Interleukin-37 has A Promising Cardioprotective Effect on Isoproterenol-Induced Myocardial Infarction / La Interleucina-37 tiene un Efecto Cardioprotector Prometedor sobre el Infarto de Miocardio Inducido por Isoproterenol

SUMMARY: The main cause of mortality and disability globally is myocardial infarction (MI). Isoproterenol (ISO), a β-adrenoceptor agonist, has been used to induce rat myocardial necrosis. Whereas interleukin-37 (IL-37) has anti-inflammatory and cytoprotective properties. The study aimed to investigate the potential protective effects of IL-37 administration on cardiac architecture, oxidative stress, and inflammatory markers during ISO-induced MI in rats. Three groups of adult male rats were used in this study, the normal control group (n=8), ISO-induced MI group (n=8) that received isoproterenol hydrochloride (ISO) (100 mg/kg/day, SC, for the first 2 consecutive days), and IL-37-treated group (ISO+IL-37) (n=8) that received recombinant human IL-37 (40 µg/kg /day, intraperitoneally, for 2 weeks during and after ISO injections. Heart rate (HR.) and ECG changes were monitored. Some oxidative stress markers such as superoxide dismutase (SOD), nitric oxide (NOx), malondialdehyde (MDA), and glutathione (GSH) tissue levels in the tissue homogenate were assayed. Interleukin- 6 (IL-6), tumor necrosis factor- α (TNF-α), caspase-8, P53, and C- reactive protein (CRP) were among the inflammatory markers examined. In addition, serum levels of creatinine kinase (CK-MB) and lactate dehydrogenase (LDH) were analyzed to evaluate the myocardial injury. For histological analysis, tissues were sectioned, fixed in paraffin, and stained with hematoxylin and eosin (H&E), Masson Trichrome and, immunohistochemical against NF-kB, TNF-α, and Caspase-9. IL-37 improved ECG changes, cardiac enzyme markers, and some inflammatory markers of oxidative stress in ISO-induced MI. It also improved the histopathological and immunohistochemical changes in MI. In conclusion: IL-37 might be a promising therapeutic modality in myocardial infarction.

La principal causa de mortalidad y discapacidad a nivel mundial es el infarto de miocardio (IM). El isoproterenol (ISO), un agonista de los receptores adrenérgicos β, se ha utilizado para inducir necrosis miocárdica en ratas. Mientras que la interleucina-37 (IL-37) tiene propiedades antiinflamatorias y citoprotectoras. El estudio tuvo como objetivo investigar los posibles efectos protectores de la administración de IL-37 en la arquitectura cardíaca, el estrés oxidativo y los marcadores inflamatorios durante el infarto de miocardio inducido por ISO en ratas. En este estudio se utilizaron tres grupos de ratas macho adultas, el grupo control normal (n=8), el grupo con IM inducido por ISO (n=8) que recibió clorhidrato de isoproterenol (ISO) (100 mg/kg/día, SC, durante los primeros 2 días consecutivos) y el grupo tratado con IL-37 (ISO+IL- 37) (n=8) que recibió IL-37 humana recombinante (40 µg/kg/día, por vía intraperitoneal, durante 2 semanas durante y después de las inyecciones de ISO. Se monitorearon la frecuencia cardíaca (FC) y los cambios en el ECG. Se analizaron algunos marcadores de estrés oxidativo como la superóxido dismutasa (SOD), el óxido nítrico (NOx), el malondialdehído (MDA) y los niveles tisulares de glutatión (GSH) en el homogeneizado de tejido. La interleucina-6 (IL-6), el factor de necrosis tumoral-α (TNF-α), la caspasa-8, la P53 y la proteína C reactiva (CRP) se encontraban entre los marcadores inflamatorios examinados. Se analizaron los niveles de creatinoquinasa (CK-MB) y lactato deshidrogenasa (LDH) para evaluar la lesión miocárdica; para el análisis histológico se seccionaron los tejidos, se fijaron en parafina y se tiñeron con hematoxilina y eosina (H&E), Tricromo de Masson e inmunohistoquímica contra NF-kB, TNF-α y Caspasa-9. IL-37 mejoró los cambios de ECG, los marcadores de enzimas cardíacas y algunos marcadores inflamatorios de estrés oxidativo en el IM inducido por ISO. Además mejoró los cambios histopatológicos e inmunohistoquímicos en MI. En conclusión: la IL-37 podría ser una modalidad terapéutica prometedora en el infarto de miocardio.

Research progress on the anti-inflammatory effect of interleukin 37 and its role in asthma / 中华微生物学和免疫学杂志

IL-37 is a member of the IL-1 family of cytokines, which functions as a natural suppressor of inflammatory and immune responses. 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 anti-inflammatory mechanism of IL-37. It also summarizes the research progress of expression and its role in bronchial asthma, a heterogeneous chronic airway inflammatory disease.

Research progress on the relationship between IL-37 and periodontitis / 口腔疾病防治

@#Periodontitis is the inflammation of periodontal tissue caused by dental plaque, which absorbs the alveolar bone and cementum. The immune response triggered by CD4+T cells is the key factor for the aggravation of periodontitis. The activation of dendritic cells and the receptor activator of the NF-κB ligand (RANKL) pathway is an important link in the alveolar bone resorption of periodontal tissue. Pro-inflammatory factors such as interferon-γ (IFN-γ), tumor necrosis factor (TNF-α) and interleukin-1β (IL-1β) also play important roles in the development of periodontitis. Interleukin-37(IL-37), which is a newly discovered cytokine in the IL-1 family, has five shear variants from a to e, among which the clover β-structure encoded by exon 4 plays an important role in the binding of cytokines and the corresponding receptors. IL-37 has strong anti-inflammatory and inhibition of autoimmunity, can enter the nucleus with the help of caspase-1 and bind with Smad proteins to regulate the transcription of pro-inflammatory genes. Extracellular IL-37 can bind to IL-18 binding protein and inhibit the production of pro-inflammatory factors. IL-37 can inhibit the progression of periodontitis by inhibiting the RANKL signaling pathway, inhibiting the proliferation and differentiation of dendritic cells and CD4+T cells, binding to Smad proteins, and releasing pro-inflammatory factors such as IFN-γ and TNF-α. The IL-37 concentration in periodontal tissue can indicate the progression of periodontitis. Few studies have described the interaction between the anti-inflammatory factor IL-37 and periodontitis. Thus, in this paper, the structure and function of IL-37 and the related factors between IL-37 and periodontitis will be reviewed.

Expression and significance of IL-37 and IL-6 in aqueous humor of patients with primary open angle glaucoma / 国际眼科杂志(Guoji Yanke Zazhi)

@#AIM: To test concentrations of IL-37 and IL-6 in aqueous humor samples of patients with primary open angle glaucoma(POAG), and analyze the potential relationship to intraocular pressure(IOP)and mean defect of visual field. <p>METHODS: Prospective consecutive non-randomized comparative cohort study was conducted. Totally 25 POAG patients and 25 age related cataract(ARC)patients in Nanjing Medical University Eye Hospital from June, 2019 to January, 2020 were collected. The levels of IL-37 and IL-6 in the aqueous humor were detected by enzyme-linked immunosorbent assay(ELISA). The IOP and mean defect of visual field of patients in the POAG group were also measured.<p>RESULTS: The IL-37 concentrations in aqueous humor of POAG group and control group were 25.80±2.87pg/mL and 23.75±3.88pg/mL respectively(<i>P</i><0.05). The IL-6 concentrations in aqueous humor of POAG group and control group were 43.87±7.75pg/mL and 36.53±7.60pg/mL respectively(<i>P</i><0.05). In POAG group, the concentration of IL-37 was significantly positively correlated with mean defect of visual field(<i>r</i>=0.4520, <i>P</i><0.05), the concentration of IL-6 was significantly positively correlated with IOP(<i>r</i>=0.5817, <i>P</i><0.05).<p>CONCLUSION: Significant differences in aqueous humor levels of IL-37 and IL-6 between glaucoma and control patients support the hypothesis that immune inflammation are involved in the pathogenesis of POAG.

Research progress of mechanism of IL-37 in rheumatoid arthritis / 上海交通大学学报（医学版）

Rheumatoid arthritis (RA) is a chronic progressive autoimmune disorder, the mechanism of which is not clear yet. Cytokines play a key role in the pathogenesis of RA. Recent studies on cytokine involvement in autoimmune diseases have found that, as a new member of interleukin-1 (IL-1) family, IL-37 can participate in the regulation of signaling pathway and play its anti-inflammatory role by extracellular binding to membrane receptor and intracellular complex formation. Studies have shown that the expression level of IL-37 in healthy people is extremely low and overexpressed in RA patients, and the serum level of IL-37 in RA patients is positively correlated with the level of pro-inflammation cytokines such as tumor necrosis factor-α (TNF-α), IL-6 and IL-1α, the level of C reactive protein and 28-joint disease activity score (DAS28). However, IL-37 treatment can alleviate the inflammation and pathological symptoms of collagen-induced arthritis (CIA) mice, which indicates that IL-37 has anti-inflammatory effect via negative feedback. The specific anti-inflammatory mechanism may be related to mothers against decapentaplegic homolog 3 (SMAD3) pathway and nuclear factor kappa-B (NF-κB) pathway. This article reviews the structure and expression of IL-37, the receptor and its signal pathway and the function and its mechanism in RA, which provides references for the further study of IL-37 and RA.

Expression of the recombinant precursor and putative mature forms of human Interleukin-37 Isoform B (IL-37b) in E. coli expression system

@#<p style="text-align: justify;"><strong>BACKGROUND AND OBJECTIVES: </strong>IL-37b is a cytokine that may exist in several forms, including a full-length precursor protein and its putative mature forms (IL-37b cleaved at E21, 146, and K53, respectively). In recent years, the role of IL-37b has been associated with the regulation of inflammation and inflammatory diseases. Previous studies focused on the intracellular activity of the cytokine, while the bioactivities of its variants when introduced in the extracellular environment has been limited and require further investigation. To enable this, the study produced precursor and truncated forms of IL-37b in an E.coli expression system.</p><p style="text-align: justify;"><strong>METHODOLOGY:</strong> Recombinant proteins of the full-length (FL) and shorter forms (E21, 146, and K53) of IL-37b were produced in IPTG-induced E. coli BL21-CodonPlus(DE3)-RIPL strain and subsequently purified using Ni2+ NTA affinity, ion exchange, and size exclusion chromatography. The identity of the proteins was confirmed through western blotting and LC-MS.</p><p style="text-align: justify;"><strong>RESULTS:</strong> Findings showed that the masses of the expressed proteins correspond to their respective theoretical masses with 24,134.75 +0.04 Da for FL, 21,919.63 +0.80 Da for E21, 19,298.57 +0.04 Da for 146, and 18,551.21 +0.04 Da for K53 at 90-95% purity. This confirms that the correct proteins have been produced and at high purity. Further, the tendency of FL to homodimerize was observed in this study, which may have implications in the extracellular processing and bioactivity of FL.</p><p style="text-align: justify;"><strong>CONCLUSION:</strong> This study describes the successful expression and purification of recombinant precursor and putative mature forms of IL-37b in E.coli, which can be utilized for downstream characterization. </p>

Construction and characterization of a eukaryotic expression vector of full-length and mature IL-37b / 中国比较医学杂志

Objective To construct a eukaryotic expression vector pEGFP N1/IL-37b of full-length and mature IL-37b,and to detect the expression of both full-length and mature IL-37b in RAW 264.7 cells, a mouse macrophage cell line. Methods To construct the eukaryotic vectors of full-length and mature IL-37b by using plasmid pUBC/IL-37b as a template containing the coding region of IL-37b full-length gene. To detect the expression of IL-37b by western blot and confocal microscopy after transfected the recombinant plasmid into RAW 264.7 cells, and to detect the inhibition of full-length and mature IL-37b on IL-6 production by real-time PCR. Results Eukaryotic vectors pEGFP N1/IL-37b expressed full-length and mature IL-37b after transfection in cells, which inhibited LPS-induced IL-6 production. Conclusions Eukaryotic vectors of full-length and mature IL-37b can be successfully constructed,and lays a foundation for further study of anti-inflammation functions and mechanisms of IL-37b.

Establishment of a double antibody sandwich ELISA for detection of human IL-37 / 中国免疫学杂志

Objective:To establish a double antibody sandwich ELISA assay for detection of human IL-37 in serum.Methods: Mouse anti-human IL-37 monoclonal antibody was used as capturing antibody,rabbit anti-human IL-37 polyclonal antibodies served as detection antibody,HRP labeled goat anti-rabbit IgG employed as second antibody and recombinant human IL-37 protein used as reference standard for the establishment of a doubleantibody sandwich ELISA.The working conditions were optimized,such as sensitivity,linear range,reproducibility and evaluated the serum IL-37 in patients with Dengue fever.Results: The sensitivity of the established ELISA method was 1.465 μg/L approximately.Likewise,the linearity range of this method was about (1.465-46.875) μg/L.Further,the co efficient of variation (CV) of inter-batch and intra-batch in this study were 6.6％ and 11.7％,respectively.Notably,this method could be used in the detection of IL-37 in serum of the patients with Dengue fever,showing that the level of IL-37 in Dengue fever patients was much higher than that in healthy controls.Conclusion: The double antibody sandwich ELISA assay for the detection of human IL-37 was successfully established,which can be apply to detect of human IL-37 in clinical samples.

Expression, purification and activity assay of human IL-37b in E.coli / 中国比较医学杂志

Objective To investigate the expression of recombinant IL-37b protein and removal of the endotoxin, and identify its biological activity.Methods The prokaryotic expression vector pET28/IL-37b was constructed and to transform Escherichia coli (E.coli) Rosetta.After induction with IPTG, the recombinant protein was purified through Ni2+-NTA gel column and identified by SDS-PAGE and Coomassie brilliant blue staining.Then, the endotoxin protein was removed and was treated with LPS-stimulated RAW 264.7 cells.The culture supernatant was collected.The expression of IL-6 was detected by ELISA and the biological activity of the protein was identified.Results The recombinant IL-37b with high purity was expressed and the endotoxin produced by prokaryotic expression was reduced, and it was identified to have good biological activity.Conclusions In this study a recombinant IL-37b protein with high biological activity is successfully obtained.

Increasing Expression of IL-3 7 in Peripheral Blood Mononuclear Cell of Patients with Primary Biliary Cirrhosis and Its Clinical Significance / 现代检验医学杂志

Objective To test the expression level of IL-37 in peripheral blood mononuclear cells (PBMCs)of patients with primary biliary cirrhosis (PBC)and further explore its clinical significance in the pathological process of PBC.Methods Pe-ripheral blood samples were collected from 42 patients diagnosed as PBC and 38 health individuals examined at the same time during June 2013 to August 2015 in Changhai Hospital.PBMCs were separated by sucrose density gradient centrifugation, qualified Real Time-Polymerase Chain Reaction (qRT-PCR)was used to measure IL-37 mRNA expression level in PBMCs. Enzyme-Linked Immuno Sorbent Assay (ELISA)was to measure the protein level of IL-37,IL-6,IL-17,TNF-α,TGF-β,IL-18 and IL-23 in plasma.Meanwhile,the pathological stages of PBC cases were recorded.Pearson correlation analysis was performed on IL-37 and IL-6,TNF-α,IL-17,TGF-β,IL-18 and IL-23.Spearman rank correlation analysis was on IL-37 and pathological stages of PBC.Results The mRNA and protein level of IL-37 in experimental and controlled group were 2.81 ±0.94 vs 1.09±0.56,356.14±169.36 pg/ml vs 86.68±48.23 pg/ml separately(t=9.811,9.462,P<0.000 1),with sta-tistical differences.The correlation analysis showed that IL-37 was positively related with IL-17,TNF-α,IL-6 and TGF-β(r=0.561 2,0.661 9,0.672 1,0.765 3,P<0.001),and disease stages (Ⅰ~Ⅳ)(rs=0.348 9,P<0.05).Conclusion IL-37 might involve in the pathological process of PBC,and it is significant for disease prediction and diagnosis.

IL-37 protects hepatocyte injury against hypoxia/reoxygenation by promoting polarization of M2-type macrophages / 复旦学报（医学版）

Objective To investigate the protective effect of IL-37 on hepatocyte injury against hypoxia/reoxygenation (H/R) by promoting polarization of M2-type macrophages and its molecular mechanisms.Methods Real-time fluorescent quantitative PCR (qRT-PCR) and Western blot were used to detect the levels of IL-37 mRNA and protein in human monocyte-macrophage THP-1 cells with different polarizations.The lentivirus with IL-37 gene was infected into THP-1 cells.The levels of CD206,CD86,ARG1 and iNOS mRNA was detected by qRT-PCR.The levels of CD163 and CD86 protein was detected by flow cytometric analysis.THP-1 cells and L02 cells were co-cultured by Transwell and treated with H/R.The survival rate and apoptotic rate of L02 cells were detected.The levels of alanine transaminase (ALT) and aspartate aminotransferase (AST) in culture medium were measured.The levels of STAT6 and its phosphorylation in THP-1 cells were detected by Western blot.Results The levels of IL-37 mRNA and protein were up-regulated in M2-type macrophages.IL-37 promoted the polarization of M2-type macropahges.M2-type macrophages induced by IL-37 were cocultured with L02 cells,the survival rate was significantly increased by H/R treatment (P =0.015),while the apoptotic rate,ALT level and AST level were significantly decreased (P＜0.001).The level of phosphorylated STAT6 in THP-1 cells overexpressing IL-37 was up-regulated (P ＜ 0.01).Conclusions IL-37 can induce polarization of M2-type macrophages and protect hepatocyte injury against H/R.Its mechanism may be related to STAT6 signal pathways.

IL-37b alleviates septic shock through inhibition of immune responses related to dendritic cells / 中国比较医学杂志

Objective To express the recombinant IL-37b protein and to investigate its role in the regulation of immune responses. Methods The prokaryotic expression vector pET28/IL-37b was constructed. The recombinant IL-37b protein was induced to be expressed and was purified using Ni2+-NTA gel column. C57BL/6 J mice were treated with IL-37b and injected with lipopolysaccharide(LPS)to induce septic shock,and the expression levels of IL-1β,IL-6,IFN-γ in the serum of the mice were detected. Dendritic cells from bone marrow of the mice were isolated and cultured, and were treated with IL-37b. After LPS-induced activation, the expression levels of marker molecules such as CD40, CD80 and MHCII on the cell surface, and cytokines such as IL-1β, IL-10, IL-12 and TNF-α in the culture supernatants were detected by flow cytometry. The CD4 +T cells from mice were isolated and the inhibitory effects of IL-37b on the expression of IFN-γ,TNF-α and IL-10 in the culture supernatants of T cells after induction by LPS were detected. Results IL-37b reduced the expression levels of proinflammatory cytokines in the serum of septic shock mice. IL-37b also inhibited the expression of co-stimulatory molecules and proinflammatory cytokines of the mouse dendritic cells, and suppress the activation of CD4 +T cells in vitro. Conclusions Purified recombinant IL-37b protein has high bioactivity, and can alleviate septic shock in organisms through inhibiting the activation of dendritic cells and related T cell immune responses.

Expression and clinical significance of interleukins-37 in patients with chronic kidney disease / 国际检验医学杂志

Objective To investigate the level change of interleukin-37(IL-37) and its clinical significance in the patients with chronic kidney disease(CKD) and nephrotic syndrome(NS) .Methods 57 cases of CKD (CKD group) and 13 cases of NS (NS group) in the Affiliated Donghua Hospital of Sun Yat-sen University from September to November 2016 were selected .The CKD group was redivided into the CKD stage 1 ,stage 3 and stage 5 groups .At the same time 22 individuals undergoing physical examina-tion were selected as the healthy control group .The ELISA sandwich method was adopted to detect the plasma IL-37 level .Then the detection results were statistically analyzed .Results The level of plasma IL-37 in the CKD group and NS group was significant-ly higher than that in the healthy control group ,the difference was statistically significant (P<0 .01);the level of plasma IL-37 had no statistical difference among the CKD stage 1 group ,CKD stage 3 group and CKD stage 5 group(P>0 .05);the plasma IL-37 lev-el after treatment in the CKD group and NS group was decreased compared with before treatment ,the difference was statistically significant(P<0 .01);the plasma IL-37 level in CKD patients was positively correlated with the WBC and lymphocyte cells levels . Conclusion The patients with CKD and NS have high level expression of plasma IL-37 ,which might have good auxiliary diagnostic value for CKD and NS .

Expression and Clinical Significance of Blood IL-37 in Patients with Chronic HBV / 现代检验医学杂志

Objective To study the expression levels of IL-37 in serum in chronic HBV(CHB)patients,and investigate their clinical significance in CHB patients.Methods The expression levels of IL-37 in serum from 35 CHB patients and 35 health-y controls were quantified by ELISA.This study also tested ALT,AST,HBsAg,HBeAg,HBV DNA,TNF-αand IL-10 in the serum of CHB patients,and also analyzed the relationship between the levels of IL-37 and ALT,AST,HBsAg,HBeAg, HBV DNA,TNF-α,IL-10 levels.Results The expression levels of IL-37 was increased in CHB patients 437.5±152.7 pg/ml compared to healthy donors(63.0±2.1 pg/ml).The difference between the two groups was statistically significant(t=2.45,P=0.017).The levels of IL-37 was found to correlate with ALT(r=0.406,P=0.019)and IL-10(r=0.433,P=0.035)but not AST,HBsAg,HBeAg,HBV DNA and TNF-α.Conclusion This study reveals the levels of IL-37 in CHB patients was higher than healthy controls,and IL-37 may play an important role in liver damage and HBV chronic infection.

Expression and significance discussion of IL-37 inhibits IL-18 in rat pulmonary fibrosis models / 中国免疫学杂志

Objective:To investigate the expression of IL-37 and IL-18 in the lung tissue of rats with bleomycin induced pulmonary fibrosis,and to explore the expression and significance of PF in the lung. Methods:45 Sprague Wistar rats were randomly divided into normal control group(N Group),bleomycin group(B group),dexamethasone group(D group),15 rats in each group. B group and D group rats were given intratracheal injection of bleomycin 4 mg/kg,pulmonary fibrosis model was made,N group was given the same volume of normal saline as control group D,rats in pulmonary fibrosis model based on second days of daily intraperitoneal injection of dexamethasone 3 mg/kg;N, B group rats were intraperitoneally injected with normal saline as control. The rats were sacrificed after modeling 7,14,28 days,HE staining was used to evaluate the lung tissue pathological changes;hydroxyproline in lung tissue was measured by alkali hydrolysis and enzyme linked immunosorbent assay(HYP),the content of IL-37,the determination of ex-pression of IL-18mRNA in lung tissue by RT-PCR. Results:①HE staining showed that B, D group of rat lung tissue pathological changes by alveolar inflammation gradually developed into liver fibrosis;B,D group HYP content increased gradually with the elapse of time,for 28 days(P<0. 05).②B,D group IL-37,the expression of IL-18mRNA on the seventh day increased to the highest point. After gradually reduced,to 28 days were higher than N group,the difference was statistically significant(P<0. 05).③The expression of IL-37 and IL-18mRNA in group D was lower than that in group B at the same time(P<0. 05). Conclusion:IL-37,IL-18 play an important role in the early stage of pulmonary fibrosis in rats,and may be involved in the occurrence and development of pulmonary fibrosis.

IL-37 inhibits osteoporosis via regulating M-CSF and inhibiting IL-6-JAK2/STAT3 signaling pathway / 中国免疫学杂志

Objective:To investigate the mechanism of IL-37 in inhibiting osteoporosis. Methods:Ninety-seven patients with osteoporosis and eighty-one fracture surgery patients without osteoporosis in our hospital from Jan 2013 to Dec 2015 were selected as study subjects. The serum level of IL-37 and IL-6 were detected. Construction of IL-37 transgenic mice, the C57BL/6J mice, IL-37 transgenic mice were set in sham operation group ( Sham ) , operation group ( ovariectomy, OVX ) respectively. The serum level of estrogen,alkaline phosphatase( ALP) ,calcium and phosphorus were detected after 8 weeks. The bilateral femur and spine of mice were collect after sacrifice,the morphology and structure of the femur were analyzed,and the bone density was measured by bone density me-ter. The bone marrow stromal cells( BMSCs) were isolated and cultured in vitro. The proliferation ability of BMSCs,expression of M-CSF and IL-6,and the activation of STAT3 were detected. IL-37 was transfected into mouse osteoblast MC3T3-E1 cell,M-CSF and IL-6 in cultured supernatant were measured by ELISA. Apoptosis of MC3T3-E1 cells were detected by flow cytometry. The activation of STAT3 was detected by Western blot. Results:The serum level of IL-37 in patients with osteoporosis were significantly lower than control group (P<0. 05),while IL-6 was significantly higher than control group(P<0. 05). The serum level of estrogen,calcium and phosphorus in OVX group of C57BL/6J mice and IL-37 transgenic mice were significantly lower than the sham operation group(P<0. 05),while the level of ALP was significantly higher than sham operation group ( P<0. 05 ) , but the serum level of calcium and phosphorus in OVX group of IL-37 transgenic mice were significantly higher than C57BL/6J mice(P<0. 05). The pathological section of femur and spine BMD showed that the bone tissue in C57BL/6J mice and IL-37 transgenic mice in OVX group were damaged and the bone density decreased significantly,but IL-37 transgenic mice was significantly better than C57BL/6J mice(P<0. 05). The proliferation ability BMSCs in OVX group of IL-37 transgenic mice was significantly higher than C57BL/6J,while the activation of STAT3 and expression of M-CSF were significantly lower than C57BL/6J(P<0. 05). The expression of M-CSF and IL-6 were inhibited after MC3T3-E1 cell was transfected with IL-37,and the activation of STAT3 were also inhibited after IL-37 transfection. The results of flow cytometry showed that IL-37 could significantly inhibit the apoptosis of MC3T3-E1 cells. Conclusion:The serum level of IL-37 in patients with osteoporosis decreased significantly. IL-37 may inhibit the proliferation of BMSCs and inhibit the apoptosis of osteoblasts by regulating the expression of M-CSF and the activation of IL-6-JAK2/STAT3 signaling pathway.

Expression and significance discussion of IL-37 inhibits IL-18 in rat pulmonary fibrosis models / 中国免疫学杂志

Objective:To investigate the expression of IL-37 and IL-18 in the lung tissue of rats with bleomycin induced pulmonary fibrosis,and to explore the expression and significance of PF in the lung. Methods:45 Sprague Wistar rats were randomly divided into normal control group(N Group),bleomycin group(B group),dexamethasone group(D group),15 rats in each group. B group and D group rats were given intratracheal injection of bleomycin 4 mg/kg,pulmonary fibrosis model was made,N group was given the same volume of normal saline as control group D,rats in pulmonary fibrosis model based on second days of daily intraperitoneal injection of dexamethasone 3 mg/kg;N, B group rats were intraperitoneally injected with normal saline as control. The rats were sacrificed after modeling 7,14,28 days,HE staining was used to evaluate the lung tissue pathological changes;hydroxyproline in lung tissue was measured by alkali hydrolysis and enzyme linked immunosorbent assay(HYP),the content of IL-37,the determination of ex-pression of IL-18mRNA in lung tissue by RT-PCR. Results:①HE staining showed that B, D group of rat lung tissue pathological changes by alveolar inflammation gradually developed into liver fibrosis;B,D group HYP content increased gradually with the elapse of time,for 28 days(P<0. 05).②B,D group IL-37,the expression of IL-18mRNA on the seventh day increased to the highest point. After gradually reduced,to 28 days were higher than N group,the difference was statistically significant(P<0. 05).③The expression of IL-37 and IL-18mRNA in group D was lower than that in group B at the same time(P<0. 05). Conclusion:IL-37,IL-18 play an important role in the early stage of pulmonary fibrosis in rats,and may be involved in the occurrence and development of pulmonary fibrosis.

IL-37 inhibits osteoporosis via regulating M-CSF and inhibiting IL-6-JAK2/STAT3 signaling pathway / 中国免疫学杂志

Objective:To investigate the mechanism of IL-37 in inhibiting osteoporosis. Methods:Ninety-seven patients with osteoporosis and eighty-one fracture surgery patients without osteoporosis in our hospital from Jan 2013 to Dec 2015 were selected as study subjects. The serum level of IL-37 and IL-6 were detected. Construction of IL-37 transgenic mice, the C57BL/6J mice, IL-37 transgenic mice were set in sham operation group ( Sham ) , operation group ( ovariectomy, OVX ) respectively. The serum level of estrogen,alkaline phosphatase( ALP) ,calcium and phosphorus were detected after 8 weeks. The bilateral femur and spine of mice were collect after sacrifice,the morphology and structure of the femur were analyzed,and the bone density was measured by bone density me-ter. The bone marrow stromal cells( BMSCs) were isolated and cultured in vitro. The proliferation ability of BMSCs,expression of M-CSF and IL-6,and the activation of STAT3 were detected. IL-37 was transfected into mouse osteoblast MC3T3-E1 cell,M-CSF and IL-6 in cultured supernatant were measured by ELISA. Apoptosis of MC3T3-E1 cells were detected by flow cytometry. The activation of STAT3 was detected by Western blot. Results:The serum level of IL-37 in patients with osteoporosis were significantly lower than control group (P<0. 05),while IL-6 was significantly higher than control group(P<0. 05). The serum level of estrogen,calcium and phosphorus in OVX group of C57BL/6J mice and IL-37 transgenic mice were significantly lower than the sham operation group(P<0. 05),while the level of ALP was significantly higher than sham operation group ( P<0. 05 ) , but the serum level of calcium and phosphorus in OVX group of IL-37 transgenic mice were significantly higher than C57BL/6J mice(P<0. 05). The pathological section of femur and spine BMD showed that the bone tissue in C57BL/6J mice and IL-37 transgenic mice in OVX group were damaged and the bone density decreased significantly,but IL-37 transgenic mice was significantly better than C57BL/6J mice(P<0. 05). The proliferation ability BMSCs in OVX group of IL-37 transgenic mice was significantly higher than C57BL/6J,while the activation of STAT3 and expression of M-CSF were significantly lower than C57BL/6J(P<0. 05). The expression of M-CSF and IL-6 were inhibited after MC3T3-E1 cell was transfected with IL-37,and the activation of STAT3 were also inhibited after IL-37 transfection. The results of flow cytometry showed that IL-37 could significantly inhibit the apoptosis of MC3T3-E1 cells. Conclusion:The serum level of IL-37 in patients with osteoporosis decreased significantly. IL-37 may inhibit the proliferation of BMSCs and inhibit the apoptosis of osteoblasts by regulating the expression of M-CSF and the activation of IL-6-JAK2/STAT3 signaling pathway.

Inhibitory effect of IL-37 on inflammation-related diseases / 中国比较医学杂志

Inteleukin-37 is a member of IL-1 family and originally named as IL-1F7.It has five different subtypes (IL-37a-e).It has been reported that IL-37 suppresses pro-inflammatory cytokines production of a variety of immune cells, and further regulate innate immune response. In addition, IL-37 has protective effects on colitis, arthritis, pancreatitis and other inflammatory diseases that induced by exogenous stimuli. In a word, IL-37 is a novel anti-inflammatory cytokine and plays an important role in a variety of inflammation-related diseases.

Plasma IL-37 levels in patients with acute coronary syndrome / 实用医学杂志

Objective To evaluate the role of plasma IL-37 levels in patients with acute coronary syndrome (ACS). Methods Plasma biomarkers IL-37, CRP and NT-proBNP levels were measured in 40 patients with stable angina pectoris (SA group), 65 patients with unstable angina pectoris (UA group), 47 patients with acute myocardial infarction (AMI group) and 60 control patients. Results The plasma IL-37, CRP and NT-proBNP levels were significantly increased in patients with ACS patients. A correlation analysis showed that the plasma IL-37 levels were positively correlated with the levels of CRP and NT-proBNP, and negatively correlated with LVEF. Conclusions The results indicated that the plasma IL-37 levels are associated with the onset of ACS symptoms.