Interleukin-37 Inhibits Interleukin-1ß-Induced Articular Chondrocyte Apoptosis by Suppressing Reactive Oxygen Species.

Objective: Chondrocyte apoptosis has been considered a crucial mechanism that is responsible for cartilage destruction in osteoarthritis (OA). The mechanism of interleukin-37 (IL-37) on chondrocyte apoptosis has not been clearly determined in the pathogenesis of OA. Here, we explored the role of IL-37 in the regulation of cellular apoptosis in rat chondrocytes stimulated by IL-1ß. Methods: Rat chondrocytes were used in in vitro study, and were stimulated with IL-1ß (10 ng/mL) and/or recombinant IL-37 (rIL-37; 100 ng/mL) after cytotoxicity assessments using these cytokines were conducted. After rIL-37 treatment of chondrocytes stimulated with IL-1ß, the cell proliferation assay, apoptosis assays, including expression of mitochondrial apoptosis-related markers, flow cytometry analysis of annexin V-FITC/propidium iodide (PI), cell cycle analysis, and Hoechst 33342 staining, and reactive oxygen species (ROS) measurement were used. Results: IL-1ß induced expression of inflammatory cytokines and triggered degradation of the extracellular matrix of rat chondrocytes, but this effect was significantly attenuated by rIL-37 treatment. Enhanced ROS generation following IL-1ß stimulation was reduced in a dose-dependent manner after stimulation with rIL-37. IL-1ß induced pro-apoptotic markers and suppressed anti-apoptotic markers in rat chondrocytes. Flow cytometry using annexin V-FITC/PI revealed that IL-1ß increased the apoptosis rate of rat chondrocytes, and that this effect was markedly reversed by treatment with rIL-37. Conclusions: IL-37 potently attenuated IL-1ß-mediated apoptosis of rat chondrocytes by blocking ROS production. This study suggests that IL-37 can serve as a novel anti-cytokine therapy in OA by blocking chondrocyte apoptosis.

The Protective Role of Interleukin-37 in Cardiovascular Diseases through Ferroptosis Modulation.

The role of ferroptosis and iron metabolism dysregulation in the pathophysiology of cardiovascular diseases is increasingly recognized. Conditions such as hypertension, cardiomyopathy, atherosclerosis, myocardial ischemia/reperfusion injury, heart failure, and cardiovascular complications associated with COVID-19 have been linked to these processes. Inflammation is central to these conditions, prompting exploration into the inflammatory and immunoregulatory molecular pathways that mediate ferroptosis and its contribution to cardiovascular disease progression. Notably, emerging evidence highlights interleukin-37 as a protective cytokine with the ability to activate the nuclear factor erythroid 2-related factor 2 pathway, inhibit macrophage ferroptosis, and attenuate atherosclerosis progression in murine models. However, a comprehensive review focusing on interleukin-37 and its protective role against ferroptosis in CVD is currently lacking. This review aims to fill this gap by summarizing existing knowledge on interleukin-37, including its regulatory functions and impact on ferroptosis in conditions such as atherosclerosis and myocardial infarction. We also explore experimental strategies and propose that targeting interleukin-37 to modulate ferroptosis presents a promising therapeutic approach for the prevention and treatment of cardiovascular diseases.

Important Roles of Interleukin-36, Interleukin-37, and Interleukin-38 Cytokines in the Pathogenesis of Rosacea.

Background: Rosacea is a chronic inflammatory skin disease. Previous studies have determined that IL-36, IL-37, and IL-38 may play a role in the pathogenesis of various inflammatory diseases. Aims and Objectives: The present study aims to evaluate the relationship of these cytokines with rosacea. Materials and Methods: A total of 100 individuals, including 50 patients with rosacea and 50 healthy controls, were included in the study. IL-36, IL-37, and IL-38 levels were measured using the ELISA method by taking serum samples from all participants. Results: The mean serum levels of IL-36, IL-37, and IL-38 in the patient group were 52.17 ± 24.07 pg/ml, 18.46 ± 8.18 pg/ml, and 25.74 ± 8.36 ng/l, respectively. The mean serum levels of IL-36, IL-37, and IL-38 in the control group were 32.99 ± 19.90 pg/ml, 44.61 ± 22.27 pg/ml, and 45.61 ± 17.32 ng/l, respectively. The difference between the serum levels of IL-36, IL-37, and IL-38 in the patient and control groups was statistically significant (P < 0.001). Conclusion: Based on these findings, an increase in IL-36 and a decrease in IL-37 and IL-38 may contribute to the pathogenesis of rosacea. Future rosacea treatments could target and/or interact with these possible steps in the pathogenesis of rosacea.

Anti-Inflammatory Effect of Atorvastatin and Rosuvastatin on Monosodium Urate-Induced Inflammation through IL-37/Smad3-Complex Activation in an In Vitro Study Using THP-1 Macrophages.

Objective: The pleiotropic effect of hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) is responsible for potent defense against inflammatory response. This study evaluated the inhibitory effects of HMG-CoA reductase inhibitors on the monosodium urate (MSU)-induced inflammatory response through the regulation of interleukin-37 (IL-37) expression. Methods: Serum was collected from patients with gout (n = 40) and from healthy controls (n = 30). The mRNA and protein expression of the target molecules IL-1ß, IL-37, caspase-1, and Smad3 were measured in THP-1 macrophages stimulated with MSU, atorvastatin, or rosuvastatin using a real-time quantitative polymerase chain reaction and Western blot assay. Transfection with IL-1ß or Smad3 siRNA in THP-1 macrophages was used to verify the pharmaceutical effect of statins in uric-acid-induced inflammation. Results: Serum IL-37 levels in gout patients were significantly higher than in controls (p < 0.001) and was associated with the serum uric acid level (r = 0.382, p = 0.008). THP-1 cells stimulated with MSU markedly induced IL-37 mRNA expression and the transition of IL-37 from the cytoplasm to the nucleus. Recombinant IL-37 treatment dose-dependently inhibited activation of caspase-1 and IL-1ß in MSU-induced inflammation. Atorvastatin and rosuvastatin attenuated caspase-1 activation and mature IL-1ß expression but augmented translocation of IL-37 from the cytoplasm to the nucleus. Atorvastatin and rosuvastatin induced phosphorylation of Smad3 in THP-1 cells treated with MSU crystals. Statins potently attenuated translocation of IL-37 from the cytoplasm to the nucleus in THP-1 macrophages transfected with Smad3 siRNA compared to cells with negative control siRNA. Conclusions: This study revealed that statins inhibit the MSU-induced inflammatory response through phosphorylated Smad3-mediated IL-37 expression in THP-1 macrophages.

IL-37 protects against house dust mite-induced airway inflammation and airway epithelial barrier dysfunction via inhibiting store-operated calcium entry.

BACKGROUND: Airway epithelial barrier dysfunction has been proved to contribute to the development of type 2 inflammation of asthma. Interleukin (IL)-37 is a negative regulator of immune responses and allergic airway inflammation. However, whether IL-37 has any effect on airway epithelial barrier has been unknown. METHODS: We evaluated the role of IL-37 in both mouse model and cultured 16HBE cells. Histology and ELISA assays were used to evaluate airway inflammation. FITC-dextran permeability assay was used to evaluate the airway epithelial barrier function. Immunofluorescence, western blot and quantitative Real-Time PCR (RT-PCR) were used to evaluate the distribution and expression of tight junction proteins. RT-PCR and Ca2+ fluorescence measurement were used to evaluate the mRNA expression and activity of store-operated calcium entry (SOCE). RESULTS: IL-37 inhibited house dust mite (HDM)-induced airway inflammation and decreased the levels of IgE in serum and type 2 cytokines in bronchoalveolar lavage fluid (BALF) compared to asthmatic mice. IL-37 protected against HDM-induced airway epithelial barrier dysfunction, including reduced leakage of FITC-dextran, enhanced expression of TJ proteins, and restored the membrane distribution of TJ proteins. Moreover, IL-37 decreased the level of IL-33 in the BALF of asthmatic mice and the supernatants of HDM-treated 16HBE cells. IL-37 decreased the peak level of Ca2+ fluorescence induced by thapsigargin and HDM, and inhibited the mRNA expression of Orai1, suggesting an inhibiting effect of IL-37 on SOCE in airway epithelial cells. CONCLUSION: IL-37 plays a protective role in airway inflammation and HDM-induced airway epithelial barrier dysfunction by inhibiting SOCE.

IL-37 possesses both anti-inflammatory and antiviral effects against Middle East respiratory syndrome coronavirus infection.

BACKGROUND: The aim was to elucidate the function of IL-37 in middle east respiratory syndrome coronavirus (MERS-CoV) infection, thereby providing a novel therapeutic strategy for managing the clinical treatment of inflammatory response caused by respiratory virus infection. METHODS: We investigated the development of MERS by infecting hDPP4 mice with hCoV-EMC (107 TCID50 [50% tissue culture infectious dose]) intranasally. We infected A549 cells with MERS-CoV, which concurrently interfered with IL-37, detecting the viral titer, viral load, and cytokine expression at certain points postinfection. Meanwhile, we administered IL-37 (12.5 µg/kg) intravenously to hDPP4 mice 2 h after MERS-CoV-2 infection and collected the serum and lungs 5 days after infection to investigate the efficacy of IL-37 in MERS-CoV infection. RESULTS: The viral titer of MERS-CoV-infected A549 cells interfering with IL-37 was significantly reduced by 4.7-fold, and the viral load of MERS-CoV-infected hDPP4 mice was decreased by 59-fold in lung tissue. Furthermore, the administration of IL-37 suppressed inflammatory cytokine and chemokine (monocyte chemoattractant protein 1, interferon-γ, and IL-17A) expression and ameliorated the infiltration of inflammatory cells in hDPP4 mice. CONCLUSION: IL-37 exhibits protective properties in severe pneumonia induced by MERS-CoV infection. This effect is achieved through attenuation of lung viral load, suppression of inflammatory cytokine secretion, reduction in inflammatory cell infiltration, and mitigation of pulmonary injury.

Neutrophil-derived nanovesicles deliver IL-37 to mitigate renal ischemia-reperfusion injury via endothelial cell targeting.

Renal ischemia-reperfusion injury (IRI) is one of the most important causes of acute kidney injury (AKI). Interleukin (IL)-37 has been suggested as a novel anti-inflammatory factor for the treatment of IRI, but its application is still limited by its low stability and delivery efficiency. In this study, we reported a novel engineered method to efficiently and easily prepare neutrophil membrane-derived vesicles (N-MVs), which could be utilized as a promising vehicle to deliver IL-37 and avoid the potential side effects of neutrophil-derived natural extracellular vesicles. N-MVs could enhance the stability of IL-37 and targetedly deliver IL-37 to damaged endothelial cells of IRI kidneys via P-selectin glycoprotein ligand-1 (PSGL-1). In vitro and in vivo evidence revealed that N-MVs encapsulated with IL-37 (N-MV@IL-37) could inhibit endothelial cell apoptosis, promote endothelial cell proliferation and angiogenesis, and decrease inflammatory factor production and leukocyte infiltration, thereby ameliorating renal IRI. Our study establishes a promising delivery vehicle for the treatment of renal IRI and other endothelial damage-related diseases.

Role of Platelet/Lymphocyte, Neutrophil/Lymphocyte, and Interleukin-37/Interleukin-17 Ratios in the Occurrence and Treatment of Rheumatoid Arthritis.

This study was designed to investigate the correlation of neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and interleukin (IL)-37/IL-17 ratio with the incidence/treatment of rheumatoid arthritis (RA). Firstly, fifty-eight patients with RA treated at the first affiliated hospital of Xinjiang Medical University from January 2018 to January 2019 were selected as the RA group; forty-nine healthy volunteers were enrolled in the control group. RA patients were treated with disease-modifying anti-rheumatic drugs (DMARDs). Next, the NLR, PLR, IL-37, IL-17 and 28-joint disease activity score using erythrocyte sedimentation rate (DAS28-ESR) were deleted in two groups. Subsequently, Spearman correlation analysis was adopted for the correlations of various indicators before and after treatment in two groups. According to the analysis results, the levels of NLR, PLR, IL-37, and IL-17 before treatment in the RA group were higher than those in the control group (P < .05), but the difference in the IL-37/IL-17 level between the two groups was not significant (P > .05). After treatment, NLR, PLR, and IL-37/IL-17 levels were significantly reduced in RA patients (P < .05). NLR and PLR were significantly positively correlated with DAS28-ESR, ESR and C-reactive protein (CRP), of which represented the disease activity of RA. NLP was strongly correlated with IL-37/IL-17. Collectively, NLR, PLR, IL-37, and IL-17 are closely related to the occurrence of RA. In addition, NLR and IL-37/IL-17 are more suitable than PLR in reflecting the therapeutic effect. Therefore, IL-37/IL-17 can be considered as a new indicator for reflecting the treatment effectiveness of RA.

Serum Levels of Interleukins in Endometriosis Patients: A Systematic Review and Meta-analysis.

OBJECTIVE: The aims of this systematic review and meta-analysis were to produce a comprehensive survey of the serum levels of interleukins (ILs) in untreated people with endometriosis compared with people without endometriosis. DATA SOURCES: A systematic literature search of English language studies within Cinahl, Medline Complete, PubMed, and Scopus from inception to May 2023 was performed. METHODS OF STUDY SELECTION: We included studies that compared IL serum levels in people with endometriosis to those without endometriosis. Meta-analysis was performed on IL-1RA, IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-17A, IL-18, IL-23, and IL-37. TABULATION, INTEGRATION, AND RESULTS: The systematic search retrieved 651 studies, of which 77 underwent a full-text review. A total of 30 studies met inclusion criteria for the meta-analysis. IL-1Ra, IL-6, and IL-37 serum levels were 2.56 (95% CI 2.20-2.92, p <.001), 1.38 (95% CI 0.58-2.17, p <.001), and 1.77 (95% CI 1.33-2.20, p <.001) standard deviations higher in the patients with endometriosis compared with patients without endometriosis while IL-23 serum levels 0.40 (95% CI -0.73 to -0.07, p = .02) standard deviations lower, respectively. CONCLUSION: There is mounting evidence that ILs, especially IL-6, may be good candidates for unique noninvasive diagnostic tools and/or treatment pathways for endometriosis.

The multi-protective effect of IL-37-Smad3 against ox-LDL induced dysfunction of endothelial cells.

Atherosclerosis is a lipid-driven inflammatory arterial disease, with one crucial factor is oxidized low-density lipoprotein (ox-LDL), which can induce endothelial dysfunction through endoplasmic reticulum stress (ERS). Interleukin-37 (IL-37) exerts vascular protective functions. This study aims to investigates whether IL-37 can alleviate ERS and autophagy induced by ox-LDL, therely potentialy treating atherosclerosis. We found that ox-LDL enhances the wound healing rate in Rat Coronary Artery Endothelial Cells (RCAECs) and IL-37 reduce the ox-LDL-induced pro-osteogenic response, ERS, and autophagy by binding to Smad3. In RCAECs treated with ox-LDL and recombinant human IL-37, the wound healing rate was mitigated. The expression of osteogenic transcription factors and proteins involved in the ERS pathway was reduced in the group pretreated with IL-37 and ox-LDL. However, these responses were not alleviated when Smads silenced. Electron microscopy revealed that the IL-37/Smad3 complex could suppress endoplasmic reticulum autophagy under ox-LDL stimulation. Thus, IL-37 might treat atherosclerosis through its multi-protective effect by binding Smad3.

IL-37 dampens immunosuppressive functions of MDSCs via metabolic reprogramming in the tumor microenvironment.

Interleukin-37 (IL-37) has been shown to inhibit tumor growth in various cancer types. However, the immune regulatory function of IL-37 in the tumor microenvironment is unclear. Here, we established a human leukocyte antigen-I (HLA-I)-matched humanized patient-derived xenograft hepatocellular carcinoma (HCC) model and three murine orthotopic HCC models to study the function of IL-37 in the tumor microenvironment. We found that IL-37 inhibited HCC growth and promoted T cell activation. Further study revealed that IL-37 impaired the immunosuppressive capacity of myeloid-derived suppressor cells (MDSCs). Pretreatment of MDSCs with IL-37 before adoptive transfer attenuated their tumor-promoting function in HCC tumor-bearing mice. Moreover, IL-37 promoted both glycolysis and oxidative phosphorylation in MDSCs, resulting in the upregulation of ATP release, which impaired the immunosuppressive capacity of MDSCs. Collectively, we demonstrated that IL-37 inhibited tumor development through dampening MDSCs' immunosuppressive capacity in the tumor microenvironment via metabolic reprogramming, making it a promising target for future cancer immunotherapy.

Relationship between Cytokines and Metabolic Syndrome Components: Role of Pancreatic-Derived Factor, Interleukin-37, and Tumor Necrosis Factor-α in Metabolic Syndrome Patients.

The metabolic syndrome (MetS) is a serious public health issue that affects people all over the world. Notably, insulin resistance, prothrombotic activity, and inflammatory state are associated with MetS. This study aims to explore the relationship between cytokines and tumor necrosis factor-α (TNF-α), pancreatic-derived factor (PANDER), and interleukin (IL-)-37 and the accumulation of MetS components. Eligible participants were divided into four groups as follows: group 1, patients with dyslipidemia; group 2, patients with dyslipidemia and obesity; group 3, patients with dyslipidemia, obesity, and hypertension; and group 4, patients with dyslipidemia, obesity, hypertension, and hyperglycemia. This study exhibited that serum levels of TNF-α and PANDER were significantly elevated (P < 0.001) in the MetS groups, while IL-37 level and IL-37 mRNA expression were significantly decreased (P < 0.001) relative to healthy controls. Moreover, this study has revealed significant correlations (P < 0.001) between MetS components and TNF-α, PANDER, and IL-37 levels in MetS patients. The aforementioned results suggested the association between the proinflammatory cytokine (TNF-α and PANDER) and anti-inflammatory cytokine (IL-37) with the accumulation of MetS components. Hence, the overall outcome indicated that PANDER and IL-37 may be considered novel biomarkers associated with increased risk of MetS and can be used as a promising therapeutic target in preventing, ameliorating, and treating metabolic disorders. Supplementary Information: The online version contains supplementary material available at 10.1007/s12291-022-01079-z.

Expression of interleukin-37 in patients with diabetic kidney disease and its regulatory activity to the cytotoxic function of CD8 +T lymphocytes / 中华肾脏病杂志

Objective:To investigate interleukin-37 (IL-37) expression in patients with diabetic kidney disease (DKD), and to assess the regulation of exogenous IL-37 on CD8 + T cell function in DKD patients. Methods:A cross-section study was carried out. Twenty healthy controls, thirty-six patients with diabetes mellitus type 2 (T2DM), and forty-seven DKD patients were enrolled in the study. Peripheral blood was collected. Plasma and peripheral blood mononuclear cells were isolated. IL-37 and soluble IL-1 receptor 8 (IL-1R8) levels in the plasma were measured by enzyme-linked immunosorbent assay (ELISA). IL-18 receptor α chain (IL-18Rα), IL-1R8 and immune checkpoint molecules levels in CD8 + T cells were measured by flow cytometry. CD8 + T cells were purified, and were stimulated with recombinant IL-37. CD8 + T cells were co-cultured with HEK293 cells in either direct contact or indirect contact manner. Levels of perforin, granzyme B, interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) were measured by ELISA. The proportion of target cell death was assessed by measuring lactate dehydrogenase level. Results:Plasma IL-37 levels in DKD patients [(63.42±23.30) ng/L] were significant lower than those in healthy controls [(143.02±50.67) ng/L] and T2DM patients [(87.88±40.62) ng/L] ( t=8.848, P<0.001; t=3.456, P<0.001). Plasma IL-37 level had good predictive values for T2DM in health individuals and for DKD in T2DM patients [the area under the curve was 0.797 (95% CI 0.676-0.917, P<0.001) and 0.691 (95% CI 0.576-0.807, P=0.003), respectively]. Plasma IL-37 level was negatively correlated with urea nitrogen ( r=-0.313, P=0.032) and creatinine ( r=-0.477, P<0.001), and positively correlated with estimated glomerular filtration rate (eGFR) ( r s=0.478, P<0.001) in DKD patients. IL-1R8 + CD8 + cell proportion in DKD patients (33.60%±9.47%) was significantly higher compared to healthy controls (16.29%±5.97%) and T2DM patients (17.13%±4.85%) ( t=7.545, 9.516, both P<0.001), but did not correlate with fast blood glucose, urea nitrogen, creatinine, or eGFR (all P>0.05). There were no statistical differences of IL-18Rα + CD8 + cell proportion, soluble IL-1R8 level, or immune checkpoint molecule proportion in CD8 + T cells among healthy controls, T2DM patients, and DKD patients (all P>0.05). Perforin and granzyme B secretions by CD8 + T cells were significantly elevated in DKD patients compared with healthy controls [(108.78±12.42) ng/L vs. (94.60±10.07) ng/L, t=3.096, P=0.005; (261.34±48.79) ng/L vs. (166.28±30.80) ng/L, t=3.387, P=0.002] and T2DM patients [(108.78±12.42) ng/L vs. (92.58±14.71) ng/L, t=3.263, P=0.003; (261.34±48.79) ng/L vs. (170.66±39.24) ng/L, t=2.627, P=0.014]. There were no significant differences of either IFN-γ or TNF-α secretions by CD8 + T cells among healthy controls, T2DM patients, and DKD patients (all P>0.05). In direct contact co-culture manner, CD8 + T cell-induced HEK293 cell death was down- regulated (13.03%±4.97% vs. 17.88%±5.19%, t=2.235, P=0.037). The levels of perforin [(222.02±25.79) ng/L vs. (294.30±25.58) ng/L, t=6.603, P<0.001], granzyme B [(416.27±90.24) ng/L vs. (524.71±115.53) ng/L, t=2.454, P=0.023], IFN-γ [(23.66±4.20) ng/L vs. (35.18±8.51) ng/L, t=4.026, P<0.001] and TNF-α [(1.62±0.29) μg/L vs. (2.09±0.57) μg/L, t=2.302, P=0.034] were also reduced as well. In indirect contact co-culture manner, there were no significant differences of CD8 + T cell-induced HEK293 cell death, perforin, or granzyme B levels between no stimulation and IL-37 stimulation (all P>0.05). IFN-γ and TNF-α levels in the supernatants were reduced in response to IL-37 stimulation [(23.56±6.24) ng/L vs. (32.56±9.90) ng/L, t=2.550, P=0.019; (1.41±0.31) μg/L vs. (2.10±0.44) μg/L, t=4.011, P<0.001]. Conclusion:IL-37 level is reduced in DKD patients.Exogenous IL-37 suppresses the cytotoxicity of CD8 + T cells in DKD patients.

Levels of IL-37 and CCL11 in serum of pregnant women infected with group B streptococcus in late pregnancy and their predictive efficacy for maternal and infant outcomes / 国际检验医学杂志

Objective To explore the levels of interleukin-37(IL-37)and CC type modified chemokine 11(CCL11)in serum of pregnant women infected with group B streptococcus in late pregnancy and their predic-tive efficacy for maternal and infant outcomes.Methods A total of 86 pregnant women with reproductive tract B streptococcus infection in late pregnancy treated in the hospital from December 2020 to December 2022 were selected as the study group,and 76 pregnant women with normal physical examination admitted during the same period were selected as the control group.The levels of IL-37 and CCL11 in serum of all pregnant women were detected by enzyme-linked immunosorbent assay.According to whether the pregnant women with group B streptococcus infection in late pregnancy had adverse maternal and infant outcomes,they were divided into normal pregnancy outcome group(50 cases)and adverse pregnancy outcome group(36 cases).Receiver operating characteristic(ROC)curve was used to evaluate the diagnostic value of serum IL-37 and CCL11 on maternal and infant outcomes of pregnant women with reproductive group B streptococcus infection in late pregnancy.Multivariate Logistic regression was used to analyze the factors affecting maternal and in-fant outcomes of pregnant women with reproductive group B streptococcus infection in late pregnancy.Results The levels of IL-37 and CCL11 in the study group were higher than those in the control group(P<0.05).The incidence rate of adverse outcomes in the study group was significantly higher than that in the control group(P<0.05).The proportion of abortion history and the proportion of vaginal microecological disorders and levels of IL-37 and CCL11 and in adverse pregnancy outcome group were higher than those in normal pregnancy outcome group(P<0.05).ROC curve results showed that the area under the curve(AUC)of IL-37 and CCL11 for predicting adverse maternal and infant outcomes of pregnant women infected with group B streptococcus in late pregnancy were 0.876(95%CI:0.824-0.920)and 0.788(95%CI:0.748-0.830),re-spectively.The AUC of the combined prediction of adverse maternal and infant outcomes of pregnant women infected with group B streptococcus were 0.927(95%CI:0.889-0.970).Multivariate Logistic regression a-nalysis results showed that serum IL-37(OR=3.604,95%CI:2.106-6.166),CCL11(OR=4.250,95%CI:2.074-8.709),abortion history(OR=2.707,95%CI:1.688-4.342)and vaginal microecological disorders(OR=3.504,95%CI:1.993-6.162)were risk factors for adverse maternal and infant outcomes in pregnant women infected with group B streptococcus in late pregnancy(P<0.05).Conclusion The levels of IL-37 and CCL11 in serum of pregnant women infected with reproductive group B streptococcus in late pregnancy are in-creased,which are related to adverse pregnancy outcomes,and are expected to be effective indicator for predic-ting adverse pregnancy outcomes of pregnant women infected with reproductive group B streptococcus in late pregnancy.

Interleukin-37 contributes to endometrial regenerative cell-mediated immunotherapeutic effect on chronic allograft vasculopathy.

BACKGROUND AIMS: Chronic allograft vasculopathy (CAV) remains a predominant contributor to late allograft failure after organ transplantation. Several factors have already been shown to facilitate the progression of CAV, and there is still an urgent need for effective and specific therapeutic approaches to inhibit CAV. Human mesenchymal-like endometrial regenerative cells (ERCs) are free from the deficiencies of traditional invasive acquisition methods and possess many advantages. Nevertheless, the exact immunomodulation mechanism of ERCs remains to be elucidated. METHODS: C57BL/6 (B6) mouse recipients receiving BALB/c mouse donor abdominal aorta transplantation were treated with ERCs, negative control (NC)-ERCs and interleukin (IL)-37-/-ERCs (ERCs with IL-37 ablation), respectively. Pathologic lesions and inflammatory cell infiltration in the grafts, splenic immune cell populations, circulating donor-specific antibody levels and cytokine profiles were analyzed on postoperative day (POD) 40. The proliferative capacities of Th1, Th17 and Treg subpopulations were assessed in vitro. RESULTS: Allografts from untreated recipients developed typical pathology features of CAV, namely endothelial thickening, on POD 40. Compared with untreated and IL-37-/-ERC-treated groups, IL-37-secreting ERCs (ERCs and NC-ERCs) significantly reduced vascular stenosis, the intimal hyperplasia and collagen deposition. IL-37-secreting ERCs significantly inhibited the proliferation of CD4+T cells, reduced the proportions of Th1 and Th17 cells, but increased the proportion of Tregs in vitro. Furthermore, in vitro results also showed that IL-37-secreting ERCs significantly inhibited Th1 and Th17 cell responses, abolished B-cell activation, diminished donor-specific antibody production and increased Treg proportions. Notably, IL-37-secreting ERCs remarkably downregulated the levels of pro-inflammatory cytokines (interferon-γ, tumor necrosis factor-α, IL-1ß, IL-6 and IL-17A) and increased IL-10 levels in transplant recipients. CONCLUSIONS: The knockdown of IL-37 dramatically abrogates the therapeutic ability of ERCs for CAV. Thus, this study highlights that IL-37 is indispensable for ERC-mediated immunomodulation for CAV and improves the long-term allograft acceptance.

Potential Role of IL-37 in Atopic Dermatitis.

Interleukin 37 (IL-37) is a recently discovered member of the IL-1 cytokine family that appears to have anti-inflammatory and immunosuppressive effects in various diseases. IL-37 acts as a dual-function cytokine, exerting its effect extracellularly by forming a complex with the receptors IL-18 α (IL-18Rα) and IL-1R8 and transmitting anti-inflammatory signals, as well as intracellularly by interacting with Smad3, entering the nucleus, and inhibiting the transcription of pro-inflammatory genes. Consequently, IL-37 is linked to IL-18, which plays a role in the pathogenesis of atopic dermatitis (AD), consistent with our studies. Some isoforms of IL-37 are expressed by keratinocytes, monocytes, and other skin immune cells. IL-37 has been found to modulate the skewed T helper 2 (Th2) inflammation that is fundamental to the pathogenesis of AD. This review provides an up-to-date summary of the function of IL-37 in modulating the immune system and analyses its potential role in the pathogenesis of AD. Moreover, it speculates on IL-37's hypothetical value as a therapeutic target in the treatment of AD.

[Expression of interleukin-37, vascular endothelial growth factor A, and transforming growth factor-ß1 and their correlation with T cells in children with primary immune thrombocytopenia]. / å„¿ç«¥åŽŸå‘å ç–«æ€§è¡€å°æ¿å‡å°‘ç—‡IL-37、VEGFA、TGF-ß1çš„è¡¨è¾¾åŠå ¶ä¸ŽTç»†èƒžçš„ç›¸å ³æ€§ç ”ç©¶.

OBJECTIVES: To investigate the expression of interleukin-37 (IL-37), vascular endothelial growth factor A (VEGFA), and transforming growth factor-ß1 (TGF-ß1) in children with primary immune thrombocytopenia (ITP) and their correlation with T cells. METHODS: A retrospective analysis was conducted on 45 children with ITP (ITP group) who were admitted to Handan Central Hospital from January 2020 to April 2022, and 30 healthy children who underwent physical examination during the same period were included as the healthy control group. The mRNA expression levels of IL-37, VEGFA, and TGF-ß1 and the levels of regulatory T cells (Treg) and helper T cells 17 (Th17) were measured before and after treatment, and the correlation between the mRNA expression levels of IL-37, VEGFA, and TGF-ß1 and the levels of Treg, Th17, and Treg/Th17 ratio were analyzed. RESULTS: Compared with the healthy control group, the ITP group had a significantly higher mRNA expression level of IL-37 and a significantly higher level of Th17 before and after treatment, as well as significantly lower mRNA expression levels of VEGFA and TGF-ß1 and significantly lower levels of Treg and Treg/Th17 ratio (P<0.05). After treatment, the ITP group had significant reductions in the mRNA expression level of IL-37 and the level of Th17 and significant increases in the mRNA expression levels of VEGFA and TGF-ß1 and the levels of Treg and Treg/Th17 ratio (P<0.05). Correlation analysis showed that in the ITP group, the mRNA expression levels of IL-37 and TGF-ß1 were negatively correlated with the levels of Treg and Treg/Th17 ratio (P<0.05) and were positively correlated with the level of Th17 (P<0.05) before and after treatment; the mRNA expression level of VEGFA was positively correlated with the levels of Treg and Treg/Th17 ratio (P<0.05) and was negatively correlated with the Th17 level (P<0.05) before and after treatment. CONCLUSIONS: Abnormal expression levels of IL-37, VEGFA, and TGF-ß1 may be observed in children with ITP, which is significantly associated with the imbalance of Treg/Th17 ratio. It is speculated that the cytokines such as IL-37, VEGFA, and TGF-ß1 may be involved in the development and progression of ITP or may become important potential targets for the treatment of children with ITP. Citation:Chinese Journal of Contemporary Pediatrics, 2023, 25(11): 1131-1136.

[Effect of Hispidulin on Proliferation and Apoptosis of Leukemia K562 Cells by Up-Regulating IL-37].

OBJECTIVE: To investigate the effect and underlying mechanism of hispidulin on the proliferation and apoptosis of leukemia K562 cells. METHODS: K562 cells were cultured in vitro and treated with 0, 5, 25 or 100 µmol/L hispidulin for 24 h. Cell proliferation and apoptosis were detected by CCK-8 and flow cytometry, respectively. Western blot was used to assess the expression of Bax, Bcl-2 and interleukin (IL)-37 proteins. Bone marrow mononuclear cells were extracted from 17 chronic myeloid leukemia patients and 21 healthy individuals by Ficoll-Hypaque density gradient method, and the expression of IL-37 protein was measured by Western blot. K562 cells with IL-37 overexpression or knockdown were constructed, and then treated with 0 or 100 µmol/L hispidulin for 24 h. Cell proliferation, apoptosis and protein expression of Bax and Bcl-2 were determined in the same way as above. RESULTS: After K562 cells were treated with hispidulin, the cell inhibition rate, apoptosis rate, and the protein expression of Bax and IL-37 were significantly increased (P <0.05), but the cell proliferation and expression of Bcl-2 protein were decreased (P <0.05). The expression of IL-37 protein in bone marrow mononuclear cells of the leukemia patient was 0.24±0.03, which was significantly lower than 0.91±0.05 of healthy controls (P <0.05). Overexpression of IL-37 significantly promoted inhibition rate, apoptosis rate, and expression of Bax protein in K562 cells (P <0.05), but suppressed the expression of Bcl-2 protein (P <0.05). In addition, knockdown of IL-37 could reverse the effects of hispidulin on proliferation and apoptosis of K562 cells. CONCLUSION: Hispidulin inhibits the proliferation and induces apoptosis of leukemia K562 cells, which may be related to the up-regulation of IL-37 protein in cells.

Correlation analysis of IL-37 gene polymorphisms and susceptibility to chronic HBV infection among Han people in Central China.

Hepatitis B virus (HBV) is responsible for various liver diseases, such as chronic hepatitis B (CHB), liver fibrosis, liver cirrhosis (LC) and hepatocellular carcinoma (HCC), which pose a significant threat to human health. An ineffective immune response to HBV can result in viral chronicity. Interleukin-37 (IL-37), an immunomodulator, is capable of inhibiting both innate and adaptive immune responses. It is believed that single nucleotide polymorphisms (SNPs) within the IL-37 gene could contribute to the regulation of HBV clearance. Our aim to conduct this study was to investigate whether SNPs in the IL-37 gene were associated with the risk of chronic HBV infection in adults. A total of 342 participants, consisting of 171 cases and 171 controls, were recruited for this study. Sanger sequencing was employed for genotyping six SNPs (rs3811042 G/A, rs3811043 G/C, rs2466449 A/G, rs3811045 C/T, rs3811046 T/G and rs3811047G/A). There was no significant difference in allele and genotype distribution between the two groups, and the constructed haplotypes were not found to be associated with the risk of chronic HBV infection. Our results revealed that there was no relationship between these six SNPs (rs3811042G/A, rs3811043G/C, rs2466449A/G, rs3811045C/T, rs3811046T/G and rs3811047G/A) in the IL-37 gene and susceptibility to chronic HBV infection among Han people in Central China.