• Caspase 9 gene
• IL-15
• IL-22
• IL-37
• Interleukins
• Polycystic Ovary Syndrome

• CD8+ T cells
• Cervical cancer
• IL-37
• Pulsed electromagnetic field
• SMAD3/p38/NF-κB signaling pathway
• Tumor immune microenvironment

• Animals
• CD8-Positive T-Lymphocytes/immunology
• Interleukin-1/genetics
• Interleukin-1/metabolism
• Uterine Cervical Neoplasms/therapy
• Uterine Cervical Neoplasms/pathology
• Uterine Cervical Neoplasms/immunology
• Uterine Cervical Neoplasms/genetics
• Uterine Cervical Neoplasms/metabolism
• Humans
• Female
• Mice
• Apoptosis
• Electromagnetic Fields
• Signal Transduction
• Disease Progression
• Mice, Transgenic
• Cell Proliferation
• Cell Line, Tumor
• Xenograft Model Antitumor Assays
• HeLa Cells
• Oxidative Stress
• Magnetic Field Therapy/methods

• 2023YFS0092 Sichuan Science and Technology Program
• ZYGX2021YGLH216 Fundamental Research Funds for the Central Universities

• GSDMD
• IL37
• NLRP3
• OSCC
• macrophage

• Humans
• Mouth Neoplasms/metabolism
• Mouth Neoplasms/pathology
• Mouth Neoplasms/genetics
• Animals
• Carcinoma, Squamous Cell/metabolism
• Carcinoma, Squamous Cell/pathology
• Carcinoma, Squamous Cell/genetics
• Interleukin-1/metabolism
• Interleukin-1/genetics
• Mice
• Cell Line, Tumor
• Macrophages/metabolism
• Macrophages/immunology
• Gene Expression Regulation, Neoplastic
• NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
• Cell Proliferation
• Inflammasomes/metabolism
• Female
• Cytokines/metabolism
• Male

• 2023ZDXM019 Chongqing Health Commission ＆ Science and Technology Bureau Foundation
• 81800999 National Natural Science Foundation of China
• National Natural Science Foundation of China

• Apoptosis
• Autophagy
• Fine particulate matter (PM2.5)
• Interleukin (IL)-37
• Lung injury

• Animals
• Humans
• Mice
• Autophagy/drug effects
• Interleukins/pharmacology
• Lung Injury/chemically induced
• Lung Injury/drug therapy
• Particulate Matter/toxicity
• Proto-Oncogene Proteins c-akt/metabolism
• Signal Transduction
• TOR Serine-Threonine Kinases/genetics
• TOR Serine-Threonine Kinases/metabolism

• IL-37
• anti-tumor
• immunomodulation
• immunotherapy
• inflammation inhibition

• Humans
• Adaptive Immunity
• Cytokines/immunology
• Neoplasms/therapy
• Neoplasms/metabolism
• Signal Transduction
• Tumor Microenvironment
• Interleukin-1/immunology

• IL-37
• cytokines
• inflammatory bowel disease
• innate immune response
• intestinal barrier
• intestinal organoid
• tight junctions

• Humans
• Mice
• Animals
• Tumor Necrosis Factor-alpha/metabolism
• Intestinal Mucosa
• Immunity, Innate
• Cytokines/metabolism
• RNA, Messenger/metabolism
• Interleukin-1/genetics
• Interleukin-1/metabolism

• MC_PC_17230 Medical Research Council
• Deutsche Forschungsgemeinschaft
• Berlin Institute of Health

• il-37
• hepatitis
• liver injury
• liver fibrosis
• hcc

• Humans
• Carcinoma, Hepatocellular/pathology
• Liver Neoplasms/pathology
• Cytokines
• Hepatitis
• Tumor Microenvironment

• 20211458 Foundation of Traditional Chinese Medicine Bureau of Guangdong Province
• 2022108 Foundation of Student Innovation Ability Promotion Plan of Guangzhou Medical University
• 20190220 Foundation of Qingyuan People's Hospital (Qingyuan, Guangdong

• advanced stage
• biomarker
• bladder cancer
• interleukin (IL-)37
• survival

• chronic inflammation
• cytokine IL-37
• diagnostic utility
• older adults
• type 2 diabetes

• Female
• Humans
• Anti-Inflammatory Agents/therapeutic use
• Biomarkers
• Cytokines/metabolism
• Diabetes Mellitus, Type 2/drug therapy
• Inflammation/metabolism
• Prognosis

• biomarker
• infiltration rates
• interleukin (IL-)37
• lung adenocarcinoma
• survival

• Arterial stiffness
• Behçet's disease
• Interleukin 37

The anti-inflammatory cytokine interleukin-37 (IL-37) belongs to the IL-1 family but is not expressed in mice. We used a human IL-37 (hIL-37tg) expressing mouse, which has been subjected to various models of local and systemic inflammation as well as immunological challenges. Previous studies reveal an immunomodulatory role of IL-37, which can be characterized as an important suppressor of innate immunity. Here, we examined the functions of IL-37 in the central nervous system and explored the effects of IL-37 on neuronal architecture and function, microglial phenotype, cytokine production and behavior after inflammatory challenge by intraperitoneal LPS-injection. In wild-type mice, decreased spine density, activated microglial phenotype and impaired long-term potentiation (LTP) were observed after LPS injection, whereas hIL-37tg mice showed no impairment. In addition, we crossed the hIL-37tg mouse with an animal model of Alzheimer’s disease (APP/PS1) to investigate the anti-inflammatory properties of IL-37 under chronic neuroinflammatory conditions. Our results show that expression of IL-37 is able to limit inflammation in the brain after acute inflammatory events and prevent loss of cognitive abilities in a mouse model of AD.

• mouse
• neuroscience

• FOXP3
• IL-37
• Jurkat
• Treg
• regulatory T cell

• Cytokines/metabolism
• Forkhead Transcription Factors/metabolism
• Humans
• Interleukin-1/metabolism
• Jurkat Cells
• Phenotype
• T-Lymphocytes, Regulatory

• R01 AI156534 NIAID NIH HHS
• I01 BX001228 BLRD VA
• P30 CA046934 NCI NIH HHS
• R01 CA197919 NCI NIH HHS
• P30 AR057212 NIAMS NIH HHS

• Immune thrombocytopenic purpura
• interleukin-37
• transforming growth factor-β1
• vascular endothelial growth factor A

Interleukin-37 (IL-37) is an effective anti-inflammatory factor and acts through intracellular and extracellular pathways, inhibiting the effects of other inflammatory cytokines, such as IL-1β, IL-6, and tumor necrosis factor-α (TNF-α), thereby exerting powerful anti-inflammatory effects. In numerous recent studies, the anti-inflammatory effects of IL-37 have been described in many autoimmune diseases, colitis, and tumors. However, the current research on IL-37 in the field of the central nervous system (CNS) is not only less, but mainly for clinical research and little discussion of the mechanism. In this review, the role of IL-37 and its associated inflammatory factors in common CNS diseases are summarized, and their therapeutic potential in CNS diseases identified.

Interleukin (IL)-37 has an important function in limiting excessive inflammation. Its expression is increased in numerous inflammatory and autoimmune conditions and correlates with disease activity, suggesting it could have potential as a disease biomarker. Nevertheless, a reference range has yet to be determined. Our aim was to establish the first reference range of circulating IL-37 levels in healthy adult humans. PubMed was searched for studies reporting blood IL-37 concentrations in healthy adult subjects as measured by enzyme-linked immunosorbent assay. Nineteen studies were included in the analysis. Mean IL-37 levels were weighted by sample sizes, and weighted mean lower and upper levels ( ± 2SD of means) were calculated to provide a weighted mean and reference range. IL-37 levels were quantified in either serum or plasma from a total of 1035 (647 serum; 388 plasma) healthy subjects. The serum, plasma and combined matrix weighted means (reference ranges) were 72.9 (41.5 – 104.4) pg/mL, 83.9 (41.1 – 126.8) pg/mL, and 77.1 (41.4 – 112.8) pg/mL, respectively. There were no significant differences between serum and plasma means and upper and lower limits. Study means and upper IL-37 levels were significantly higher in Chinese population studies. From our analysis, a preliminary reference range for circulating IL-37 levels in healthy human adults has been established. In order to determine a reliable reference range for clinical application, large, prospective, multi-ethnic, healthy population studies are necessary. In addition, demographics, sample matrix, collection, processing and storage methods potentially affecting IL-37 detection levels should be thoroughly investigated.

• biomarker
• healthy
• interleukin-37
• plasma
• reference range
• serum

IL-37 is a recently discovered cytokine in the IL-1 family exerting broad protective effects on inflammatory diseases, autoimmune diseases, and cancer. Immune and non-immune cells produce the IL-37 precursor upon pro-inflammatory stimuli. Intracellularly, caspase-1 cleaves and activates IL-37, and its mature form binds to Smad3; this complex translocates into the nucleus where it suppresses cytokine production, consequently reducing inflammation. Extracellularly, IL-37 forms a complex with IL-18Rα and IL-1R8 (formerly TIR8 or SIGIRR) that transduces anti-inflammatory signals by the suppression of NF-κB and MAPK and the activation of Mer-PTEN-DOK pathways. During inflammation, IL-37 suppresses the expression of several pro-inflammatory cytokine in favor to the expression of the anti-inflammatory ones by the regulation of macrophage polarization, lipid metabolism, inflammasome function, TSLP synthesis and miRNAs function. Moreover, IL-37 not only regulates the innate and acquired immunity, but also improves aging-associated immunosenescence. Furthermore, IL-37 exerts an inhibitory effect on tumor angiogenesis and metastasis, and progression. Finally, IL-37 may have a potential ability to reduce excessive inflammation since it is aberrantly expressed in patients with inflammatory diseases, autoimmune diseases, and cancer, thus, it may be used as a marker for different types of diseases. Therefore, this review provides an updated view of the role of IL-37 in human health and disease, and discusses the potential of IL-37 as a therapeutic target and biomarker in inflammatory diseases, autoimmune diseases, and cancer.

• IL-1 family
• acquired immunity
• autoimmune disease
• cancer
• inflammation
• regulatory cytokine

Interleukin-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.

The aim of this study was to evaluate IL-37 as a prognostic factor and its possible mechanism of action.

Polymerase 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.

IL-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.

Our 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.

• IL-6
• acute myeloid leukemia
• interleukin-37
• prognosis

The aim of this study was to evaluate the usefulness of serum interleukin (IL)-37 and IL-18 as disease activity markers of adult-onset Still’s disease (AOSD) and to compare their related clinical features. Forty-five patients with a set of high and subsequent low disease activity status of AOSD were enrolled. Modified Pouchot (mPouchot) score and serologic disease activity markers including levels of IL-37 and IL-18 were compared between high and low disease activity status. The relationships between disease activity parameters and differences in levels of cytokines according to each disease manifestation were evaluated in high disease activity status. mPouchot score and all disease activity markers including IL-37 and IL-18 significantly declined after treatment. Though both cytokines positively correlated with mPouchot score, the two did not correlate with each other in high disease activity status. IL-18 positively correlated with ferritin, AST, and LDH while IL-37 correlated better with CRP. The expression level of IL-37 was related to leukocytosis while IL-18 was related to pleuritis, pneumonitis, abnormal LFT, and hyperferritinemia. In addition, patients in the IL-18 dominant group presented with higher LDH levels and required a higher mean corticosteroid dose. In conclusion, IL-37 and IL-18 are disease activity markers reflecting different aspects of AOSD that can complement each other.

• adult-onset Still’s disease
• interleukin-18
• interleukin-37

• IL-1R8
• Inflammation
• Interleukin 37
• Neuroprotection
• Spinal cord injury
• Treatment

Background: Interleukin 37 (IL-37), a member of IL-1 family, broadly suppresses inflammation in many pathological conditions by acting as a dual-function cytokine in that IL-37 signals via the extracellular receptor complex IL1-R5/IL-1R8, but it can also translocate to the nucleus. However, whether IL-37 exerts beneficial actions in neuroinflammatory diseases, such as multiple sclerosis, remains to be elucidated. Thus, the goals of the present study were to evaluate the therapeutic effects of IL-37 in a mouse model of multiple sclerosis, and if so, whether this is mediated via the extracellular receptor complex IL-1R5/IL-1R8.

Methods: We used a murine model of MS, the experimental autoimmune encephalomyelitis (EAE). We induced EAE in three different single and double transgenic mice (hIL-37tg, IL-1R8 KO, hIL-37tg-IL-1R8 KO) and wild type littermates. We also induced EAE in C57Bl/6 mice and treated them with various forms of recombinant human IL-37 protein. Functional and histological techniques were used to assess locomotor deficits and demyelination. Luminex and flow cytometry analysis were done to assess the protein levels of pro-inflammatory cytokines and different immune cell populations, respectively. qPCRs were done to assess the expression of IL-37, IL-1R5 and IL-1R8 in the spinal cord of EAE, and in blood peripheral mononuclear cells and brain tissue samples of MS patients.

Results: We demonstrate that IL-37 reduces inflammation and protects against neurological deficits and myelin loss in EAE mice by acting via IL1-R5/IL1-R8. We also reveal that administration of recombinant human IL-37 exerts therapeutic actions in EAE mice. We finally show that IL-37 transcripts are not up-regulated in peripheral blood mononuclear cells and in brain lesions of MS patients, despite the IL-1R5/IL-1R8 receptor complex is expressed.

Conclusions: This study presents novel data indicating that IL-37 exerts therapeutic effects in EAE by acting through the extracellular receptor complex IL-1R5/IL-1R8, and that this protective physiological mechanism is defective in MS individuals. IL-37 may therefore represent a novel therapeutic avenue for the treatment of MS with great promising potential.

• IL-1R8
• IL-37
• cytokines
• experimental autoimmune encephalomyelitis
• multiple sclerosis

IL‐38 is a newly identified cytokine that belongs to the IL‐1 family. In our previous study, we found elevated plasma levels of IL‐38 in patients with systemic lupus erythematosus (SLE). However, the clear relationship of IL‐38 expression in plasma, peripheral blood mononuclear cells (PBMCs) and clinical and laboratory features needs elucidation. Additionally, we evaluated the possible role of IL‐38 in regulating production of inflammatory cytokines in PBMCs in vitro. A pristane‐induced murine lupus model was used to further demonstrate the effects of IL‐38 on cytokines in vivo and discuss the significance of IL‐38 in lupus development. The results showed that mRNA expression of IL‐38 in PBMCs of patients with SLE was elevated compared with volunteers, and expression of IL‐38 in both plasma and PBMCs was strongly related to clinical features, such as haematuria and proteinuria, and correlated with a SLEDAI score. Plasma levels of TNF‐α, IL‐1β, IL‐6 and IL‐23 were elevated in patients with SLE and were related to plasma levels of IL‐38. In vitro, PBMCs of patients with SLE stimulated with IL‐38 showed a decreased expression of the four inflammatory cytokines compared with PBMCs of patients without treatment. Interestingly, IL‐38 administration in lupus mice significantly reduced the development of lupus, such as reduced proteinuria, improved histological examinations of the kidneys and down‐regulated inflammatory cytokines. In conclusion, IL‐38 may suppress synthesis of pro‐inflammatory cytokines and therefore regulate lupus pathogenesis.

• IL-38
• autoimmunity
• inflammation
• lupus

•

Sepsis infects more than 48.9 million people world-wide, with 19.7 million deaths.

Cytokine storm generates during various systemic acute infections, including sepsis and current pandemic called COVID-19 (severe) causing devastating inflammatory conditions, which include multi-organ failure or multi-organ dysfunction syndrome (MODS) and death of the patient. Toll-like receptors (TLRs) are one of the major pattern recognition receptors (PRRs) expressed by immune cells as well as non-immune cells, including neurons, which play a crucial role in generating cytokine storm. They recognize microbial-associated molecular patterns (MAMPs, expressed by pathogens) and damage or death-associate molecular patterns (DAMPs; released and/expressed by damaged/killed host cells). Upon recognition of MAMPs and DAMPs, TLRs activate downstream signaling pathways releasing several pro-inflammatory mediators [cytokines, chemokines, interferons, and reactive oxygen and nitrogen species (ROS or RNS)], which cause acute inflammation meant to control the pathogen and repair the damage. Induction of an exaggerated response due to genetic makeup of the host and/or persistence of the pathogen due to its evasion mechanisms may lead to severe systemic inflammatory condition called sepsis in response to the generation of cytokine storm and organ dysfunction. The activation of TLR-induced inflammatory response is hardwired to the induction of several negative feedback mechanisms that come into play to conclude the response and maintain immune homeostasis. This state-of-the-art review describes the importance of TLR signaling in the onset of the sepsis-associated cytokine storm and discusses various host-derived endogenous negative regulators of TLR signaling pathways. The subject is very important as there is a vast array of genes and processes implicated in these negative feedback mechanisms. These molecules and mechanisms can be targeted for developing novel therapeutic drugs for cytokine storm-associated diseases, including sepsis, severe COVID-19, and other inflammatory diseases, where TLR-signaling plays a significant role.

• Cytokine storm
• Cytokines
• Innate Immunity
• PAMPs
• Sepsis
• TLRs

• AIM2
• ASC
• NLRP3
• caspase-1
• inflammasome
• interleukin 18
• interleukin 1β
• interleukin 37
• pyroptosis

• Animals
• Cells, Cultured
• Inflammasomes/metabolism
• Interleukin-1/analysis
• Interleukin-1/metabolism
• Interleukins/analysis
• Interleukins/metabolism
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic

• Genetic
• Iran
• Multiple sclerosis
• Risk factor

• Genetic Predisposition to Disease
• Humans
• Inflammation Mediators/metabolism
• Intercellular Signaling Peptides and Proteins/metabolism
• Iran
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Multiple Sclerosis/genetics
• Protein Kinases/metabolism

• IL-37
• Immunology
• Inflammation
• Skin

• Allergic diseases
• Anti-inflammatory effect
• Hypersensitivity
• Inflammation
• Interleukin-37

• Antiretroviral Therapy, Highly Active
• Cytokines/metabolism
• HIV Infections/drug therapy
• HIV Infections/immunology
• Humans
• Inflammation Mediators/metabolism
• Interleukin-1/metabolism
• Leukocytes, Mononuclear/drug effects
• Leukocytes, Mononuclear/metabolism
• RNA, Viral/metabolism
• Receptors, Interleukin-1/metabolism
• Solubility

• IL-37
• Treg cells
• blood
• melanoma
• secretome

• Biomarkers, Tumor/metabolism
• Cells, Cultured
• Female
• Humans
• Interleukin-1/metabolism
• Male
• Melanoma/metabolism
• RNA, Messenger/metabolism
• T-Lymphocytes, Regulatory/metabolism
• Transforming Growth Factor beta/metabolism
• Up-Regulation/physiology

• I01 BX001228 BLRD VA
• P30 CA046934 NCI NIH HHS
• R01 CA197919 NCI NIH HHS
• P30 AR057212 NIAMS NIH HHS
• R03 CA125833 NCI NIH HHS

• autoimmune disease
• cytokine
• immune thrombocytopenia
• interleukin-37

• Anti-inflammation
• Cytokine receptor
• Deubiquitinating enzyme
• Protein stability

• Anti-inflammatory property
• Cytokine
• Functional characterization
• Genetic transformation
• Human IL-37
• Plant molecular farming
• Recombinant protein

• Cytokines/metabolism
• Humans
• Immunity, Innate/genetics
• Immunity, Innate/physiology
• Interleukin-1/genetics
• Interleukin-1/metabolism
• Plants, Genetically Modified/genetics
• Plants, Genetically Modified/metabolism
• Recombinant Proteins/genetics
• Recombinant Proteins/metabolism
• Nicotiana/genetics
• Nicotiana/metabolism

• Animals
• Atherosclerosis/metabolism
• Cell Line
• Cell Movement
• Coronary Vessels/metabolism
• Endothelial Cells/metabolism
• Gene Expression Regulation
• Humans
• Inflammation/metabolism
• Intercellular Adhesion Molecule-1/metabolism
• Interleukin-1/metabolism
• Interleukin-18/metabolism
• Mice
• NF-kappa B p50 Subunit/metabolism
• Neutrophils/metabolism
• Plaque, Atherosclerotic/metabolism
• Signal Transduction
• Toll-Like Receptor 2/metabolism

• IL-37
• Rheumatoid arthritis
• SNP
• p.Thr42Ala
• rs3811047

Interleukin (IL)-37 has emerged as a novel anti-inflammatory cytokine that play an immunosuppressive role in regulating inflammatory response. This study aimed to measure IL-37 levels in the plasma and peripheral blood mononuclear cells (PBMCs) of patients with systemic juvenile idiopathic arthritis (sJIA), and to establish the correlation between IL-37 levels and disease activity, laboratory parameters and inflammatory cytokines.

The mRNA levels of IL-37 in PBMCs and plasma IL-37 concentrations in 46 sJIA patients and 30 age- and sex-matched healthy controls were measured by real-time polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. The correlations between plasma IL-37 levels and disease activity, laboratory parameters and inflammatory cytokines in sJIA were analyzed by Spearman correlation test. PBMCs from the sJIA patients were stimulated with recombinant human IL-37 (rhIL-37) protein, expressions of IL-1β, IL-6, TNF-α and IL-17 were detected by RT-PCR and ELISA.

Plasma levels of IL-37 and relative IL-37 mRNA expression were significantly elevated in sJIA patients, especially in active sJIA patients, when compared with the healthy controls (P < 0.001). Furthermore, patients with active disease showed higher IL-37 mRNAs and plasma protein levels than those with inactive disease as well as healthy controls. Plasma IL-37 levels were correlated with disease activity and inflammatory cytokines (IL-6, TNF-α, IL-17 and GM-CSF) in sJIA patients. The productions of inflammatory cytokines such as IL-6, TNF-α, IL-17 in PBMCs from sJIA patients were obviously decreased after recombinant IL-37 stimulation, whereas the production of IL-1β was not changed.

Our results demonstrate that levels of IL-37 were higher in sJIA patients, which were correlated with disease activity and sJIA related inflammatory cytokines. In addition, rhIL-37 down-regulates the expressions of inflammatory cytokines form PBMCs in sJIA patients, suggesting that IL-37 may have the potential role as a natural inhibitor for the pathogenesis and therapy of sJIA.

The online version of this article (10.1186/s12967-018-1655-8) contains supplementary material, which is available to authorized users.

• Inflammatory cytokines
• Interleukin-37
• Peripheral blood mononuclear cells
• Systemic juvenile idiopathic arthritis

• Amino Acid Sequence
• Animals
• Chronic Periodontitis/blood
• Chronic Periodontitis/genetics
• Chronic Periodontitis/pathology
• Disease Models, Animal
• Female
• Genetic Loci
• Genetic Variation
• Genome-Wide Association Study
• Gingival Crevicular Fluid/metabolism
• HEK293 Cells
• Haplotypes/genetics
• Humans
• Inflammation/blood
• Inflammation/metabolism
• Inflammation/pathology
• Interleukin-1/genetics
• Interleukin-1/metabolism
• Interleukin-1beta/blood
• Interleukin-1beta/genetics
• Interleukin-1beta/metabolism
• Leukocytes, Mononuclear/metabolism
• Mice, Transgenic
• Periodontium/pathology
• Polymorphism, Single Nucleotide/genetics
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• Stroke/genetics
• Tooth Loss/genetics

• HHSN268201100010C NHLBI NIH HHS
• R01 HL059367 NHLBI NIH HHS
• HHSN268201100011I NHLBI NIH HHS
• U01 HG004402 NHGRI NIH HHS
• HHSN268201100006C NHLBI NIH HHS
• HHSN268201100005I NHLBI NIH HHS
• R01 DE023836 NIDCR NIH HHS
• HHSN268201100007I NHLBI NIH HHS
• R01 HL087641 NHLBI NIH HHS
• R01 DE021418 NIDCR NIH HHS
• HHSN268201100009I NHLBI NIH HHS
• R01 DE011551 NIDCR NIH HHS
• F32 DE026688 NIDCR NIH HHS
• P30 ES010126 NIEHS NIH HHS
• T90 DE021986 NIDCR NIH HHS
• UL1 RR025005 NCRR NIH HHS
• HHSN268201100008C NHLBI NIH HHS
• HHSN268201100005G NHLBI NIH HHS
• F32 DE026688 NIDCR NIH HHS
• HHSN268201100008I NHLBI NIH HHS
• HHSN268201100007C NHLBI NIH HHS
• HHSN268201100011C NHLBI NIH HHS
• R01 HL086694 NHLBI NIH HHS
• HHSN268201100009C NHLBI NIH HHS
• HHSN268201100005C NHLBI NIH HHS
• U.S. Department of Health & Human Services | NIH | National Institute of Dental and Craniofacial Research (NIDCR)

• IL-37
• energy metabolism
• food intake
• high fat diet

• IL-1 family
• Toll-like receptors
• inflammation
• metabolism
• regulatory cytokines

• Adaptive Immunity
• Animals
• Autoimmune Diseases/immunology
• Humans
• Immune Tolerance
• Inflammation/immunology
• Interleukin-1/metabolism
• Mice
• Signal Transduction

IL-1 family regulatory cytokine IL-37b can suppress innate immunity and inflammatory activity in inflammatory diseases. In this study, IL-37b showed remarkable in vitro suppression of inflammatory tumor necrosis factor-α, IL-1β, IL-6, CCL2, and CXCL8 production in the coculture of human primary eosinophils and human bronchial epithelial BEAS-2B cells with the stimulation of bacterial toll-like receptor-2 ligand peptidoglycan, while antagonizing the activation of intracellular nuclear factor-κB, PI3K–Akt, extracellular signal-regulated kinase 1/2, and suppressing the gene transcription of allergic inflammation-related PYCARD, S100A9, and CAMP as demonstrated by flow cytometry, RNA-sequencing, and bioinformatics. Results therefore elucidated the novel anti-inflammation-related molecular mechanisms mediated by IL-37b. Using the house dust mite (HDM)-induced humanized asthmatic NOD/SCID mice for preclinical study, intravenous administration of IL-37b restored the normal plasma levels of eosinophil activators CCL11 and IL-5, suppressed the elevated concentrations of Th2 and asthma-related cytokines IL-4, IL-6, and IL-13 and inflammatory IL-17, CCL5, and CCL11 in lung homogenate of asthmatic mice. Histopathological results of lung tissue illustrated that IL-37b could mitigate the enhanced mucus, eosinophil infiltration, thickened airway wall, and goblet cells. Together with similar findings using the ovalbumin- and HDM-induced allergic asthmatic mice further validated the therapeutic potential of IL-37b in allergic asthma. The above results illustrate the novel IL-37-mediated regulation of intracellular inflammation mechanism linking bacterial infection and the activation of human eosinophils and confirm the in vivo anti-inflammatory activity of IL-37b on human allergic asthma.

• allergic asthma
• eosinophils
• interleukin-37
• signal transduction
• transcriptional profile

• Interleukin 37
• alcoholic liver disease
• alcoholic steatohepatitis
• ethanol (EtOH)

IL-37 is a new member of IL-1 family and possesses five different isoforms (named as IL-37 a–e). IL-37b has been demonstrated as a physiological suppressor of immune responses. However, the function of other isoforms remains unknown. Here, we show that IL-37d possesses anti-inflammatory roles both in vitro and in vivo. Firstly, IL-37d is expressed in peripheral blood mononuclear cells (PBMCs) and umbilical cords-derived mesenchymal stem cells (UCMSCs). Secondly, IL-37d overexpression markedly inhibits IL-1β-induced IL-6 production in A549 cells. Consistently, bone marrow-derived macrophages (BMDMs) from IL-37d transgenic mice express low levels of pro-inflammatory cytokines (such as IL-6 and TNF-α) following LPS stimulation, compared with those from wild-type mice. Furthermore, IL-37d transgenic mice produce less pro-inflammatory cytokines, and show much less degree of LPS-induced endotoxemia in vivo. Mechanistically, IL-37d interacts with Smad3 and promotes nuclear translocation of pSmad3. SIS3 (a specific Smad3 inhibitor) treatment completely blocks the inhibitory effects of IL-37d. Thus, our data indicate that IL-37d is a functional cytokine that negatively regulates pro-inflammatory cytokines expression in a Smad3-dependent manner.

Interleukin-37 (IL-37) is an IL-1 family cytokine discovered in recent years and has 5 different isoforms. As an immunosuppressive factor, IL-37 can suppress excessive immune response. IL-37 plays a role in protecting the body against endotoxin shock, ischemia-reperfusion injury, autoimmune diseases, and cardiovascular diseases. In addition, IL-37 has a potential antitumor effect. IL-37 and its receptors may serve as novel targets for the study, diagnosis, and treatment of immune-related diseases and tumors.

• ROCK activity
• acute coronary syndrome
• interleukin -37