Suppression Of Tumorigenicity 2 Research Articles

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.

Prediction of maternal and foetal outcomes among patients with preeclampsia using circulatory biomarkers (MMP-9 & ST2) - A prospective cohort study

IntroductionPreeclampsia is one of the major causes of maternal and foetal morbidity and mortality worldwide. Its complications include but are not limited to eclampsia, intracerebral haemorrhage and cardiovascular diseases in the later stages of life. The combination of clinical and risk variables and a panel of multiple biomarkers will help clinicians in risk stratification and prognostication of clinical outcomes among preeclamptic women. We evaluated MMP-9 (matrix metalloproteinase - 9) and ST2 (suppression of tumorigenicity 2) for utility as biomarkers and for predicting maternal and foetal outcomes in women with preeclampsia. MethodsThis prospective cohort study involved 49 preeclamptic women and 80 healthy controls. Biomarkers were measured in plasma using ELISA. The patients were followed up to assess maternal and foetal outcomes. ResultsThe mean value of MMP-9 was 2.42 ng/mL in the preeclamptic group and 2.67 ng/mL in controls. The mean value of ST2 (1937.4 ± 747.81) in the preeclamptic group was high compared to the control group (1005.7 ± 683.6) and the difference was significant (P = 0.0001). The study population was divided into those with high and low MMP-9 and those with high and low ST2. Lower levels of MMP-9 seemed to be related to both early and late onset preeclampsia. The ROC (Receiver Operating Characteristic) curve did not show the ability to predict maternal and foetal outcomes. DiscussionOur study demonstrated that women with preeclampsia had low MMP-9 and high ST2 compared to healthy pregnant women. But neither of the biomarkers could predict complications of preeclampsia.

Serum levels of interleukin-33, soluble ST2 and IgE in patients with asthma: a case-control study

Introduction Interleukins play a very important role in the pathophysiology of asthma. Interleukin-33 (IL-33) is a partially explored cytokine in asthma. It binds with a specific receptor called suppression of tumorigenicity 2 (ST2). The study aims to evaluate the serum levels of IL-33, sST2 and IgE in asthmatic patients and healthy controls and its further association with the forced expiratory volume in one second (FEV 1%) and absolute eosinophil count. Materials and Methods We enrolled 100 asthmatic patients and 57 healthy subjects for the study. We measured serum levels of IgE, IL-33, and sST2. Based on serum IgE levels, patients were divided into allergic and non-allergic groups. Statistical analysis was done by using Graph pad prism software 8. Results We found significantly elevated levels of IL-33 and IgE in asthmatic patients as compared to healthy subjects. However, sST2 levels were significantly lower in asthmatic patients than in healthy subjects. FEV1% values were decreased in uncontrolled asthmatic patients. In addition, serum levels of IL-33 were significantly correlated with the IgE. Furthermore, we found a significant correlation between IL-33 and AEC in allergic asthmatic patients. Conclusion In this study, we reported elevated IL-33 and IgE levels and decreased sST2 levels in asthmatic patients compared to healthy controls. IL-33 and sST2 may act as inflammatory biomarkers for allergic diseases such as asthma.

Interleukin-33 as a Potential Therapeutic Target in Gastric Cancer Patients: Current Insights.

Gastric cancer is a significant global health problem as it is the fifth most prevalent cancer worldwide and the fourth leading cause of cancer-related mortality. While cytotoxic chemotherapy remains the primary treatment for advanced GC, response rates are limited. Recent progresses, focused on molecular signalling within gastric cancer, have ignited new hope for potential therapeutic targets that may improve survival and/or reduce the toxic effects of traditional therapies. Carcinomas are generally initiated when critical regulatory genes get mutated, but the progression to malignancy is usually supported by the non-neoplastic cells that create a conducive environment for transformation and progression to occur. Interleukin 33 (IL-33) functions as a dual activity cytokine as it is also a nuclear factor. IL-33 is usually present in the nuclei of the cells. Upon tissue damage, it is released into the extracellular space and binds to its receptor, suppression of tumorigenicity 2 (ST2) L, which is expressed on the membranes of the target cells. IL-33 signalling activates the T Helper 2 (Th2) immune response among other responses. Although the studies on the role of IL-33 in gastric cancer are still in the early stages, they have revealed potentially important (though sometimes conflicting) functions or roles in cancer development and progression. The pro-tumorigenic roles include induction and the recruitment of tumor-associated immune cells, promoting metaplasia progression, and inducing stem cell like and EMT properties in gastric cancer cells. Therapeutic interventions to disrupt these functions may provide a unique strategy for gastric cancer prevention and treatment. This review aims to provide a summary of the role of IL-33 in GC, state its multiple functions in relation to GC, and show potential avenues for promising therapeutic investigation.

EASIX-1year and late mortality after allogeneic stem cell transplantation

AbstractPatients with hematological malignancies who survive the first year after allogeneic stem cell transplantation (allo-SCT) without relapse have a substantial risk of nonrelapse mortality (NRM) and missing predictive markers. The Endothelial Activation and Stress Index (EASIX) predicts endothelial complications and NRM early after allo-SCT. We hypothesized that EASIX assessed 1 year after allo-SCT in survivors who were disease free may predict late NRM. Survivors who were relapse-free at 1 year after allo-SCT were retrospectively studied in 2 independent cohorts (training cohort, n = 610; merged validation cohort, n = 852). EASIX determined 1 year after allo-SCT correlated with the overall survival (OS), NRM, and relapse. Serum endothelial and inflammatory markers were measured in the training cohort and correlated with EASIX-1year, which predicted OS and NRM but not relapse risk in both the training and validation cohorts in univariable and multivariable Cox regression analyses. Brier score and c-index analyses validated the univariable EASIX effects. There was no significant interaction between EASIX-1year and incidence of chronic graft-versus-host disease (GVHD) on OS. EASIX-1year predicted the outcome irrespective of preexisting comorbidities. Principal causes of NRM in both training and validation cohorts were infections with and without GVHD as well as cardiovascular complications. EASIX-1year correlated with sCD141 and interleukin-18 but not with C-reactive protein, suppressor of tumorigenicity-2, angiopoietin-2, CXCL9, or CXCL8. To our knowledge, EASIX-1year is the first validated predictor of late overall and NRM. Patients who are high risk as defined by EASIX-1year might be considered for intensified surveillance and prophylactic measures.

Effects of total alkaloids from Alstonia scholaris (L.) R. Br. on ovalbumin-induced asthma mice

Ethnopharmacological relevanceMore than 300 million people worldwide suffer from asthma, a chronic respiratory inflammatory disease. Total alkaloids (TA) were extracted from the ethnic medicinal plant Alstonia solaris (L.) R.Br., which is used to treat respiratory diseases. They may be effective drugs for treating asthma, but research is still needed to determine their effectiveness and mechanism in treating asthma. Aim of the studyTo further understand TA's role in the treatment of asthma and to support the phase II trial of the drug. Materials and methodsIn this study, we investigated the effects of TA in a mouse asthma model produced by Ovalbumin (OVA). H&E and PAS staining were used to observe the histopathological features of lung. airway hyperresponsiveness (AHR) was detected by ventilator; The expression of interleukin (IL)-33, suppression of tumorigenicity 2 (ST2) and E-cadherin in the lungs was evaluated by IHC. The concentrations of Mucin5AC (MUC5AC), eotaxin, IL-4, IL-5, IL-9, IL-13, interferon (IFN)-γ, IL-6, IL-8, IL-17A, IL-33, IL-25, thymic stromal lymphopoietin (TSLP), monocyte chemoattractant protein 1 (MCP-1), leukotriene (LT) B4, LTC4, LTD4, LTE4 in bronchoalveolar lavage fluid (BALF) and total IgE (tIgE), OVA-Specific IgE (OVA-IgE) in serum were measured by ELISA. ILC2s and eosinophils were detected in lung tissue by flow cytometry. The gene expression levels of IL-33 and ST2 were detected by RT-qPCR. ResultsAdministration of TA reduced pulmonary inflammatory symptoms, MUC5AC production in the BALF, and AHR. At the same time, TA inhibited eotaxin production and eosinophil recruitment. Moreover, TA significantly decreased Th2 and Th17 cytokines and increased Th1 cytokines, contributing to restore the balance between Th1 and Th2 and Th17 cytokines. TA may reduce ILC2s numbers by inhibiting IL-33, IL-25, and TSLP levels in BALF and IL-33/ST2 signaling in lung tissue. Finally, TA decreased tIgE, OVA-IgE, and MCP-1 levels and subsequently inhibited mast cell activation and leukotriene release. ConclusionsThese findings imply that TA may be an effective immunoregulatory medication for the management and prevention of asthma.

Salivary IL-33 and sST2 levels in relation to TLR2 rs111200466 polymorphism and periodontitis.

Toll-like receptor-2 (TLR2) signalling pathway is involved in the regulation of interleukin (IL)-33 and its receptor suppression of tumorigenicity-2 (ST2). This study aimed to compare salivary IL-33 and soluble ST2 (sST2) levels of periodontitis patients with those of periodontally healthy individuals in relation to their TLR2 rs111200466 23-bp insertion/deletion polymorphism within the promoter region. Unstimulated saliva samples were collected, and periodontal parameters were recorded from 35 periodontally healthy individuals and 44 periodontitis patients. Non-surgical treatments were applied to periodontitis patients, and sample collections and clinical measurements were repeated 3 months following therapy. Salivary IL-33 and sST2 levels were measured with enzyme-linked immunosorbent assay kits, and TLR2 rs111200466 polymorphism was detected by polymerase chain reaction. Elevated salivary IL-33 (p = 0.007) and sST2 (p = 0.020) levels were observed in periodontitis patients, in comparison to controls. sST2 levels declined 3-months following treatment (p < 0.001). Increased salivary IL-33 and sST2 levels were found to be associated with periodontitis, with no significant relation to the TLR2 polymorphism. Periodontitis, but not TLR2 rs111200466 polymorphism, is associated with elevated salivary sST2 and possibly IL-33 levels, and periodontal treatment is effective in reducing salivary sST2 levels.

IL-33/ST2 axis of human amnion fibroblasts participates in inflammatory reactions at parturition

BackgroundInflammation of the fetal membranes is an indispensable event of labor onset at both term and preterm birth. Interleukin-33 (IL-33) is known to participate in inflammation via ST2 (suppression of tumorigenicity 2) receptor as an inflammatory cytokine. However, it remains unknown whether IL-33/ST2 axis exists in human fetal membranes to promote inflammatory reactions in parturition.MethodsThe presence of IL-33 and ST2 and their changes at parturition were examined with transcriptomic sequencing, quantitative real-time polymerase chain reaction, Western blotting or immunohistochemistry in human amnion obtained from term and preterm birth with or without labor. Cultured primary human amnion fibroblasts were utilized to investigate the regulation and the role of IL-33/ST2 axis in the inflammation reactions. A mouse model was used to further study the role of IL-33 in parturition.ResultsAlthough IL-33 and ST2 expression were detected in both epithelial and fibroblast cells of human amnion, they are more abundant in amnion fibroblasts. Their abundance increased significantly in the amnion at both term and preterm birth with labor. Lipopolysaccharide, serum amyloid A1 and IL-1β, the inflammatory mediators pertinent to labor onset, could all induce IL-33 expression through NF-κB activation in human amnion fibroblasts. In turn, via ST2 receptor, IL-33 induced the production of IL-1β, IL-6 and PGE2 in human amnion fibroblasts via the MAPKs-NF-κB pathway. Moreover, IL-33 administration induced preterm birth in mice.ConclusionIL-33/ST2 axis is present in human amnion fibroblasts, which is activated in both term and preterm labor. Activation of this axis leads to increased production of inflammatory factors pertinent to parturition, and results in preterm birth. Targeting the IL-33/ST2 axis may have potential value in the treatment of preterm birth.

The Effect of Elective Ligation of the Arteriovenous Fistula on Cardiac and Renal Functions in Kidney Transplant Recipients.

Kidney transplantation (KTx) is considered as the best kidney replacement therapy and arteriovenous fistula (AVF) is the preferred vascular access for hemodialysis. The systematic ligation of a functioning AVF in stable kidney transplant recipients remains debatable. In this prospective study, we investigated the hemodynamic impact of the surgical closure of AVF in KTRs. Forty-three KTRs underwent an ambulatory blood pressure monitoring (24h-ABPM) before surgical closure of AVF (T0) and 12 months later (M12), as well as measurement of serum cardiac biomarkers (i.e., soluble suppression of tumorigenicity 2 (ST2), N-terminal pro b-type natriuretic peptide (NT-proBNP) and Galectin-3). Serum tests were also performed 6 months after AVF closure (M6). An echocardiographic exam was done at each time-point. All serum creatinine values were collected to compare the individual eGFR slopes before versus after AVF closure. The latest measure of the AVF flow (QAVF) prior to KTx was recorded. Diastolic blood pressure (DBP) significantly raised from T0 to M12: + 4.4±7.3 mmHg (p=0.0003) for 24h, + 3.8±7.4 mmHg (p=0.0018) during the day, and + 6.3±9.9 mmHg (p=0.0002) during the night, leading to an increased proportion of KTRs with ESH-defined arterial hypertension after AVF ligation. No change was observed for systolic BP. NT-proBNP significantly dropped between T0 and M6 (345 [190; 553] to 230 [118; 458] pg/mL, p=0.0001) and then remained stable from M6 to M12, while ST2 and Galectin-3 levels did not change from T0 to M12. We observed a significant decrease of left ventricular (LV) end-diastolic volume, LV end-systolic volume, LV mass, interventricular septum diameter, left atrial (LA) volume, and tricuspid annular plane systolic excursion from T0 to M6, and then a stability from M6 to M12. LV ejection fraction and eGFR slope remained stable during the whole study. These observations remained unchanged after adjustment for QAVF. The closure of a patent AVF in KTRs is associated with elevation of DBP, drop of serum NT-proBNP levels, reduction of LV/LA dimensions, and stable eGFR slope.

Interleukin-33 promotes the epithelial-mesenchymal transition of renal tubular epithelial cells via the NF-κB/Twist1 signalling pathway

Objectives: Epithelial-mesenchymal transition (EMT) of renal tubular epithelial cells (RTECs) is a pathogenic factor for renal interstitial fibrosis (RIF). Interleukin-33 (IL-33) is related to the occurrence and development of RIF, but the underlying mechanism remains unclear. Here, we investigated whether IL-33 mediates the EMT of RTECs by activating the NF-κB/Twist1 signalling pathway. Methods: In vivo, the RIF animal model induced by unilateral ureteral obstruction (UUO) was established. The effects of exogenous IL-33 and anti-IL-33 antibodies were evaluated. In vitro, the EMT of RTECs was induced by IL-33. The inhibition of the nuclear factor kappa-B (NF-κB) by the pyrrolidine dithiocarbamate (PDTC) and the knockdown of the suppression of tumorigenicity 2 (ST2) by small interference RNA were used to observe whether IL-33 mediates the EMT of RTECs through the NF-κB/Twist1 signaling pathway. Results: In vivo, exogenous IL-33 significantly aggravated UUO-induced pathological damage and collagen deposition, down-regulated E-cadherin expression, and up-regulated α-smooth muscle actin and Vimentin expressions. Moreover, exogenous IL-33 increased the levels of phospho-IκB-α (p-IκB-α) and phospho-NF-κB p65 (p-NF-κB p65), NF-κB p65 nuclear translocation, and Twist1 nuclear expression. However, these effects were reversed by the anti-IL-33 antibody. In vitro , the increases in the levels of p-IκB-α, p-NF-κB p65, NF-κB p65 nuclear translocation, and Twist1 nuclear expression induced by IL-33 were inhibited by the knockdown of PDTC or ST2. IL-33-mediated EMT of RTECs was also significantly reversed. However, NF-κB inhibitor PDTC had no significant effect on ST2 expression. Conclusions: The IL-33/ST2 axis may up-regulate the expression of Twist1 through the NF-κB signalling pathway, thereby inducing the EMT of RTECs and leading to RIF.

Extended characterization of IL-33/ST2 as a predictor for wound age determination in skin wound tissue samples of humans and mice.

Interleukin (IL)-33, an important inflammatory cytokine, is highly expressed in skin wound tissue and serum of humans and mice, and plays an essential role in the process of skin wound healing (SWH) dependent on the IL-33/suppression of tumorigenicity 2 (ST2) pathway. However, whether IL-33 and ST2 themselves, as well as their interaction, can be applied for skin wound age determination in forensic practice remains incompletely characterized. Human skin samples with injured intervals of a few minutes to 24 hours (hs) and mouse skin samples with injured intervals of 1 h to 14 days (ds) were collected. Herein, the results demonstrated that IL-33 and ST2 are increased in the human skin wounds, and that in mice skin wounds, there is an increase over time, with IL-33 expression peaking at 24 hs and 10 ds, and ST2 expression peaking at 12 hs and 7 ds. Notably, the relative quantity of IL-33 and ST2 proteins < 0.35 suggested a wound age of 3 hs; their relative quantity > 1.0 suggested a wound age of 24 hs post-mouse skin wounds. In addition, immunofluorescent staining results showed that IL-33 and ST2 were consistently expressed in the cytoplasm of F4/80-positive macrophages and CD31-positive vascular endothelial cells with or without skin wounds, whereas nuclear localization of IL-33 was absent in α-SMA-positive myofibroblasts with skin wounds. Interestingly, IL-33 administration facilitated the wound area closure by increasing the proliferation of cytokeratin (K) 14 -positive keratinocytes and vimentin-positive fibroblasts. In contrast, treating with its antagonist (i.e., anti-IL-33) or receptor antagonist (e.g., anti-ST2) exacerbated the aforementioned pathological changes. Moreover, treatment with IL-33 combined with anti-IL-33 or anti-ST2 reversed the effect of IL-33 on facilitating skin wound closure, suggesting that IL-33 administration facilitated skin wound closure through the IL-33/ST2 signaling pathway. Collectively, these findings indicate that the detection of IL-33/ST2 might be a reliable biomarker for the determination of skin wound age in forensic practice.

Discovery of highly immunogenic spleen-resident FCGR3+CD103+ cDC1s differentiated by IL-33-primed ST2+ basophils

Recombinant interleukin-33 (IL-33) inhibits tumor growth, but the detailed immunological mechanism is still unknown. IL-33-mediated tumor suppression did not occur in Batf3−/− mice, indicating that conventional type 1 dendritic cells (cDC1s) play a key role in IL-33-mediated antitumor immunity. A population of CD103+ cDC1s, which were barely detectable in the spleens of normal mice, increased significantly in the spleens of IL-33-treated mice. The newly emerged splenic CD103+ cDC1s were distinct from conventional splenic cDC1s based on their spleen residency, robust effector T-cell priming ability, and surface expression of FCGR3. DCs and DC precursors did not express Suppressor of Tumorigenicity 2 (ST2). However, recombinant IL-33 induced spleen-resident FCGR3+CD103+ cDC1s, which were found to be differentiated from DC precursors by bystander ST2+ immune cells. Through immune cell fractionation and depletion assays, we found that IL-33-primed ST2+ basophils play a crucial role in the development of FCGR3+CD103+ cDC1s by secreting IL-33-driven extrinsic factors. Recombinant GM-CSF also induced the population of CD103+ cDC1s, but the population neither expressed FCGR3 nor induced any discernable antitumor immunity. The population of FCGR3+CD103+ cDC1s was also generated in vitro culture of Flt3L-mediated bone marrow-derived DCs (FL-BMDCs) when IL-33 was added in a pre-DC stage of culture. FL-BMDCs generated in the presence of IL-33 (FL-33-DCs) offered more potent tumor immunotherapy than control Flt3L-BMDCs (FL-DCs). Human monocyte-derived DCs were also more immunogenic when exposed to IL-33-induced factors. Our findings suggest that recombinant IL-33 or an IL-33-mediated DC vaccine could be an attractive protocol for better tumor immunotherapy.

Extracellular ATP accelerates cell death and decreases tight junction protein ZO-1 in hypoxic cochlear strial marginal cells in neonatal rats

In the cochlea, extracellular ATP (eATP) plays an important role in both physiological and pathological processes, but its role in the hypoxic cochlea remains unclear. The present study aims to investigate the relationship between eATP and hypoxic marginal cells (MCs) in the stria vascularis in cochlea. Combining various methodologies, we found that eATP accelerates cell death and decreases tight junction protein zonula occludens-1 (ZO-1) in hypoxic MCs. Flow cytometry and western blot analyses revealed an increase in apoptosis levels and suppression of autophagy, indicating that eATP causes additional cell death by increasing the apoptosis of hypoxic MCs. Given that autophagy inhibits apoptosis to protect MCs under hypoxia, apoptosis is probably enchanced by suppressing autophagy. Interleukin-33(IL-33)/suppression of tumorigenicity-2(ST-2)/matrix metalloprotein 9(MMP9) pathway activation was also observed during the process. Further experiments involving the use of additional IL-33 protein and an MMP9 inhibitor indicated that this pathway is responsible for the damage to the ZO-1 protein in hypoxic MCs. Our study revealed an adverse effect of eATP on the survival and ZO-1 protein expression of hypoxic MCs, as well as the underlying mechanism.

Crosstalk between Interleukin-1 Receptor-Like 1 and Transforming Growth Factor-β Receptor Signaling Promotes Renal Fibrosis

IL-33, a member of the IL-1 family, acts as an alarmin in immune response. Epithelial-mesenchymal transition and transforming growth factor-β (TGF-β)–induced fibroblast activation are key events in the development of renal interstitial fibrosis. The current study found increased expression of IL-33 and interleukin-1 receptor-like 1 (IL1RL1, alias ST2), the receptor for IL-33, in human fibrotic renal tissues. In addition, IL-33– or ST2-deficient mice showed significantly reduced levels of fibronectin, α-smooth muscle actin, and vimentin, and increased E-cadherin levels. In HK-2 cells, IL-33 promotes the phosphorylation of the TGF-β receptor (TGF-βR), Smad2, and Smad3, and the production of extracellular matrix (ECM), with reduced expression of E-cadherin. Blocking TGF-βR signaling or suppressing ST2 expression impeded Smad2 and Smad3 phosphorylation, thereby reducing ECM production, suggesting that IL-33–induced ECM synthesis requires cooperation between the two pathways. Mechanistically, IL-33 treatment induced a proximate interaction between ST2 and TGF-βRs, activating downstream Smad2 and Smad3 for ECM production in renal epithelial cells. Collectively, this study identified a novel and essential role for IL-33 in promoting TGF-β signaling and ECM production in the development of renal fibrosis. Therefore, targeting IL-33/ST2 signaling may be an effective therapeutic strategy for renal fibrosis.

COVID-19 and the Cardiovascular System: Requiem for a Medical Minotaur.

COVID-19 and the Cardiovascular System: Requiem for a Medical Minotaur.

Clinicopathological and Prognostic Relevance of Tumoral Suppression of Tumorigenicity 2 Expression in Patients With Surgically Resected Pancreatic Carcinoma.

The interleukin (IL)-33/suppression of tumorigenicity 2 (ST2) pathway promotes cancer development and remodels the tumor microenvironment. However, the role of tumoral ST2 expression remains controversial in some solid malignancies. In this study, we have investigated the clinicopathological and prognostic relevance of tumoral ST2 expression in patients with resected pancreatic carcinoma after neoadjuvant chemoradiotherapy. We analyzed data from 76 patients with surgically resected pancreatic ductal adenocarcinoma after neoadjuvant chemoradiotherapy, between 2009 and 2018. Tissue microarrays were constructed and immunohistochemical analysis was performed for ST2. Associations between variables were analyzed using chi-square tests. Disease-specific survival (DSS) and disease-free survival (DFS) were analyzed using log-rank tests. High expression of ST2, which was observed in 43 patients (57%), was more frequent in patients with high T status (p=0.002), lymphatic invasion (p=0.049), and ≤50% of tumor cells destroyed by chemoradiotherapy (p=0.043; Evans grade I-IIA vs. IIB). In stage I patients, DFS was significantly lower in patients with high ST2 expression (median, 10.6 months) than in those with low ST2 expression (median, 43.4 months; p=0.046). High tumoral ST2 expression is associated with high T status, lymphatic invasion, and lower histopathological response grade in patients with pancreatic carcinoma after neoadjuvant chemoradiotherapy.

Effect of acupuncture pretreatment of "Quchi"(LI11) and "Xuehai" (SP10) on mast cells and IL-33/ST2 in rats with urticaria

To observe the effect of electroacupuncture (EA) pretreatment at "Quchi "(LI11) and "Xuehai "(SP10) on expression of interleukin (IL)-33, suppression of tumorigenicity 2 (ST2) and mast cell degranulation in sensitive area of skin tissue in rats with urticaria, so as to explore its mechanisms underlying prevention of urticaria. A total of 32 male SD rats were randomly divided into blank control, model, EA preconditioning and medication groups, with 8 rats in each group. The urticaria model was established by topical injection of the prepared anti-ovalbumin serum (foreign serum, 0.1 mL/spot) along the bilateral sides of the spinal column on the back, followed by injection of mixture solution of ovalbumin, 0.5% evans blue and normal saline via the tail vein 48 h later. EA intervention (2 Hz/15 Hz, 1 mA) was applied to bilateral LI11 and SP10 for 20 min, once daily for 7 d before modeling.Back sensitization was started from the 5th day on. Rats of the medication group received gavage of loratadine, and those of the model group received gavage of the same volume of normal saline. The diameter of evans blue spots at the back skin tissue was measured; the histopathological changes of the blue spot tissues were observed by light microscope after H.E. staining. The state of degranulation of mast cells in the subcutaneous loose connective tissue was observed by using toluidine blue staining. Serum IgE and histamine contents were detected by ELISA, and the immunoactivity of IL-33 and ST2 in the skin and subcutaneous tissues of the sensitized spots (evans blue exudation spots) was observed by immunohistochemistry. Compared with the blank control group, the diameter of evans blue spot, degranulation rate of mast cells, serum IgE and histamine contents, and the immunoactivity of IL-33 and ST2 in the evans blue exudation spot tissues were significantly increased in the model group (P<0.01). In comparison with the model group, the increase of the above-mentioned indexes was reversed in both EA and medication groups (P<0.01，P<0.05). No significant differences were found between the EA and medication groups in down-regulating the levels of the 6 indexes. H.E. staining of the blue spot tissues of rats in the model group showed incomplete structure of the epidermal layer of the skin, unclear interface of tissues, incomplete keratinization, chaotic epidermal cells, disorderly arrangement of fibers in the dermis, and infiltration of inflammatory cells and edema, which was relatively milder in the EA and medication groups. EA preconditioning can prevent urticaria (reduce size and sensitive reactions) in rats, which may be associated with its functions in lowering the level of IgE through inhibiting IL-33 and ST2.

IL-33/ST2 antagonizes STING signal transduction via autophagy in response to acetaminophen-mediated toxicological immunity

BackgroundInterleukin-33 (IL-33), defined as "alarming", exert diverse functions through signaling via the suppression of tumorigenicity 2 (ST2). However, the physiological roles of IL-33/ST2 signaling during acetaminophen (APAP)-induced liver injury are still poorly understood by modern medicine (AILI). This research aims to explore the relationship between IL-33/ST2 and stimulator of interferon (IFN) response cGAMP interactor 1 (STING)-mediated signal transduction.MethodsC57BL/6N mice (WT) and IL-33-deficient mice (KO) were intraperitoneally injected with APAP (250 mg/kg). Recombinant IL-33 (500 ng/mouse) and the cGAS/STING inhibitor RU.521 (200 g/kg) were combined to treat AILI. For mechanistic research in vitro, CRISPR-mediated KD technology, immunoprecipitation, mass spectrometry, and immunofluorescence were utilized.ResultsWe discovered that IL-33 deficient mice had increased APAP-induced hepatotoxicity, DNA accumulation, and type 1 IFN production. Mechanistic analysis revealed that IL-33/ST2 enhanced the interaction between Beclin-1 and STING, disrupting STING dimerization, IRF3 phosphorylation, nuclear transport, and IFN-1 gene transcription in HepaRG and Huh7 cells. Beclin-1 interacted with the C-terminus of STING, causing Lys338 acetylation and autophagy degradation of STING. ST2 depletion increased STING signal transduction and IFN-1 promoter activity. Surprisingly, the cGAS/STING inhibitor RU.521 and recombinant IL-33 together improved AILI in vivo.ConclusionsThese results shed insight on the potential of inhibiting cGAS/STING as a therapy for AILI and emphasize the crucial role of IL-33/ST2 signaling in the regulation of APAP-induced STING signaling.7gSjYBv15HDd7Gp_h4w39CVideo Graphical

Interleukin-33 facilitates liver regeneration through serotonin-involved gut-liver axis.

Insufficient liver regeneration causes post-hepatectomy liver failure and small-for-size syndrome. Identifying therapeutic targets to enhance hepatic regenerative capacity remains urgent. Recently, increased IL-33 was observed in patients undergoing liver resection and in mice after partial hepatectomy (PHx). The present study aims to investigate the role of IL-33 in liver regeneration after PHx and to elucidate its underlying mechanisms. We performed PHx in IL-33 -/- , suppression of tumorigenicity 2 (ST2) -/- , and wild-type control mice, and found deficiency of IL-33 or its receptor ST2 delayed liver regeneration. The insufficient liver regeneration could be normalized in IL-33 -/- but not ST2 -/- mice by recombinant murine IL-33 administration. Furthermore, we observed an increased level of serotonin in portal blood from wild-type mice, but not IL-33 -/- or ST2 -/- mice, after PHx. ST2 deficiency specifically in enterochromaffin cells recapitulated the phenotype of delayed liver regeneration observed in ST2 -/- mice. Moreover, the impeded liver regeneration in IL-33 -/- and ST2 -/- mice was restored to normal levels by the treatment with (±)-2,5-dimethoxy-4-iodoamphetamine, which is an agonist of the 5-hydroxytrytamine receptor (HTR)2A. Notably, in vitro experiments demonstrated that serotonin/HTR2A-induced hepatocyte proliferation is dependent on p70S6K activation. Our study identified that IL-33 is pro-regenerative in a noninjurious model of liver resection. The underlying mechanism involved IL-33/ST2-induced increase of serotonin release from enterochromaffin cells to portal blood and subsequent HTR2A/p70S6K activation in hepatocytes by serotonin. The findings implicate the potential of targeting the IL-33/ST2/serotonin pathway to reduce the risk of post-hepatectomy liver failure and small-for-size syndrome.

Dysregulated brain regulatory T cells fail to control reactive gliosis following repeated antigen stimulation

This study was undertaken to investigate the role of CD4+FoxP3+ regulatory Tcells (Tregs) in regulating neuroinflammation during viral Ag-challenge and re-challenge. CD8+ lymphocytes persisting within tissues are designated tissue-resident memory Tcells (TRM), within brain: bTRM. Reactivation of bTRM with Tcell epitope peptides generates rapid antiviral recall, but repeated stimulation leads to cumulative dysregulation of microglial activation, proliferation, and prolonged neurotoxic mediator production. Here, we show Tregs were recruited into murine brains following prime-CNS boost, but displayed altered phenotypes following repeated Ag-challenge. In response to repeated Ag, brain Tregs (bTregs) displayed inefficient immunosuppressive capacity, along with reduced expression of suppression of tumorigenicity 2 (ST2) and amphiregulin (Areg). Exvivo Areg treatment revealed reduced production of neurotoxic mediators such as iNOS, IL-6, and IL-1β, and decreased microglial activation and proliferation. Taken together, these data indicate bTregs display an unstable phenotype and fail to control reactive gliosis in response to repeated Ag-challenge.