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Pulmonary arterial hypertension (PAH) is characterized by stenosis and occlusions of small pulmonary arteries, leading to elevated pulmonary arterial pressure and right heart failure. Although accumulating evidence shows the importance of interleukin (IL)-6 in the pathogenesis of PAH, the target cells of IL-6 are poorly understood. Using mice harboring the floxed allele of gp130, a subunit of the IL-6 receptor, we found substantial Cre recombination in all hematopoietic cell lineages from the primitive hematopoietic stem cell level in SM22α-Cre mice. We also revealed that a CD4+ cell-specific gp130 deletion ameliorated the phenotype of hypoxia-induced pulmonary hypertension in mice. Disruption of IL-6 signaling via deletion of gp130 in CD4+ T cells inhibited phosphorylation of signal transducer and activator of transcription 3 (STAT3) and suppressed the hypoxia-induced increase in T helper 17 cells. To further examine the role of IL-6/gp130 signaling in more severe PH models, we developed Il6 knockout (KO) rats using the CRISPR/Cas9 system and showed that IL-6 deficiency could improve the pathophysiology in hypoxia-, monocrotaline-, and Sugen5416/hypoxia (SuHx)-induced rat PH models. Phosphorylation of STAT3 in CD4+ cells was also observed around the vascular lesions in the lungs of the SuHx rat model, but not in Il6 KO rats. Blockade of IL-6 signaling had an additive effect on conventional PAH therapeutics, such as endothelin receptor antagonist (macitentan) and soluble guanylyl cyclase stimulator (BAY41-2272). These findings suggest that IL-6/gp130 signaling in CD4+ cells plays a critical role in the pathogenesis of PAH.
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Hipertensão Pulmonar , Interleucina-6 , Animais , Camundongos , Ratos , Linfócitos T CD4-Positivos/patologia , Receptor gp130 de Citocina/genética , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/patologia , Hipóxia/patologia , Interleucina-6/genética , Artéria Pulmonar/patologiaRESUMO
Anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis (DM) is characterized by amyopathic DM with interstitial lung disease (ILD). Patients with anti-MDA5 antibody-associated ILD frequently develop rapidly progression and present high mortality rate in the acute phase. Here, we established a murine model of ILD mediated by autoimmunity against MDA5. Mice immunized with recombinant murine MDA5 whole protein, accompanied with complete Freund's adjuvant once a week for four times, developed MDA5-reactive T cells and anti-MDA5 antibodies. After acute lung injury induced by intranasal administration of polyinosinic-polycytidylic acid [poly (I:C)] mimicking viral infection, the MDA5-immunized mice developed fibrotic ILD representing prolonged respiratory inflammation accompanied by fibrotic changes 2 wk after poly (I:C)-administration, while the control mice had quickly and completely recovered from the respiratory inflammation. Treatment with anti-CD4 depleting antibody, but not anti-CD8 depleting antibody, suppressed the severity of MDA5-induced fibrotic ILD. Upregulation of interleukin (IL)-6 mRNA, which was temporarily observed in poly (I:C)-treated mice, was prolonged in MDA5-immunized mice. Treatment with anti-IL-6 receptor antibody ameliorated the MDA5-induced fibrotic ILD. These results suggested that autoimmunity against MDA5 exacerbates toll-like receptor 3-mediated acute lung injury, and prolongs inflammation resulting in the development of fibrotic ILD. IL-6 may play a key role initiating ILD in this model.
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Lesão Pulmonar Aguda , Dermatomiosite , Doenças Pulmonares Intersticiais , Melanoma , Humanos , Animais , Camundongos , Dermatomiosite/diagnóstico , Dermatomiosite/complicações , Prognóstico , Progressão da Doença , Autoimunidade , Helicase IFIH1 Induzida por Interferon/genética , Autoanticorpos , Doenças Pulmonares Intersticiais/diagnóstico , Interleucina-6 , Inflamação/complicações , Estudos RetrospectivosRESUMO
Galectins (Gals), a family of multifunctional glycan-binding proteins, have been traditionally defined as ß-galactoside binding lectins. However, certain members of this family have shown selective affinity toward specific glycan structures including human milk oligosaccharides (HMOs) and blood group antigens. In this work, we explored the affinity of human galectins (particularly Gal-1, -3, -4, -7, and -12) toward a panel of oligosaccharides including HMOs and blood group antigens using a complementary approach based on both experimental and computational techniques. While prototype Gal-1 and Gal-7 exhibited differential affinity for type I versus type II Lac/LacNAc residues and recognized fucosylated neutral glycans, chimera-type Gal-3 showed high binding affinity toward poly-LacNAc structures including LNnH and LNnO. Notably, the tandem-repeat human Gal-12 showed preferential recognition of 3-fucosylated glycans, a unique feature among members of the galectin family. Finally, Gal-4 presented a distinctive glycan-binding activity characterized by preferential recognition of specific blood group antigens, also validated by saturation transfer difference nuclear magnetic resonance experiments. Particularly, we identified oligosaccharide blood group A antigen tetraose 6 (BGA6) as a biologically relevant Gal-4 ligand, which specifically inhibited interleukin-6 secretion induced by this lectin on human peripheral blood mononuclear cells. These findings highlight unique determinants underlying specific recognition of HMOs and blood group antigens by human galectins, emphasizing the biological relevance of Gal-4-BGA6 interactions, with critical implications in the development and regulation of inflammatory responses.
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Iron is an essential element for proper cell functioning, but unbalanced levels can cause cell death. Iron metabolism is controlled at the blood-tissue barriers provided by microvascular endothelial cells. Dysregulated iron metabolism at these barriers is a factor in both neurodegenerative and cardiovascular diseases. Mammalian iron efflux is mediated by the iron efflux transporter ferroportin (Fpn). Inflammation is a factor in many diseases and correlates with increased tissue iron accumulation. Evidence suggests treatment with interleukin 6 (IL-6) increases intracellular calcium levels and calcium is known to play an important role in protein trafficking. We have shown that calcium increases plasma membrane localization of the iron uptake proteins ZIP8 and ZIP14, but if and how calcium modulates Fpn trafficking is unknown. In this article, we examined the effects of IL-6 and calcium on Fpn localization to the plasma membrane. In HEK cells expressing a doxycycline-inducible GFP-tagged Fpn, calcium increased Fpn-GFP membrane presence by 2 h, while IL-6 increased membrane-localized Fpn-GFP by 3 h. Calcium pretreatment increased Fpn-GFP mediated 55Fe efflux from cells. Endoplasmic reticulum calcium stores were shown to be important for Fpn-GFP localization and iron efflux. Use of calmodulin pathway inhibitors showed that calcium signaling is important for IL-6-induced Fpn relocalization. Studies in brain microvascular endothelial cells in transwell culture demonstrated an initial increase in 55Fe flux with IL-6 that is reduced by 6 h coinciding with upregulation of hepcidin. Overall, this research details one pathway by which inflammatory signaling mediated by calcium can regulate iron metabolism, likely contributing to inflammatory disease mechanisms.
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Cálcio , Proteínas de Transporte de Cátions , Membrana Celular , Interleucina-6 , Ferro , Transporte Proteico , Proteínas de Transporte de Cátions/metabolismo , Proteínas de Transporte de Cátions/genética , Humanos , Interleucina-6/metabolismo , Interleucina-6/genética , Ferro/metabolismo , Membrana Celular/metabolismo , Cálcio/metabolismo , Células HEK293 , Animais , Células Endoteliais/metabolismo , Hepcidinas/metabolismo , Hepcidinas/genéticaRESUMO
BACKGROUND: Genetic and experimental studies support a causal involvement of IL-6 (interleukin-6) signaling in atheroprogression. Although trials targeting IL-6 signaling are underway, any benefits must be balanced against an impaired host immune response. Dissecting the mechanisms that mediate the effects of IL-6 signaling on atherosclerosis could offer insights about novel drug targets with more specific effects. METHODS: Leveraging data from 522 681 individuals, we constructed a genetic instrument of 26 variants in the gene encoding the IL-6R (IL-6 receptor) that proxied for pharmacological IL-6R inhibition. Using Mendelian randomization, we assessed its effects on 3281 plasma proteins quantified with an aptamer-based assay in the INTERVAL cohort (n=3301). Using mediation Mendelian randomization, we explored proteomic mediators of the effects of genetically proxied IL-6 signaling on coronary artery disease, large artery atherosclerotic stroke, and peripheral artery disease. For significant mediators, we tested associations of their circulating levels with incident cardiovascular events in a population-based study (n=1704) and explored the histological, transcriptomic, and cellular phenotypes correlated with their expression levels in samples from human atherosclerotic lesions. RESULTS: We found significant effects of genetically proxied IL-6 signaling on 70 circulating proteins involved in cytokine production/regulation and immune cell recruitment/differentiation, which correlated with the proteomic effects of pharmacological IL-6R inhibition in a clinical trial. Among the 70 significant proteins, genetically proxied circulating levels of CXCL10 (C-X-C motif chemokine ligand 10) were associated with risk of coronary artery disease, large artery atherosclerotic stroke, and peripheral artery disease, with up to 67% of the effects of genetically downregulated IL-6 signaling on these end points mediated by decreases in CXCL10. Higher midlife circulating CXCL10 levels were associated with a larger number of cardiovascular events over 20 years, whereas higher CXCL10 expression in human atherosclerotic lesions correlated with a larger lipid core and a transcriptomic profile reflecting immune cell infiltration, adaptive immune system activation, and cytokine signaling. CONCLUSIONS: Integrating multiomics data, we found a proteomic signature of IL-6 signaling activation and mediators of its effects on cardiovascular disease. Our analyses suggest the interferon-γ-inducible chemokine CXCL10 to be a potentially causal mediator for atherosclerosis in 3 vascular compartments and, as such, could serve as a promising drug target for atheroprotection.
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Aterosclerose , Quimiocina CXCL10 , Interleucina-6 , Proteogenômica , Humanos , Aterosclerose/genética , Quimiocina CXCL10/metabolismo , Doença da Artéria Coronariana/genética , Estudo de Associação Genômica Ampla , Interleucina-6/metabolismo , Análise da Randomização Mendeliana , Doença Arterial Periférica , Proteômica , Acidente Vascular Cerebral/genéticaRESUMO
BACKGROUND: Heart failure is associated with a high rate of mortality and morbidity, and ventricular remodeling invariably precedes heart failure. Ventricular remodeling is fundamentally driven by mechanotransduction that is regulated by both the nervous system and the immune system. However, it remains unknown which key molecular factors govern the neuro/immune/cardio axis that underlies mechanotransduction during ventricular remodeling. Here, we investigated whether the mechanosensitive Piezo cation channel-mediated neurogenic inflammatory cascade underlies ventricular remodeling-related mechanotransduction. METHODS: By ligating the left coronary artery of rats to establish an in vivo model of chronic myocardial infarction (MI), lentivirus-mediated thoracic dorsal root ganglion (TDRG)-specific Piezo1 knockdown rats and adeno-associated virus-PHP.S-mediated TDRG neuron-specific Piezo1 knockout mice were used to investigate whether Piezo1 in the TDRG plays a functional role during ventricular remodeling. Subsequently, neutralizing antibody-mediated TDRG IL-6 (interleukin-6) inhibition rats and adeno-associated virus-PHP.S-mediated TDRG neuron-specific IL-6 knockdown mice were used to determine the mechanism underlying neurogenic inflammation. Primary TDRG neurons were used to evaluate Piezo1 function in vitro. RESULTS: Expression of Piezo1 and IL-6 was increased, and these factors were functionally activated in TDRG neurons at 4 weeks after MI. Both knockdown of TDRG-specific Piezo1 and deletion of TDRG neuron-specific Piezo1 lessened the severity of ventricular remodeling at 4 weeks after MI and decreased the level of IL-6 in the TDRG or heart. Furthermore, inhibition of TDRG IL-6 or knockdown of TDRG neuron-specific IL-6 also ameliorated ventricular remodeling and suppressed the IL-6 cascade in the heart, whereas the Piezo1 level in the TDRG was not affected. In addition, enhanced Piezo1 function, as reflected by abundant calcium influx induced by Yoda1 (a selective agonist of Piezo1), led to increased release of IL-6 from TDRG neurons in mice 4 weeks after MI. CONCLUSIONS: Our findings point to a critical role for Piezo1 in ventricular remodeling at 4 weeks after MI and reveal a neurogenic inflammatory cascade as a previously unknown facet of the neuronal immune signaling axis underlying mechanotransduction.
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Inflamação , Canais Iônicos , Infarto do Miocárdio , Remodelação Ventricular , Animais , Masculino , Camundongos , Ratos , Modelos Animais de Doenças , Gânglios Espinais/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Interleucina-6/metabolismo , Interleucina-6/genética , Canais Iônicos/metabolismo , Canais Iônicos/genética , Mecanotransdução Celular , Camundongos Knockout , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Neurônios/metabolismo , Neurônios/patologia , Ratos Sprague-Dawley , Remodelação Ventricular/genética , Remodelação Ventricular/fisiologiaRESUMO
BACKGROUND: Liver transplantation (LT) is offered as a cure for Hepatocellular carcinoma (HCC), however 15-20% develop recurrence post-transplant which tends to be aggressive. In this study, we examined the transcriptome profiles of patients with recurrent HCC to identify differentially expressed genes (DEGs), the involved pathways, biological functions, and potential gene signatures of recurrent HCC post-transplant using deep machine learning (ML) methodology. MATERIALS AND METHODS: We analyzed the transcriptomic profiles of primary and recurrent tumor samples from 7 pairs of patients who underwent LT. Following differential gene expression analysis, we performed pathway enrichment, gene ontology (GO) analyses and protein-protein interactions (PPIs) with top 10 hub gene networks. We also predicted the landscape of infiltrating immune cells using Cibersortx. We next develop pathway and GO term-based deep learning models leveraging primary tissue gene expression data from The Cancer Genome Atlas (TCGA) to identify gene signatures in recurrent HCC. RESULTS: The PI3K/Akt signaling pathway and cytokine-mediated signaling pathway were particularly activated in HCC recurrence. The recurrent tumors exhibited upregulation of an immune-escape related gene, CD274, in the top 10 hub gene analysis. Significantly higher infiltration of monocytes and lower M1 macrophages were found in recurrent HCC tumors. Our deep learning approach identified a 20-gene signature in recurrent HCC. Amongst the 20 genes, through multiple analysis, IL6 was found to be significantly associated with HCC recurrence. CONCLUSION: Our deep learning approach identified PI3K/Akt signaling as potentially regulating cytokine-mediated functions and the expression of immune escape genes, leading to alterations in the pattern of immune cell infiltration. In conclusion, IL6 was identified to play an important role in HCC recurrence.
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Carcinoma Hepatocelular , Aprendizado Profundo , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas , Transplante de Fígado , Recidiva Local de Neoplasia , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Transplante de Fígado/efeitos adversos , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Regulação Neoplásica da Expressão Gênica/genética , Transcriptoma/genética , Perfilação da Expressão Gênica , Transdução de Sinais/genética , Redes Reguladoras de Genes/genética , Mapas de Interação de Proteínas/genética , Masculino , Feminino , Biomarcadores Tumorais/genética , Pessoa de Meia-IdadeRESUMO
Advances in the digital pathology field have facilitated the characterization of histology samples for both clinical and preclinical research. However, uncovering subtle correlations between bioimaging, clinical and molecular parameters requires extensive statistical analysis. As a user-friendly software, Hourglass, simplifies multiparametric dataset analysis through intuitive data visualization and statistical tools. Systemic analysis of interleukin-6 (IL-6)/pStat3 signaling pathway through Hourglass revealed differences in regional immune cell composition within tumors. Moreover, these regional disparities were partially mediated by sex. Overall, Hourglass simplifies information extraction from complex datasets, resolving overlooked regional and global spatial tumor differences. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/patologia , Transdução de Sinais , Software , Reino UnidoRESUMO
BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is a severe disease involving dysregulated type 2 inflammation. However, the role other inflammatory pathways play in AERD is poorly understood. OBJECTIVE: We sought to broadly define the inflammatory milieu of the upper respiratory tract in AERD and to determine the effects of IL-4Rα inhibition on mediators of nasal inflammation. METHODS: Twenty-two AERD patients treated with dupilumab for 3 months were followed over 3 visits and compared to 10 healthy controls. Nasal fluid was assessed for 45 cytokines and chemokines using Olink Target 48. Blood neutrophils and cultured human mast cells, monocytes/macrophages, and nasal fibroblasts were assessed for response to IL-4/13 stimulation in vitro. RESULTS: Of the nasal fluid cytokines measured, nearly one third were higher in AERD patients compared to healthy controls, including IL-6 and the IL-6 family-related cytokine oncostatin M (OSM), both of which correlated with nasal albumin levels, a marker of epithelial barrier dysregulation. Dupilumab significantly decreased many nasal mediators, including OSM and IL-6. IL-4 stimulation induced OSM production from mast cells and macrophages but not from neutrophils, and OSM and IL-13 stimulation induced IL-6 production from nasal fibroblasts. CONCLUSION: In addition to type 2 inflammation, innate and IL-6-related cytokines are also elevated in the respiratory tract in AERD. Both OSM and IL-6 are locally produced in nasal polyps and likely promote pathology by negatively affecting epithelial barrier function. IL-4Rα blockade, although seemingly directed at type 2 inflammation, also decreases mediators of innate inflammation and epithelial dysregulation, which may contribute to dupilumab's therapeutic efficacy in AERD.
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Anticorpos Monoclonais Humanizados , Asma Induzida por Aspirina , Subunidade alfa de Receptor de Interleucina-4 , Interleucina-6 , Oncostatina M , Transdução de Sinais , Humanos , Oncostatina M/metabolismo , Feminino , Masculino , Pessoa de Meia-Idade , Interleucina-6/metabolismo , Interleucina-6/imunologia , Adulto , Subunidade alfa de Receptor de Interleucina-4/metabolismo , Subunidade alfa de Receptor de Interleucina-4/imunologia , Asma Induzida por Aspirina/imunologia , Mastócitos/imunologia , Mastócitos/metabolismo , Células Cultivadas , Idoso , Fibroblastos/metabolismo , Fibroblastos/imunologia , Mucosa Nasal/imunologia , Mucosa Nasal/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Neutrófilos/imunologia , Neutrófilos/metabolismoRESUMO
BACKGROUND: By acting as an environmental sensor, the ligand-induced transcription factor aryl hydrocarbon receptor (AhR) regulates acute innate and adaptive immune responses against pathogens. Here, we analyzed the function of AhR in a model for chronic systemic infection with attenuated Salmonella Typhimurium (STM). METHODS: WT and AhR-deficient mice were infected with the attenuated STM strain TAS2010 and analyzed for bacterial burden, host defense functions and inflammatory stress erythropoiesis. RESULTS: AhR-deficient mice were highly susceptible to TAS2010 infection compared with WT mice demonstrated by reduced bacterial clearance and increased mortality. STM infection resulted in macrocytic anemia and enhanced splenomegaly along with destruction of the splenic architecture in AhR-deficient mice. In addition, AhR-deficient mice displayed a major expansion of splenic immature red blood cells, indicative of infection-induced stress erythropoiesis. Elevated serum levels of erythropoietin and interleukin-6 upon infection as well as increased numbers of splenic stress erythroid progenitors already in steady state probably drive this effect and might cause the alterations in splenic immune cell compartments, thereby preventing an effective host defense against STM in AhR-deficient mice. CONCLUSIONS: AhR-deficient mice fail to clear chronic TAS2010 infection due to enhanced stress erythropoiesis in the spleen and accompanying destruction of the splenic architecture.
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Plasma lipid levels are modulated by systemic infection and inflammation; it is unknown whether these changes reflect inflammatory responses or caused directly by pathogen presence. We explored the hypothesis that anti-inflammatory intervention via interleukin 6 receptor (IL-6R) blockade would influence plasma lipid levels during severe infection and evaluated the association of plasma lipid changes with clinical outcomes. Sarilumab (monoclonal antibody blocking IL-6R) efficacy was previously assessed in patients with coronavirus disease 2019 (COVID-19) (NCT04315298). This analysis determined whether strong inflammatory reduction by sarilumab in patients with COVID-19 pneumonia of increasing severity (severe, critical, multisystem organ dysfunction) affected plasma lipid changes between day 1 and day 7 of study therapy. Baseline lipid levels reflected the presence of acute systemic infection, characterized by very low HDL-C, low LDL-C, and moderately elevated triglycerides (TGs). Disease severity was associated with progressively more abnormal lipid levels. At day 7, median lipid levels increased more in the sarilumab versus placebo group (HDL-C +10.3%, LDL-C +54.7%, TG +32% vs. HDL-C +1.7%, LDL-C +15.4%, TG +8.8%, respectively). No significant association between lipid changes and clinical outcomes was observed. In conclusion, severe-to-critical COVID-19 pneumonia causes profound HDL-C depression that is only modestly responsive to strong anti-IL-6R inflammatory intervention. Conversely, LDL-C depression is strongly responsive to IL-6R blockade, with LDL-C levels likely returning to the predisease set point. These results advance our understanding of the complex relationship between serum lipids and infection/inflammation and suggest that HDL-C depression during acute contagious disease is driven by infection and not IL-6-mediated inflammation.
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Anticorpos Monoclonais Humanizados , Tratamento Farmacológico da COVID-19 , COVID-19 , Lipídeos , Receptores de Interleucina-6 , Humanos , Receptores de Interleucina-6/antagonistas & inibidores , Receptores de Interleucina-6/sangue , Anticorpos Monoclonais Humanizados/uso terapêutico , Masculino , Feminino , Pessoa de Meia-Idade , COVID-19/sangue , COVID-19/complicações , Lipídeos/sangue , Idoso , Hospitalização , Resultado do Tratamento , SARS-CoV-2 , Adulto , Índice de Gravidade de DoençaRESUMO
Chronic inflammation is believed as the main culprit of the link between cardiovascular disease (CVD) and rheumatoid arthritis (RA). Interleukin-6 (IL-6) is a pro-inflammatory cytokine with a key role in RA pathophysiology and also correlates with joint destruction and disease activity. This study evaluates the association between IL-6 plasma level and cardiac biomarker NT-proBNP, HS-CRP, CVD predictor algorithms, Framingham Risk Score (FRS) and Systematic Coronary Risk Evaluation (SCORE), as well as with CXCL9 and its receptor, CXCR3 in RA patients compared to the controls. Sixty RA patients (30 early and 30 late) and 30 healthy persons were included in this study. IL-6 and NT-proBNP plasma levels were measured by the ELISA. Also, HS-CRP plasma levels were quantified using the immunoturbidimetric assay. The CVD risk was assessed by the FRS and SCORE. IL-6 plasma levels were significantly higher in the early and late RA patients compared to the controls (p < 0.001). There was a positive correlation between IL-6 with DAS-28 (p = 0.007, r = 0.346), BPS (p = 0.002, r = 0.396), BPD (p = 0.046, r = 0.259), SCORE (p < 0.001, r = 0.472), and FRS (p < 0.001, r = 0.553), and a negative association with HDL (p = 0.037, r = -0.270), in the patients. Also, IL-6 plasma level positively correlated with HS-CRP (p = 0.021, r = 0.297) and NT-proBNP (p = 0.045, r = 0.260) in the patients. Furthermore, a positive association was found between IL-6 plasma levels and CXCL9 (p = 0.002, r = 0.386), and CXCR3 (p = 0.018, r = 0.304) in the patients. Given the interesting association between IL-6 with various variables of CVD, IL-6 may be considered a biomarker for assessing the risk for future cardiovascular events in RA patients.
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Algoritmos , Artrite Reumatoide , Biomarcadores , Proteína C-Reativa , Doenças Cardiovasculares , Interleucina-6 , Peptídeo Natriurético Encefálico , Fragmentos de Peptídeos , Humanos , Artrite Reumatoide/sangue , Artrite Reumatoide/complicações , Biomarcadores/sangue , Feminino , Masculino , Interleucina-6/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/etiologia , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Proteína C-Reativa/metabolismo , Fragmentos de Peptídeos/sangue , Quimiocina CXCL9/sangue , Adulto , Estudos de Casos e Controles , Idoso , Fatores de Risco , Receptores CXCR3RESUMO
Rheumatoid arthritis (RA) is a systemic autoimmune disease driven by highly active autoantibody-producing B cells. Activation of B cells is maintained within ectopic germinal centres found in affected joints. Fibroblast-like synoviocytes (FLS) present in inflamed joints support B-cell survival, activation, and differentiation. CD27+ memory B cells and naive B cells show very different responses to activation, particularly by CD40 ligand (CD40L). We show that FLS-dependent activation of human B cells is dependent on interleukin-6 (IL-6) and CD40L. FLS have been shown to activate both naive and memory B cells. Whether the activating potential of FLS is different for naive and memory B cells has not been investigated. Our results suggest that FLS-induced activation of B cells is dependent on IL-6 and CD40L. While FLS are able to induce plasma cell differentiation, isotype switching, and antibody production in memory B cells, the ability of FLS to activate naive B cells is significantly lower.
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Methylene blue (MB) has been shown to reduce mortality and morbidity in vasoplegic patients after cardiac surgery. Though MB is considered to be safe, extravasation of MB leading to cutaneous toxicity has been reported. In this study, we sought to characterize MB-induced cutaneous toxicity and investigate the underlying mechanisms. To induce MB-induced cutaneous toxicity, we injected 64 adult male Sprague-Dawley rates with 200 µL saline (vehicle) or 1%, 0.1%, or 0.01% MB in the plantar hind paws. Paw swelling, skin histologic changes, and heat and mechanical hyperalgesia were measured. Injection of 1%, but not 0.1% or 0.01% MB, produced significant paw swelling compared to saline. Injection of 1% MB produced heat hyperalgesia but not mechanical hyperalgesia. Pain behaviors were unchanged following injections of 0.1% or 0.01% MB. Global transcriptomic analysis by RNAseq identified 117 differentially expressed genes (111 upregulated, 6 downregulated). Ingenuity Pathway Analysis showed an increased quantity of leukocytes, increased lipids, and decreased apoptosis of myeloid cells and phagocytes with activation of IL-1ß and Fos as the two major regulatory hubs. qPCR showed a 16-fold increase in IL-6 mRNA. Thus, using a novel rat model of MB-induced cutaneous toxicity, we show that infiltration of 1% MB into cutaneous tissue causes a dose-dependent pro-inflammatory response, highlighting potential roles of IL-6, IL-1ß, and Fos. Thus, anesthesiologists should administer dilute MB intravenously through peripheral venous catheters. Higher concentrations of MB (1%) should be administered through a central venous catheter to minimize the risk of cutaneous toxicity.
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Modelos Animais de Doenças , Hiperalgesia , Inflamação , Azul de Metileno , Ratos Sprague-Dawley , Pele , Animais , Masculino , Azul de Metileno/farmacologia , Azul de Metileno/administração & dosagem , Hiperalgesia/patologia , Hiperalgesia/induzido quimicamente , Inflamação/patologia , Inflamação/induzido quimicamente , Pele/efeitos dos fármacos , Pele/patologia , Relação Dose-Resposta a Droga , Temperatura Alta , Ratos , Interleucina-1beta/metabolismo , Interleucina-1beta/genéticaRESUMO
Humans are persistently exposed to massive amounts of blue light via sunlight, computers, smartphones, and similar devices. Although the positive and negative effects of blue light on living organisms have been reported, its impact on learning and memory remains unknown. Herein, we examined the effects of widespread blue light exposure on the learning and memory abilities of blue light-exposed mice. Ten-week-old male ICR mice were divided into five groups (five mice/group) and irradiated with blue light from a light-emitting diode daily for 6 months. After 6 months of blue light irradiation, mice exhibited a decline in memory and learning abilities, assessed using the Morris water maze and step-through passive avoidance paradigms. Blue light-irradiated mice exhibited a decreased expression of the clock gene brain and muscle arnt-like 1 (Bmal1). The number of microglia and levels of M1 macrophage CC-chemokine receptor 7 and inducible nitric oxide synthase were increased, accompanied by a decrease in M2 macrophage arginase-1 levels. Levels of angiopoietin-like protein 2 and inflammatory cytokines interleukin-6, tumor necrosis factor-α, and interleukin-1ß were elevated. Our findings suggest that long-term blue light exposure could reduce Bmal1 expression, activate the M1 macrophage/Angptl2/inflammatory cytokine pathway, induce neurodegeneration, and lead to a decline in memory.
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Immune protection associated with consuming colostrum-based peptides is effective against bacterial and viral insults. The goal for this study was to document acute changes to immune surveillance and cytokine levels after consuming a single dose of a nutraceutical blend in the absence of an immune challenge. A double-blind, randomized, placebo-controlled, cross-over pilot study involved healthy participants attending two clinic visits. Blood draws were performed pre-consumption and at 1, 2, and 24 h after consuming a blend of bovine colostrum- and hen's egg-based low-molecular-weight peptides (CELMPs) versus a placebo. Immunophenotyping was performed by flow cytometry, and serum cytokines were measured by multiplex cytokine arrays. Consumption of CELMPs triggered increased immune surveillance after 1 h, involving monocytes (p < 0.1), natural killer (NK) cells (p < 0.1), and natural killer T (NKT) cells (p < 0.05). The number of NKT cells expressing the CD25 immunoregulatory marker increased at 1 and 2 h (p < 0.1). Increased serum levels of monocyte chemoattractant protein-1 (MCP-1) was observed at 2 and 24 h (24 h: p < 0.05). Selective reduction in pro-inflammatory cytokines was seen at 1, 2, and 24 h, where the 2-h reduction was highly significant for IL-6, IFN-γ, and IL-13. The rapid, transient increase in immune surveillance, in conjunction with the reduced levels of inflammatory markers, suggests that the CELMP blend of natural peptides provides immune benefits of use in preventive medicine. Further studies are warranted in chronic inflammatory conditions.
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Ovarian cancer incidence has declined in recent decades, due in part to oral contraceptive (OC) use and tubal ligation. However, intrauterine device (IUD) use has increasingly replaced OC use. As ovarian cancer is an inflammation-related disease, we examined the association of OC use, IUD use, and tubal ligation with plasma levels of C-reactive protein (CRP), interleukin 6 (IL-6), and soluble tumor necrosis factor α receptor 2 (sTNFR2), in the Nurses' Health Study (NHS) and NHSII. After adjusting for reproductive, hormonal, and lifestyle factors, and mutual adjustment for other methods of contraception, there were no differences in inflammatory markers between ever and never use of each method. However, CRP levels decreased from an average 30.4% (-53.6, 4.4) with every 5 years since initial IUD use (P-trend=0.03), while CRP increased an average 9.9% (95% CI: 5.7, 14.3) with every 5 years of use of OC (P-trend<0.0001) as well as differences by BMI and menopausal status. Our results suggest IUD use and tubal ligation are not associated with higher circulating inflammatory markers long term, although long duration of OC use may increase generalized inflammation, which may in part explain why its protective effect wanes over time.
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The impact of Omicron infections on the clinical outcome and immune responses of myasthenia gravis (MG) remained largely unknown. From a prospective multicenter MG cohort (n = 189) with 197 myasthenic crisis (MC), we finally included 41 independent MG patients to classify into two groups: the Omicron Group (n = 13) and the Control Group (n = 28). In this matched cohort study, all-cause mortality was 7.69% (1/13) in Omicron Group and 14.29% (4/28) in Control Group. A higher proportion of elevated serum IL-6 was identified in the Omicron Group (88.89% vs 52.38%, P = 0.049). In addition, the proportions of CD3+CD8+T in lymphocytes and Tregs in CD3+CD4+ T cells were significantly elevated in the Omicron Group (both P = 0.0101). After treatment, the Omicron Group exhibited a marked improvement in MG-ADL score (P = 0.026) and MG-QoL-15 (P = 0.0357). MCs with Omicron infections were associated with elevated serum IL-6 and CD3+CD8+T response. These patients tended to present a better therapeutic response after fast-acting therapies and anti-IL-6 treatment.
Assuntos
Interleucina-6 , Miastenia Gravis , Humanos , Estudos Prospectivos , Estudos de Coortes , Qualidade de Vida , Miastenia Gravis/tratamento farmacológicoRESUMO
BACKGROUND: Despite the advances of therapies, multiple myeloma (MM) remains an incurable hematological cancer that most patients experience relapse. Tumor angiogenesis is strongly correlated with cancer relapse. Human leukocyte antigen G (HLA-G) has been known as a molecule to suppress angiogenesis. We aimed to investigate whether soluble HLA-G (sHLA-G) was involved in the relapse of MM. METHODS: We first investigated the dynamics of serum sHLA-G, vascular endothelial growth factor (VEGF) and interleukin 6 (IL-6) in 57 successfully treated MM patients undergoing remission and relapse. The interactions among these angiogenesis-related targets (sHLA-G, VEGF and IL-6) were examined in vitro. Their expression at different oxygen concentrations was investigated using a xenograft animal model by intra-bone marrow and skin grafts with myeloma cells. RESULTS: We found that HLA-G protein degradation augmented angiogenesis. Soluble HLA-G directly inhibited vasculature formation in vitro. Mechanistically, HLA-G expression was regulated by hypoxia-inducible factor-1α (HIF-1α) in MM cells under hypoxia. We thus developed two mouse models of myeloma xenografts in intra-bone marrow (BM) and underneath the skin, and found a strong correlation between HLA-G and HIF-1α expressions in hypoxic BM, but not in oxygenated tissues. Yet when stimulated with IL-6, both HLA-G and HIF-1α could be targeted to ubiquitin-mediated degradation via PARKIN. CONCLUSION: These results highlight the importance of sHLA-G in angiogenesis at different phases of multiple myeloma. The experimental evidence that sHLA-G as an angiogenesis suppressor in MM may be useful for future development of novel therapies to prevent relapse.
Assuntos
Antígenos HLA-G , Interleucina-6 , Mieloma Múltiplo , Neovascularização Patológica , Mieloma Múltiplo/sangue , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Humanos , Animais , Neovascularização Patológica/metabolismo , Antígenos HLA-G/sangue , Antígenos HLA-G/metabolismo , Camundongos , Interleucina-6/sangue , Interleucina-6/metabolismo , Masculino , Feminino , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/sangue , Pessoa de Meia-Idade , Linhagem Celular Tumoral , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Idoso , Modelos Animais de Doenças , AngiogêneseRESUMO
Acute chest syndrome (ACS) is a leading cause of morbimortality in sickle cell disease (SCD). In this prospective observational study, we investigated sputum interleukin-6 (IL-6) level as an ACS severity marker during 30 ACS episodes in 26 SCD children. Sputum IL-6 levels measured within the first 72 h of hospitalisation for ACS were significantly higher in patients with oxygen requirement ≥2 L/min, ventilation (invasive and/or non-invasive) length ≥5 days, bilateral and/or extensive opacities on chest X-ray or erythrocytapheresis requirement. Sputum IL-6 could serve as an ACS severity marker to help identify patients requiring targeted anti-inflammatory treatments such as tocilizumab.