Natural Suppressor Research Articles

Analysis of Long Noncoding RNAs in Aila-Induced Non-Small Cell Lung Cancer Inhibition.

Non-small cell lung cancer (NSCLC) has the highest morbidity and mortality among all carcinomas. However, it is difficult to diagnose in the early stage, and current therapeutic efficacy is not ideal. Although numerous studies have revealed that Ailanthone (Aila), a natural product, can inhibit multiple cancers by reducing cell proliferation and invasion and inducing apoptosis, the mechanism by which Aila represses NSCLC progression in a time-dependent manner remains unclear. In this study, we observed that most long noncoding RNAs (lncRNAs) were either notably up- or downregulated in NSCLC cells after treatment with Aila. Moreover, alterations in lncRNA expression induced by Aila were crucial for the initiation and metastasis of NSCLC. Furthermore, in our research, expression of DUXAP8 was significantly downregulated in NSCLC cells after treatment with Aila and regulated expression levels of EGR1. In conclusion, our findings demonstrate that Aila is a potent natural suppressor of NSCLC by modulating expression of DUXAP8 and EGR1.

IL-37b alleviates endothelial cell apoptosis and inflammation in Kawasaki disease through IL-1R8 pathway

Kawasaki disease (KD) is an acute vasculitis of pediatric populations that may develop coronary artery aneurysms if untreated. It has been regarded as the principal cause of acquired heart disease in children of the developed countries. Interleukin (IL)-37, as one of the IL-1 family members, is a natural suppressor of inflammation that is caused by activation of innate and adaptive immunity. However, detailed roles of IL-37 in KD are largely unclear. Sera from patients with KD displayed that IL-37 level was significantly decreased compared with healthy controls (HCs). QRT-PCR and western blot analyses showed that the expression level of IL-37 variant, IL-37b, was remarkably downregulated in human umbilical vein endothelial cells (HUVECs) exposed to KD sera-treated THP1 cells. Therefore, we researched the role of IL-37b in the context of KD and hypothesized that IL-37b may have a powerful protective effect in KD patients. We first observed and substantiated the protective role of IL-37b in a mouse model of KD induced by Candida albicans cell wall extracts (CAWS). In vitro experiments demonstrated that IL-37b alleviated endothelial cell apoptosis and inflammation via IL-1R8 receptor by inhibiting ERK and NFκB activation, which were also recapitulated in the KD mouse model. Together, our findings suggest that IL-37b play an effective protective role in coronary endothelial damage in KD, providing new evidence that IL-37b is a potential candidate drug to treat KD.

The Role of Myeloid-Derived Suppressor Cells (MDSCs) in Graft-versus-Host Disease (GVHD)

Background: Myeloid-derived suppressor cells (MDSCs) are implicated in the complex interplay involving graft-versus-leukemia (GVL) effects and graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HCT) in hematologic malignancies. Methods: A review of literature through PubMed was undertaken to summarize the published evidence on the pathophysiology and clinical implications of MDSCs in allo-HCT. Literature sources published in English since 1978 were searched, using the terms Natural Suppressor (NS) cells, MDSCs, GVHD, and allo-HCT. Results: In vivo studies demonstrated that MDSCs derived from mobilization protocols could strongly suppress allo-responses mediated by T cells and enhance T-Reg activity, thus inhibiting GVHD toxicity. However, the influence of MDSCs on the GVL effect is not fully defined. Conclusions: The induction or maintenance of MDSC suppressive function would be advantageous in suppressing inflammation associated with GVHD. Pathways involved in MDSC metabolism and the inflammasome signaling are a promising field of study to elucidate the function of MDSCs in the pathogenesis of GVHD and translate these findings to a clinical setting.

IL-37 Was Involved in Progress of Acute Myeloid Leukemia Through Regulating IL-6 Expression.

BackgroundInterleukin-37, which was discovered in 2000, is a natural suppressor of immune and inflammatory responses. Recent studies reported that IL-37 was abnormally expressed in several tumor patients, including those with hepatocellular carcinoma, gastric cancer, lung cancer, colon cancer, epithelial ovarian cancer, and multiple myeloma. However, the expression and potential function of IL-37 in leukemia remain unknown.ObjectiveThe aim of this study was to evaluate IL-37 as a prognostic factor and its possible mechanism of action.MethodsPolymerase chain reaction products were analyzed by agarose gel electrophoresis and were purified and subsequently sequenced by a genetic testing laboratory. Human PBMC was purified from whole blood samples by using Ficoll-Paque PLUS. The concentrations of human IL-37 and human IL-6 were measured using enzyme-linked immunosorbent assay (ELISA) kits.ResultsIL-37, especially isoform b and d, was expressed in the bone marrow of AML, CML, ALL, and CLL. Importantly, IL-37 expression was downregulated in newly diagnosed AML patients and restored in patients in complete remission. Moreover, a significant association was found between IL-37 expression and NPM1 mutation or possible prognosis evaluated by karyotype and gene mutation. Further analysis revealed that IL-37 expression was negatively correlated with IL-6 expression. With regard to the mechanism, recombinant human IL-37 could suppress IL-6 expression stimulated by LPS in PBMC of AML patients.ConclusionOur study suggested that IL-37 may be an important prognostic factor in AML and is involved in AML via the IL-6 signaling pathway, indicating that IL-37 is an innovative research strategy for AML pathogenesis and therapy.

The effect of artificial sweeteners on body weight of mice

Artificial Sweeteners (AS) are synthetic sugar substitutes that have sweetening potency hundreds of times more than the table sugar (sucrose). Artificial sweeteners are regarded as attractive alternatives to sugar as they add no calories to food intake. There are many hypotheses suggesting that AS may enhance appetite and cause weight gain. The aim of this study was to evaluate the effect of AS on food intake, fluid intake and body weight of mice. Acceptable daily intakes of AS solutions were administered orally to different set of mice for four weeks. The body weight, food consumption and fluid intake were measured. At the same time, the effect of Zingiber officinale extracts (natural appetite suppressor), Thymus vulgaris extracts (natural appetite inducer) and cyproheptadine (an appetite stimulant drug) on body weight of mice was evaluated. Artificial sweeteners consumption cause insignificant changes in body weight (p>0.05). However, the mean consumption of food and solutions varies significantly for some groups. The consumption of AS has no significant effect on body weight and may contribute to weight maintenance and energy balance as substitutes to high caloric sugar

Morpho functional changes in thymus of white rats in acute stress

In the thymus of animals subjected to acute stress, a decrease in lymphoid tissue was found, accompanied by the death of lymphocytes in the cortex and medulla. Acute stress leads to the appearance in the thymus of a large number of degranulating mast cells and actively functioning epithelial tubules. Psychological stress has great impacts on the immune system, particularly the leukocytes distribution. Although the impacts of acute stress on blood leukocytes distribution are well studied, however, it remains unclear how chronic stress affects leukocytes distribution in peripheral circulation. Furthermore, there is no report about the role of spleen in the blood leukocytes distribution induced by stress. Here we show that spleen contributes to the alteration of restraint stress induced blood leukocytes distribution. Our data confirmed that restraint stress induced anxiety-like behavior in mice. Furthermore, we found that restraint stress decreased the CD4/CD8 ratio and elevated the percentages of natural killer cells, monocots and polymorph nuclear myeloid-derived suppressor cell. We demonstrated that activation of hypothalamic-pituitary-adrenal axis (HPA) and sympathetic nervous system (SNS) contributes to restraint stress induced alteration of blood leukocyte distribution. Interestingly, we found that splenectomy could reverse the change of CD4/CD8 ratio induced by restraint stress. Together, our findings suggest that activation of HPA axis and SNS was responsible for the blood leukocyte subsets changes induced by restraint stress. Spleen, at least in part, contributed to the alteration in peripheral circulation induced by restraint stress.

Plasma Interleukin-37 is Elevated in Acute Ischemic Stroke Patients and Probably Associated With 3-month Functional Prognosis.

BackgroundInterleukin-37 is a novel cytokine emerging as a natural suppressor of inflammatory responses. Inflammation and the immune response play important roles in acute ischemic stroke. This study aimed at evaluating the plasma levels and the association with 3-month outcomes of interleukin-37 in acute ischemic stroke patients.Patients and MethodsIn total, 152 consecutive patients with acute ischemic stroke and 45 healthy controls were included. Plasma interleukin-37 levels were determined in the first morning after admission using an enzyme-linked immunesorbent assay. The primary outcome was the 3-month functional outcome (modified Rankin Scale score >2). Logistic regression was used to evaluate the risk and 3-month outcome of stroke according to plasma interleukin-37 level.ResultsPlasma interleukin-37 levels were significantly higher in the patients with acute ischaemic stroke than in the healthy controls (182.26 versus 97.89 pg/mL, p<0.001). Patients with large-artery atherosclerosis had significantly higher IL-37 levels than those with small-artery occlusion (202.12±35.82 versus 175.67±33.71pg/mL, p<0.001). Plasma interleukin-37 levels were positively correlated with National Institutes of Health Stroke Scale scores (r=0.521, p<0.0001) and lesion volume (r=0.442, p<0.0001). Ninety-four and 58 patients had favourable and unfavourable 3-month outcomes, respectively. Elevated plasma interleukin-37 levels were independently associated with unfavourable 3-month outcomes (adjusted odds ratio=1.033, p=0.001, 95% confidence interval: 1.015–1.056).ConclusionAdmission plasma interleukin-37 levels were significantly increased after acute ischemic stroke. Elevated interleukin-37 levels were independently associated with unfavourable 3-month prognoses in acute ischemic stroke patients. Further studies with other populations are needed.

Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene dose-sensitive AD suppressor in human brain

A population of more than six million people worldwide at high risk of Alzheimer’s disease (AD) are those with Down Syndrome (DS, caused by trisomy 21 (T21)), 70% of whom develop dementia during lifetime, caused by an extra copy of β-amyloid-(Aβ)-precursor-protein gene. We report AD-like pathology in cerebral organoids grown in vitro from non-invasively sampled strands of hair from 71% of DS donors. The pathology consisted of extracellular diffuse and fibrillar Aβ deposits, hyperphosphorylated/pathologically conformed Tau, and premature neuronal loss. Presence/absence of AD-like pathology was donor-specific (reproducible between individual organoids/iPSC lines/experiments). Pathology could be triggered in pathology-negative T21 organoids by CRISPR/Cas9-mediated elimination of the third copy of chromosome 21 gene BACE2, but prevented by combined chemical β and γ-secretase inhibition. We found that T21 organoids secrete increased proportions of Aβ-preventing (Aβ1–19) and Aβ-degradation products (Aβ1–20 and Aβ1–34). We show these profiles mirror in cerebrospinal fluid of people with DS. We demonstrate that this protective mechanism is mediated by BACE2-trisomy and cross-inhibited by clinically trialled BACE1 inhibitors. Combined, our data prove the physiological role of BACE2 as a dose-sensitive AD-suppressor gene, potentially explaining the dementia delay in ~30% of people with DS. We also show that DS cerebral organoids could be explored as pre-morbid AD-risk population detector and a system for hypothesis-free drug screens as well as identification of natural suppressor genes for neurodegenerative diseases.

IL-37b alleviates inflammation in the temporomandibular joint cartilage via IL-1R8 pathway.

ObjectivesInterleukin (IL)‐37 is a natural suppressor of innate inflammation. This study was conducted to explore the anti‐inflammatory effects of IL‐37 in temporomandibular joint (TMJ) inflammation.Materials and MethodsThe expression of IL‐37 in the TMJ was measured using ELISA and IHC. Human TMJ chondrocytes were treated with IL‐37b and IL‐1β, and inflammation‐related factors were detected. siRNA‐IL‐1R8 was transfected into chondrocytes, and the affected pathways were detected. IL‐37b was used in disc‐perforation‐induced TMJ inflammation in SD rats. Micro‐CT, IHC, real‐time PCR and histological staining were used to quantify the therapeutic effect of IL‐37b.ResultsIL‐37 was expressed in the synovium and the disc of patients with osteoarthritis (OA) and in the articular cartilage of condylar fracture patients. IL‐37 was highly expressed in synovial fluid of patients with synovitis than in those with OA and disc displacement and was closely related to visual analogue scale (VAS) score. In vitro, IL‐37b suppressed the expression of pro‐inflammatory factors. In addition, IL‐37b exerted anti‐inflammatory effects via IL‐1R8 by inhibiting the p38, ERK, JNK and NF‐κB activation, while silencing IL‐1R8 led to inflammation and upregulation of these signals. In disc‐perforation‐induced TMJ inflammation in SD rats, IL‐37b suppressed inflammation and inhibited osteoclast formation to protect against TMJ.ConclusionsIL‐37b may be a novel therapeutic agent for TMJ inflammation.

Interleukin-37 reduces inflammation and impairs phagocytosis of platelets in immune thrombocytopenia (ITP)

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by low platelet count with heterogeneous bleeding manifestations. Severe bleeding in ITP is not completely related with low platelet count. Fcγ receptor (FcγR)-mediated platelet destruction is one of the major mechanisms of ITP. Interleukin-37 (IL-37) is a fundamental natural suppressor of innate immunity and inflammatory responses in several autoimmune diseases. However, the role of IL-37 in the pathogenesis of ITP is unknown. In the present study, we identified that IL-37 expression was elevated in ITP patients, which was correlated with platelet count and the severity of bleeding in ITP, indicating that IL-37 could be a candidate in evaluating disease severity of ITP. In the in vitro study, IL-37 initiated an anti-inflammatory effect on monocytes/macrophages from ITP patients by down-regulating the phosphorylation of MAPK, AKT, and NF-κB signaling pathways. Moreover, IL-37 restored the balance of activating and inhibitory FcγRs and decreased antibody-mediated platelet phagocytosis by monocytes/macrophages. Our findings suggest that IL-37 may be a promising indicator of the disease severity and supplementation of IL-37 may be therapeutically beneficial for ITP patients.

Lactate Is a Natural Suppressor of RLR Signaling by Targeting MAVS

RLR-mediated type I IFN production plays a pivotal role in elevating host immunity for viral clearance and cancer immune surveillance. Here, we report that glycolysis, which is inactivated during RLR activation, serves as a barrier to impede type I IFN production upon RLR activation. RLR-triggered MAVS-RIG-I recognition hijacks hexokinase binding to MAVS, leading to the impairment of hexokinase mitochondria localization and activation. Lactate serves as a key metabolite responsible for glycolysis-mediated RLR signaling inhibition by directly binding to MAVS transmembrane (TM) domain andpreventing MAVS aggregation. Notably, lactate restoration reverses increased IFN production caused by lactate deficiency. Using pharmacological and genetic approaches, we show that lactate reduction by lactate dehydrogenase A (LDHA) inactivation heightens type I IFN production to protect mice from viral infection. Our study establishes a critical role of glycolysis-derived lactate in limiting RLR signaling and identifies MAVS as a direct sensor of lactate, which functions to connect energy metabolism and innate immunity.

527 Uncovering molecular mechanisms involved in the IL-37-mediated tolerogenic dendritic cells

The past few years have witnessed a breakthrough in the development of tolerogenic dendritic cell (DC) based therapies for the treatment of autoimmune diseases and solid organ transplantation. The interleukin-1 family member IL-37 is a natural suppressor of innate inflammatory and immune responses. Using mice expressing human IL-37b isoform (IL-37tg), we have previously reported that IL-37 participates in peripheral tolerance through the generation of semi-mature tolerogenic DCs. However, the molecular mechanism(s) and/or regulatory molecule(s) involved in the IL-37-mediated tolerogenic DCs are yet to be identified. Similar to IL-1a and IL-33, IL-37 has a unique property as an intracrine cytokine, functioning both intracellularly and extracellularly. To investigate extracellular mechanisms, recombinant IL-37 and neutralizing antibody to IL-37 were used. Despite their effects on IL-1β secretion, neither recombinant IL-37 nor neutralizing antibody affected the ability of DCs to activate T cell proliferation or induce regulatory T cells, suggesting that extracellular IL-37 has limited effects on DC function. Next, to understand molecular pathways altered by IL-37 in DCs, RNAs from wild-type (WT) and IL-37tg DCs were subjected for Illumina microarray analysis. GeneGo pathway analysis identified a key transcription factor NF-κB and 3 pathways including IL-10, CD40, antigen presentation pathway and HMGB1 pathways. Several differentially expressed genes were identified and verified including CXCL1, IL-10 and others. miRNA array analysis using Nanostring miRNA array kit identified immunosuppressive miRNAs. Furthermore, THP-1 human cell line transfected with IL-37 expressed similar molecular profiles to IL-37 mouse DCs and exhibited lower ability to stimulate proliferation of allogeneic naïve T cells after differentiation into DCs. Together, these findings reveal an immunosuppressive molecular pathways of DCs expressing IL-37.

Human RGS14 binds NHERF1 and regulates NPT2A‐mediated phosphate uptake: Disruption by genetic variants

RGS14 is a multifunctional scaffolding protein that integrates G protein, MAPK and Ca++/CaM signaling pathways. Most of what we know about RGS14 comes from studies in rodent brain where it acts as a natural suppressor of synaptic plasticity and hippocampal‐based learning, though other studies implicate a role for RGS14 in myocardial remodeling. Recent genome‐wide association studies have implicated RGS14 in disordered phosphate metabolism, an effect of chronic kidney disease. The RGS14 gene is adjacent to SLC34A1 on human chromosome 5 that encodes the NPT2A sodium‐phosphate cotransporter, which mediates hormone‐sensitive phosphate resorption in renal proximal tubules. Therefore, the goal of these studies was to define a possible role for RGS14 in hormone‐sensitive phosphate transport. Human/primate RGS14 differ from rodent proteins by possessing a carboxy‐terminal extension encoding a Type I PDZ ligand (DSAL). Of note, several rare human mutations have been reported in this region of RGS14 located at residues 563 and 565, corresponding to positions −1 (A565S, A565V) and −3 (D563N, D563G) of the PDZ ligand. The family of PDZ adapter proteins assemble a variety of membrane‐associated proteins, including transporters, receptors, and ion channels, and signaling molecules in short‐lived functional units. The PDZ adapter NHERF1 is expressed in renal proximal tubules, and contains two PDZ domains (PDZ1 and PDZ2). NHERF1 binds the PDZ ligand carboxy tail of NPT2A to promote its phosphate uptake, and this NPT2A:NHERF1 complex is inhibited by parathyroid hormone (PTH) acting at the PTH1 receptor. Here we report that RGS14 is expressed in proximal and distal renal tubules of humans, and that RGS14 binds to NHERF1 via the PDZ2 domain. PTH inhibits NPT2A uptake of phosphate, and RGS14 blocks this action. Of the RGS14 genetic variants tested, D563N disrupted binding to NHERF1 and RGS14 actions on PTH‐sensitive phosphate uptake, whereas D563G, A565S and A565V were innocuous. Computational analysis and molecular dynamics modeling of NHERF1 PDZ binding to the RGS14 C‐terminal PDZ ligand define the structural determinants of this interaction. Taken together, our findings are consistent with the idea that RGS14 contributes to PTH‐sensitive phosphate transport in humans, and that RGS14 coding variants may cause disordered phosphate metabolism.Support or Funding InformationNational Institutes of Health (NIH) awards DK105811, DK111427 (PAF); NS037112, NS102652 (JRH).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Characterizing a Novel RGS14:MyosinV/VI Interaction in Brain

RGS14 is a complex multifunctional signaling protein that integrates G protein, Ras/ERK and Ca++/CaM/CaMKII signaling pathways. The protein is composed of an RGS domain that binds active Gαi/o, two tandem Ras/Rap binding domains (R1, R2) which bind active H‐Ras‐GTP and Rap2A‐GTP to regulate MAP kinase signaling, a G protein regulatory (GPR) motif that binds inactive Gαi1/3, and a Ca++/CaM binding site. RGS14 is highly expressed in the hippocampus, the brain center for learning and memory, which is composed of areas CA3, CA2, and CA1. Schaffer collateral (SC) projections from CA3 to CA1 display long term potentiation (LTP), a stable potentiation in post‐synaptic strength in response to brief periods of synaptic stimulation such as during learning in animals. Within the hippocampus RGS14 is highly expressed in postsynaptic dendrites and spines of area CA2, where SC inputs from CA3 to CA2 neurons show a surprising resistance to LTP. CA2 has been shown to be important for social learning and memory, and we have shown that RGS14 is a natural suppressor of LTP and synaptic plasticity in this area. That is, loss of RGS14 in CA2 (RGS14‐KO) restores synaptic plasticity (LTP) in CA2 and markedly enhances hippocampal learning. However, it remains unknown how RGS14 interacts with other signaling proteins to regulate synaptic plasticity. In proteomic studies, RGS14 recovered from mouse brain by immunoprecipitation was subjected to mass spectrometry and proteomic analysis, showing its association with a high molecular‐weight protein complex including actin‐based myosin motor proteins (Myosin V, Myosin VI and Myosin II) and their regulatory proteins, among others. MyoV is involved in activity‐dependent insertion of AMPA glutamate receptor subunits (GluR1, GluR2) and NMDA receptors, regulation of calcium and proper positioning of calcium intracellular stores. MyoVI is enriched at the postsynaptic density where it regulates AMPA receptor recycling. These myosin classes have crucial roles in regulating synaptic plasticity and LTP. Follow up studies have shown RGS14 in complex with MyoV and MyoVI in whole brain lysates. However, it remains unclear how RGS14 interacts with MyoV/VI to regulate synaptic plasticity. Ongoing studies will determine if RGS14 binds directly or indirectly to MyoV/VI and how that is regulated, as well as elucidate the physiological function of this interaction, thereby providing insight into the functions of both RGS14 and MyoV/VI in their roles in modulating synaptic plasticity and hippocampal‐dependent learning and memory.Support or Funding InformationThis research was supported by grants NIH/NINDS to JRH (5R01NS37112 and 1R21NS074975), and in part by the Emory Neuroscience NINDS Core Facilities and NIH/NINDS under award number P30NS055077.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Elevated serum levels of interleukin-37 correlate with poor prognosis in gastric cancer.

interleukin-37 (IL-37) is as a natural suppressor of the innate inflammatory and immune responses. It has also been reported to be involved in carcinogenesis and metastasis. The present case-control study was designed to investigate the role of serum levels of IL-37 in patients with gastric cancer. serum IL-37 levels were determined using the enzyme-linked immunosorbent assay in 180 patients diagnosed with gastric cancer and 100 healthy controls. The association between IL-37 levels and clinical factors was assessed. Univariate and multivariate analyses were performed to investigate the prognostic significance of these parameters in gastric cancer. serum IL-37 levels in gastric cancer patients (5.606 ± 0.837 pg/ml) were significantly higher than those in healthy controls (2.364 ± 0.210 pg/ml, p < 0.001). High serum IL-37 levels were related to a poorly differentiated histologic type (p = 0.046) and advanced T stage (p = 0.003). The Kaplan-Meier survival analysis indicated that the high-IL-37 group had a poorer overall survival and progression-free survival (overall survival [OS]: 39.0 months vs 13.0 months, p < 0.001, progression-free survival [PFS]: 25.0 months vs 10.0 months, p < 0.001). Multivariate analyses showed serum IL-37 to be an independent prognostic factor for gastric cancer patients (OS: hazard ratios [HR] = 1.842, 95% CI: 1.190-2.854, p = 0.006; PFS: HR = 1.547, 95% CI: 1.014-2.359, p = 0.043). in conclusion, serum IL-37 levels were associated with poor overall survival and progression-free survival in gastric cancer patients. IL-37 may be a potential predictor of prognosis in gastric cancer.

A Preemptive Behaviour-based Malware Detection through Analysis of API Calls Sequence Inspired by Human Immune System

This study detects malware as it begins to execute and propose a data mining approach for malware detection using sequences of API calls in a Windows environment. We begin with some background of the study and the influence of Human Immune System in our detection mechanism, i.e. the Natural Killer (NK) and Suppressor (S) Cells. We apply the K = 10 crosses fold data validation against the dataset. We use the n-grams technique to form the data for the purpose of establishing the Knowledge Bases and for the detection stage. The detection algorithm integrates the NK and S to work in unison and statistically determine on whether a particular executable deemed as benign or malicious. The results show that we could preemptively detect malware and benign programs at the very early beginning of their execution upon inspecting the first few hundreds of the targeted API Calls. Depending on the speed of the processor and the ongoing running processes, this could just happen in a split of a second or a few. This research is as part of our initiative to build a behaviour based component of a cyber defence and this will enhance our readiness to combat zero-day attacks.

Immunoregulatory Role of Interleukin-37 in Rheumatoid Arthritis; Relation to Disease Activity and Joint Destruction

AbstractBackground: The Interleukin (IL)-37 is a member of IL-1 cytokines and reported to down-regulate inflammation as a natural suppressor of innate immune responses. We measured serum IL-37 concentration in Rheumatoid Arthritis (RA) patients and analyzed clinical disease activity and radio-graphic erosion in RA.Aim of the Study: To throw some light on Interleukin-37 (IL-37) in patients with rheumatoid arthritis and its impact on disease activity and joint damage.Subject and Methods: 30 patients diagnosed to had Rheu-matoid Arthritis (RA) selected from Outpatient Clinic of Physical Medicine, Rheumatology and Rehabilitation Depart-ment, Tanta University Hospitals fulfilling the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) 2010 criteria for diagnosis of RA, and 20 apparently healthy individuals matched in age and sex participated as controls. Patients with other autoimmune diseases, acute coronary syndrome or any current infections were excluded. Disease Activity Score in 28 joints (DAS 28) was assessed for all patients; routine laboratory investigations (rheumatoid factor RF, anti-cyclic citrullinated peptide anti CCP, complete blood count CBC, Erythrocyte Sedimentation Rate ESR & C Reactive Protein CRP) and serum level of IL 37 measured by Enzyme-Linked Immunosorbent Assay ELISA were evaluated. Degree of joint destruction was assessed by Larsen score.Results: Serum IL-37 level was significantly higher in RA patients than control and positively correlated with level of disease activity assessed by DAS-28 score, also with clinical and laboratory indicators of disease activity as well as degree of bone erosion measured by Larsen score.Conclusion: IL-37 was increased in RA patients and its level was increased with disease activity, so it could prove to be potential biomarker for RA diagnosis, disease activity assessment and curative effect observation.

Increased serum interleukin-37 (IL-37) levels correlate with oxidative stress parameters in Hashimoto's thyroiditis.

Interleukin-37 (IL-37), member of the IL-1 family, is a natural suppressor of immune and inflammatory responses. Increased serum IL-37 levels were observed in several autoimmune diseases, including Graves' disease. To our knowledge, no data on Hashimoto's thyroiditis (HT) are available in the literature. Aim of our study was to measure serum IL-37 levels and evaluate their relationship, if any, with oxidative stress markers in HT patients. We enrolled 45 euthyroid HT patients (5 M e 40 F, median age 40years) and 50 age- and sex-matched healthy controls. None was under L-thyroxine therapy. Serum IL-37 levels were measured by ELISA. Specific serum tests, such as derived reactive oxygen metabolites (d-ROMs), and biological anti-oxidant potential (BAP) test were performed in all subjects to investigate the changes in oxidative balance, and advanced glycation end products (AGEs) were determined as a specific marker of oxidative stress. IL-37 levels were significantly higher in HT than in controls (median 475 vs. 268pg/ml, P = 0.018). In the same patients, serum oxidants (d-ROMs) were increased and anti-oxidants (BAP) decreased compared with controls (P = 0.011 and < 0.0001, respectively), clearly indicating an enhanced oxidative stress. In addition, AGEs levels were higher in HT patients than in controls (210 vs. 140AU/g prot, P < 0.0001) and directly correlated with IL-37 levels (P = 0.048). At multivariate analysis, the main independent predictors that influenced IL-37 levels were both anti-thyroid antibodies (P = 0.026) and AGEs levels (P = 0.001). IL-37 is up-regulated in HT and may exert a protective role by counteracting oxidative stress and inflammation.

Suppression of inflammation and acquired immunity by IL-37.

IL-37 is a unique member of the IL-1 family of cytokines, which functions as a natural suppressor of inflammatory and immune responses. Immune and non-immune cells produce IL-37 precursor following pro-inflammatory stimuli. Following activating cleavage by caspase-1, mature IL-37 translocates to the nucleus, where it suppresses transcription of pro-inflammatory genes. Both precursor and mature IL-37 are also secreted in the extracellular space, where they bind IL-18Rα and recruit the IL-1R8 (formerly TIR8 or SIGIRR), which transduces anti-inflammatory signals by suppressing NF-kB and MAPK and by activating Mer-PTEN-DOK pathways. During inflammation, IL-37 restores the metabolism of the cell by reducing succinate, inhibiting mTOR, and activating AMPK. Transgenic mice expressing human IL-37 and wild type mice treated with recombinant human IL-37 are protected from several experimental models of inflammation, including endotoxin shock, colitis, lung and spinal cord injury, coronary artery disease, arthritis and inflammation-induced fatigue, while also exhibiting reduced adaptive immune responses. In humans, IL-37 likely functions to limit excessive inflammation: accordingly, IL-37 levels are abnormal in patients with inflammatory and autoimmune diseases. In this review, we provide an overview of the discovery and biology of IL-37, and discuss the potential for development of this cytokine as a therapeutic agent.

Decreased expression of interleukin‑37 and its anti‑inflammatory effect in allergic rhinitis.

Interleukin‑37 (IL‑37), a novel member of the IL‑1 cytokine family has been identified as a natural suppressor of innate immunity and inflammatory responses. The present study aimed to determine the expression of IL‑37 in peripheral blood mononuclear cells (PBMCs) from patients with allergic rhinitis (AR), and examine the possible immunosuppressive effect of IL‑37 on inflammatory mediators and CD4+T cells in the pathogenesis of AR. The expression levels of IL‑37 were determined in PBMCs from 39patients with AR and 43controls using reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) analysis and flow cytometry. Cytokines in the supernatants of the PBMCs and CD4+T cells, which were stimulated with lipopolysaccharide in the presence or absence of IL‑37, were assayed using enzyme‑linked immunosorbent assays and RT‑qPCR analysis. The results showed that the patients with AR exhibited significantly decreased expression of IL‑37, and increased expression levels of interleukin (IL)‑1β and IL‑6 in PBMCs. Recombinant IL‑37 (rIL‑37) inhibited the production of IL‑1p and IL‑6, and enhanced the production of IL‑27 in PBMCs from the patients with AR and the control individuals. rIL‑37 also markedly decreased the expression of IL‑17 by CD4+T cells in the patients with AR and controls. These results suggested that IL‑37 may be an important cytokine in the pathogenesis of AR. It may have a protective role in AR by inhibiting the production of proinflammatory cytokines and through suppressive regulation of the Th17 response.