years. Of 309 participants, mean age was 59 years, median eGFR 60 ml/min/1.73 m2, 45 participants died, 33 received VAD, and 25 received orthotopic heart transplantation. Higher baseline serum standardized suPAR (β coefficient = -0.36 √(ml/min/1.73 m2), 95% confidence interval (-0.48 to -0.24), p < 0.001), standardized galectin-3 (-0.14 √(ml/min/1.73 m2) (-0.27 to -0.02), p = 0.02), and log NT-proBNP (-0.23 √(ml/min/1.73 m2) (-0.31 to -0.15), p < 0.001) were associated with eGFR decline. ST2 and log NT-proBNP were associated with mortality. Higher baseline suPAR, galectin-3, and NT-proBNP are associated with eGFR decline in patients with HFrEF. Only ST2 and NT-proBNP are associated with greater mortality after controlling for other factors including change in eGFR. These biomarkers may provide prognostic value for kidney disease progression in HFrEF and inform candidacy for advanced heart failure therapies.

Amphiregulin, ST2, and REG3α biomarker risk algorithms as predictors of nonrelapse mortality in patients with acute GVHD

AbstractGraft-versus-host disease (GVHD) is a major cause of nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation. Algorithms containing either the gastrointestinal (GI) GVHD biomarker amphiregulin (AREG) or a combination of 2 GI GVHD biomarkers (suppressor of tumorigenicity-2 [ST2] + regenerating family member 3 alpha [REG3α]) when measured at GVHD diagnosis are validated predictors of NRM risk but have never been assessed in the same patients using identical statistical methods. We measured the serum concentrations of ST2, REG3α, and AREG by enzyme-linked immunosorbent assay at the time of GVHD diagnosis in 715 patients divided by the date of transplantation into training (2004-2015) and validation (2015-2017) cohorts. The training cohort (n = 341) was used to develop algorithms for predicting the probability of 12-month NRM that contained all possible combinations of 1 to 3 biomarkers and a threshold corresponding to the concordance probability was used to stratify patients for the risk of NRM. Algorithms were compared with each other based on several metrics, including the area under the receiver operating characteristics curve, proportion of patients correctly classified, sensitivity, and specificity using only the validation cohort (n = 374). All algorithms were strong discriminators of 12-month NRM, whether or not patients were systemically treated (n = 321). An algorithm containing only ST2 + REG3α had the highest area under the receiver operating characteristics curve (0.757), correctly classified the most patients (75%), and more accurately risk-stratified those who developed Minnesota standard-risk GVHD and for patients who received posttransplant cyclophosphamide-based prophylaxis. An algorithm containing only AREG more accurately risk-stratified patients with Minnesota high-risk GVHD. Combining ST2, REG3α, and AREG into a single algorithm did not improve performance.

Analysis of clinical features of heart failure in children with cardiomyopathy and improved ejection fraction.

The prognosis of children with heart failure varies considerably. After treatment, left ventricular ejection fraction (LVEF) can be improved in some children. The aim of this study was to analyze the clinical features of children with heart failure accompanied by cardiomyopathy and recovered ejection fraction [heart failure with recovered ejection fraction (HFrecEF)] and to identify the predictors of improved LVEF. Children diagnosed with heart failure in Beijing Anzhen Hospital Affiliated to Capital Medical University from 2018 to 2021 were retrospectively enrolled. According to the baseline and change of LVEF, the patients were divided into two groups: a reduced ejection fraction (HFrEF) group and an HFrecEF group. The t-test was used to evaluate the difference between the two groups. The predictive factors of ejection fraction improvement were analyzed with a logistic regression model. A total of 72 children were included in this study, including 31 (43.1%) in the HFrEF group and 41 (56.9%) in the HFrecEF group. Compared with children in the HFrEF group, children in the HFrecEF group were younger and had faster resting heart rates, lower creatinine, lower suppression of tumorigenicity 2 (ST2) expression, a lower platelet-to-lymphocyte (PLT:LYM) ratio, and smaller left atrial diameter. After a mean follow-up of 35.87 months, 26 cases returned to normal ejection fraction. In the HFrEF group, sudden cardiac death occurred in two cases, and four cases received heart transplantation. Logistic analysis showed that virus infection [odds ratio (OR) =1.279; 95% confidence interval (CI): 0.374-4.379; P=0.007], low ST2 expression (cutoff value =1.89 ng/mL: OR =1.042; 95% CI: 1.007-1.082; P=0.032), and treatment with intravenous immunoglobulin (IVIG) (OR =5.077; 95% CI: 1.458-17.684; P=0.011) were predictors of improvement in LVEF in patients with heart failure after treatment. In some patients with HFrecEF, LVEF eventually returned to normal. The combination of viral infection, low ST2 expression, and the application of IVIG therapy were found to be independent predictors of LVEF improvement in patients with heart failure after treatment.

A Day 14 Endpoint for Acute GVHD Clinical Trials

The overall response rate (ORR) 28 days after treatment has been adopted as the primary endpoint for clinical trials of acute graft versus host disease (GVHD). However, physicians often need to modify immunosuppression earlier than day (D) 28, and non-relapse mortality (NRM) does not always correlate with ORR at D28. We studied 1144 patients that received systemic treatment for GVHD in the Mount Sinai Acute GVHD International Consortium (MAGIC) and divided them into a training set (n=764) and a validation set (n=380). We used a recursive partitioning algorithm to create a Mount Sinai model that classifies patients into favorable or unfavorable groups that predicted 12 month NRM according to overall GVHD grade at both onset and D14. In the Mount Sinai model grade II GVHD at D14 was unfavorable for grade III/IV GVHD at onset and predicted NRM as well as the D28 standard response model. The MAGIC algorithm probability (MAP) is a validated score that combines the serum concentrations of suppression of tumorigenicity 2 (ST2) and regenerating islet-derived 3-alpha (REG3α) to predict NRM. Inclusion of the D14 MAP biomarker score with the D14 Mount Sinai model created three distinct groups (good, intermediate, poor) with strikingly different NRM (8%, 35%, 76% respectively). This D14 MAGIC model displayed better AUC, sensitivity, positive and negative predictive value, and net benefit in decision curve analysis compared to the D28 standard response model. We conclude that this D14 MAGIC model could be useful in therapeutic decisions and may offer an improved endpoint for clinical trials of acute GVHD treatment.

Interleukin-33/ST2 axis involvement in atrial remodeling and arrhythmogenesis

Interleukin (IL)-33, a cytokine involved in immune responses, can activate its receptor, suppression of tumorigenicity 2 (ST2), is elevated during atrial fibrillation (AF). However, the role of IL-33/ST2 signaling in atrial arrhythmia is unclear. This study explored the pathological effects of the IL-33/ST2 axis on atrial remodeling and arrhythmogenesis. Patch clamping, confocal microscopy, and Western blotting were used to analyze the electrical characteristics of and protein activity in atrial myocytes (HL-1) treated with recombinant IL-33 protein and/or ST2-neutralizing antibodies for 48 hrs. Telemetric electrocardiographic recordings, Masson's trichrome staining, and immunohistochemistry staining of the atrium were performed in mice receiving tail vein injections with nonspecific immunoglobulin (control), IL-33, and IL-33 combined with anti-ST2 antibody for 2 weeks. IL-33-treated HL-1 cells had a reduced action potential duration, lower L-type Ca2+ current, greater sarcoplasmic reticulum (SR) Ca2+ content, increased Na+/Ca2+ exchanger (NCX) current, elevation of K+ currents, and increased intracellular calcium transient. IL-33-treated HL-1 myocytes had greater activation of the calcium–calmodulin-dependent protein kinase II (CaMKII)/ryanodine receptor 2 (RyR2) axis and nuclear factor kappa B (NF-κB) / NLR family pyrin domain containing 3 (NLRP3) signaling than did control cells. IL-33 treated cells also had greater expression of Nav1.5, Kv1.5, NCX, and NLRP3 than did control cells. Pretreatment with neutralizing anti-ST2 antibody attenuated IL-33-mediated activation of CaMKII/RyR2 and NF-κB/NLRP3 signaling. IL-33-injected mice had more atrial ectopic beats and increased AF episodes, greater atrial fibrosis, and elevation of NF-κB/NLRP3 signaling than did controls or mice treated with IL-33 combined with anti-ST2 antibody. Thus, IL-33 recombinant protein treatment promotes atrial remodeling through ST2 signaling. Blocking the IL-33/ST2 axis might be an innovative therapeutic approach for patients with atrial arrhythmia and elevated serum IL-33.

ST2-Mediated Neutrophilic Airway Inflammation: A Therapeutic Target for Patients With Uncontrolled Asthma.

Suppression of tumorigenicity 2 (ST2) has been proposed as the receptor contributing to neutrophilic inflammation in patients with type 2-low asthma. However, the exact role of ST2 in neutrophil activation remains poorly understood. A total of 105 asthmatic patients (classified into 3 groups according to control status: the controlled asthma [CA], partly-controlled asthma [PA], and uncontrolled asthma [UA] groups), and 104 healthy controls were enrolled to compare serum levels of soluble ST2 (sST2) and interleukin (IL)-33. Moreover, the functions of ST2 in neutrophils and macrophages (Mϕ) were evaluated ex vivo and in vivo. Serum sST2 levels were significantly higher in the UA group than in the CA or PA groups (P < 0.05 for all) with a negative correlation between serum sST2 and forced expiratory volume in 1 second % (r = -0.203, P = 0.038). Significantly higher expression of ST2 receptors on peripheral neutrophils was noted in the UA group than in the PA or CA groups. IL-33 exerted its effects on the production of reactive oxygen species, the formation of extracellular traps from neutrophils, and Mϕ polarization/activation. In neutrophilic asthmatic mice, treatment with anti-ST2 antibody significantly suppressed proinflammatory cytokines (tumor necrosis factor-alpha and IL-17A) as well as the numbers of immune cells (neutrophils, Mϕ, and group 3 innate lymphoid cells) in the lungs. These results suggest that IL-33 induces the activation of neutrophils and Mϕ via ST2 receptors, leading to neutrophilic airway inflammation and poor control status of asthma. ST2 could be a therapeutic target for neutrophilic airway inflammation in patients with UA.

Biomarkers and Strain Echocardiography for the Detection of Subclinical Cardiotoxicity in Breast Cancer Patients Receiving Anthracyclines.

The optimal surveillance and management strategies for breast cancer patients receiving anthracycline therapy are limited by our incomplete understanding of the role of biomarkers heralding the onset of cardiotoxicity. The purpose of this study was to determine whether there is a temporal correlation between cardiac biomarkers and subclinical left ventricular dysfunction in breast cancer patients receiving anthracycline chemotherapy. Thirty-one females between 46 and 55 years old with breast cancer treated with anthracycline chemotherapy were prospectively enrolled. Cardiac biomarkers were correlated with echocardiography with speckle tracking at baseline, post-anthracycline therapy, and 6 months post-anthracycline chemotherapy. Subclinical cardiotoxicity was defined as ≥ 10% reduction in global longitudinal strain (GLS). There was a relative reduction in left ventricular ejection fraction (LVEF) ≥ 10% in 5/30 (17%) and 7/27 (26%) patients post-anthracycline therapy and 6 months post-anthracycline therapy, respectively. Subclinical cardiotoxicity was noted in 8/30 (27%) and 10/26 (38%) patients post-anthracycline and 6 months post-anthracycline therapy, respectively. Baseline N-terminal pro B-type natriuretic peptide (NT-proBNP) was the strongest predictor of LVEF (ρ = -0.45; p = 0.019), with post-therapy NT-proBNP values illustrating similar predictive value (ρ = -0.40; p = 0.038). Interim changes in suppression of tumorigenicity 2 (ST2) and galectin-3 correlated with a 6-month change in LVEF (ρ = -0.48; p = 0.012 and ρ = -0.45; p = 0.018, for ST2 and galectin-3, respectively). Changes in galectin-3 from baseline to mid-therapy paralleled changes in GLS. NT-proBNP, ST2, and galectin-3 correlate with reduced LVEF among breast cancer patients receiving anthracycline therapy. Additional trials focusing on a cardiac biomarker approach may provide guidance in the early diagnosis and management of anthracycline-induced cardiotoxicity.

Changes of immunological biomarkers in pediatric patients with seasonal allergic rhinitis

Background. Seasonal allergic rhinitis shows a constant upward trend not only among the adults but also in the children’s population. A significant percentage of patients have a moderate and severe course of the disease, which leads to a significant deterioration in their quality of life. Since the pathogenesis of allergic rhinitis is represented by a complex cascade of immunological reactions involving a number of cytokines that play a role in the development of allergic inflammation of the upper respiratory tract, the priority direction of our work was an in-depth study of the pathogenetic mechanisms of this disease. The purpose was to investigate the levels of interleukin-33 (IL-33) and its suppression of tumorigenicity 2 (ST2) receptor in the blood serum of children with hay fever, depending on the age and severity of the disease, followed by the determination of correlations of these indicators with various clinical and immunological parameters of seasonal allergic rhinitis. Materials and methods. Forty-two patients aged 6–17 years with seasonal allergic rhinitis and 26 healthy children (controls) took part in the study. Severity of nasal and extra-nasal symptoms of allergic rhinitis was determined using a visual analog scale. Skin prick testing was performed according to generally accepted standards during remission using a standard pollen panel. Quantitative measurement of serum indicators of interleukin-33 and ST2 was carried out by the method of solid-phase enzyme immunoassay. A mandatory condition for conducting the study was the presence of written informed consent from the parents. Results. The study of serum levels of IL-33 and ST2 showed statistically higher concentrations in the group of children with a severe course of seasonal allergic rhinitis, a direct correlation of medium strength between content of the above cytokines in children with a mild SAR (τ = 0.65; p &lt; 0.05) and a strong dependence in patients with moderate (τ = 0.76; p &lt; 0.01) and severe (τ = 0.80; p &lt; 0.05) course. When comparing the mean values of IL-33 and ST2, no significant changes were found depending on age and the presence of mono- or polysensitisation among patients with allergic rhinitis. In children with seasonal allergic rhinitis and concomitant bronchial asthma, there was a statistically significant tendency towards a more severe course of the disease with correspondingly higher values of IL-33 and ST2 compared to patients with isolated seasonal allergic rhinitis. Conclusions. The obtained results of the immunological study made it possible to emphasize the diagnostic significance of IL-33 and its receptor ST2 as potential biomarkers in the development of allergic inflammation in pediatric patients with seasonal manifestations of rhinitis.

Soluble suppression of tumorigenicity 2 is a potential predictor of post-liver transplant renal outcomes.

Acute kidney injury is considered an independent prognostic factor for mortality in patients with liver cirrhosis. Non-treated acute kidney injury can progress to hepatorenal syndrome with a poor prognosis. As suppression of tumorigenicity 2 (ST2) is a member of the interleukin-1 receptor family that aggravates inflammation and fibrotic changes in multiple organs, we measured soluble ST2 (sST2) level in the serum and urine of liver-transplant recipients at the time of transplantation. The serum sST2 level significantly increased in liver-transplant recipients with suppressed kidney function compared with that in recipients with normal function. In recipients with severely decreased liver function (model for end-stage liver disease score ≥ 30), the serum sST2 level was higher than that in recipients with preserved liver function (model for end-stage liver disease score ≤ 20, P = 0.028). The serum sST2 level in recipients with hepatorenal syndrome was higher than that in liver-transplant recipients without hepatorenal syndrome (P = 0.003). The serum sST2 level in patients with hepatorenal syndrome was higher than that in recipients without a history of acute kidney injury (P = 0.004). Recipients with hepatorenal syndrome and recovered kidney function showed higher sST2 levels than those who did not recover (P = 0.034). Collectively, an increase in the serum sST2 level reflects a decrease in both kidney and liver functions. Thus, measuring sST2 level at the time of liver transplantation can help predict renal outcomes.

Roles of IL-33 in the Pathogenesis of Cardiac Disorders.

Interleukin-33 (IL-33) is a member of the IL-1 cytokine family and is believed to play important roles in different diseases by binding to its specific receptor suppression of tumorigenicity 2 (ST2). In the heart, IL-33 is expressed in different cells including cardiomyocytes, fibroblasts, endothelium, and epithelium. Although many studies have been devoted to investigating the effects of IL-33 on heart diseases, its roles in myocardial injuries remain obscure, and thus further studies are mandatory to unravel the underlying molecular mechanisms. We highlighted the current knowledge of the molecular and cellular characteristics of IL-33 and then summarized its major roles in different myocardial injuries, mainly focusing on infection, heart transplantation, coronary atherosclerosis, myocardial infarction, and diabetic cardiomyopathy. This narrative review will summarize current understanding and insights regarding the implications of IL-33 in cardiac diseases and its diagnostic and therapeutic potential for cardiac disease management.

IL-33/ST2 Axis: A Potential Therapeutic Target in Neurodegenerative Diseases.

Interleukin 33 (IL-33) belongs to the IL-1 family and is localized in the nucleus. IL-33 is primarily composed of three distinct domains, namely the N-terminal domain responsible for nuclear localization, the intermediate sense protease domain, and the C-terminal cytokine domain. Its specific receptor is the suppression of tumorigenicity 2 (ST2), which is detected in serum-stimulated fibroblasts and oncogenes. While most other cytokines are actively produced in cells, IL-33 is passively produced in response to tissue damage or cell necrosis, thereby suggesting its role as an alarm following cell infection, stress, or trauma. IL-33 plays a crucial role in congenital and acquired immunity, which assists in the response to environmental stress and maintains tissue homeostasis. IL-33/ST2 interaction further produces many pro-inflammatory cytokines. Moreover, IL-33 is crucial for central nervous system (CNS) homeostasis and the pathogenic mechanisms underlying CNS degenerative disorders. The present work summarizes the structure of IL-33, its fundamental activities, and its role in immunoregulation and neurodegenerative diseases. Therefore, this work proposes that IL-33 may play a role in the pathogenic mechanism of diseases and can be used in the development of treatment strategies.