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1.
J Clin Immunol ; 44(4): 103, 2024 Apr 20.
Artículo en Inglés | MEDLINE | ID: mdl-38642164

RESUMEN

Epstein-Barr virus (EBV) infection can lead to infectious mononucleosis (EBV-IM) and, more rarely, EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH), which is characterized by a life-threatening hyperinflammatory cytokine storm with immune dysregulation. Interferon-gamma (IFNγ) has been identified as a critical mediator for primary HLH; however, the detailed role of IFNγ and other cytokines in EBV-HLH is not fully understood. In this study, we used single-cell RNA sequencing to characterize the immune landscape of EBV-HLH and compared it with EBV-IM. Three pediatric patients with EBV-HLH with different backgrounds, one with X-linked lymphoproliferative syndrome type 1 (XLP1), two with chronic active EBV disease (CAEBV), and two patients with EBV-IM were enrolled. The TUBA1B + STMN1 + CD8 + T cell cluster, a responsive proliferating cluster with rich mRNA detection, was explicitly observed in EBV-IM, and the upregulation of SH2D1A-the gene responsible for XLP1-was localized in this cluster. This proliferative cluster was scarcely observed in EBV-HLH cases. In EBV-HLH cases with CAEBV, upregulation of LAG3 was observed in EBV-infected cells, which may be associated with an impaired response by CD8 + T cells. Additionally, genes involved in type I interferon (IFN) signaling were commonly upregulated in each cell fraction of EBV-HLH, and activation of type II IFN signaling was observed in CD4 + T cells, natural killer cells, and monocytes but not in CD8 + T cells in EBV-HLH. In conclusion, impaired responsive proliferation of CD8 + T cells and upregulation of type I IFN signaling were commonly observed in EBV-HLH cases, regardless of the patients' background, indicating the key features of EBV-HLH.


Asunto(s)
Infecciones por Virus de Epstein-Barr , Linfohistiocitosis Hemofagocítica , Trastornos Linfoproliferativos , Humanos , Niño , Herpesvirus Humano 4 , Linfohistiocitosis Hemofagocítica/diagnóstico , Linfohistiocitosis Hemofagocítica/genética , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/genética , Linfocitos T CD8-positivos , Interferón gamma/genética , Trastornos Linfoproliferativos/diagnóstico , Trastornos Linfoproliferativos/genética , Trastornos Linfoproliferativos/complicaciones , Perfilación de la Expresión Génica
2.
Int J Mol Sci ; 25(7)2024 Mar 28.
Artículo en Inglés | MEDLINE | ID: mdl-38612576

RESUMEN

In a recent stereotactic body radiation therapy animal model, radiation pneumonitis and radiation pulmonary fibrosis were observed at around 2 and 6 weeks, respectively. However, the molecular signature of this model remains unclear. This study aimed to examine the molecular characteristics at these two stages using RNA-seq analysis. Transcriptomic profiling revealed distinct transcriptional patterns for each stage. Inflammatory response and immune cell activation were involved in both stages. Cell cycle processes and response to type II interferons were observed during the inflammation stage. Extracellular matrix organization and immunoglobulin production were noted during the fibrosis stage. To investigate the impact of a 10 Gy difference on fibrosis progression, doses of 45, 55, and 65 Gy were tested. A dose of 65 Gy was selected and compared with 75 Gy. The 65 Gy dose induced inflammation and fibrosis as well as the 75 Gy dose, but with reduced lung damage, fewer inflammatory cells, and decreased collagen deposition, particularly during the inflammation stage. Transcriptomic analysis revealed significant overlap, but differences were observed and clarified in Gene Ontology and KEGG pathway analysis, potentially influenced by changes in interferon-gamma-mediated lipid metabolism. This suggests the suitability of 65 Gy for future preclinical basic and pharmaceutical research connected with radiation-induced lung injury.


Asunto(s)
Lesión Pulmonar , Fibrosis Pulmonar , Traumatismos por Radiación , Animales , Lesión Pulmonar/genética , Fibrosis Pulmonar/genética , Inflamación , Interferón gamma/genética , Pulmón , Dosis de Radiación
3.
Proc Natl Acad Sci U S A ; 121(17): e2320938121, 2024 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-38635637

RESUMEN

The MYC-Associated Zinc Finger Protein (MAZ) plays important roles in chromatin organization and gene transcription regulation. Dysregulated expression of MAZ causes diseases, such as glioblastoma, breast cancer, prostate cancer, and liposarcoma. Previously, it has been reported that MAZ controls the proinflammatory response in colitis and colon cancer via STAT3 signaling, suggesting that MAZ is involved in regulating immunity-related pathways. However, the molecular mechanism underlying this regulation remains elusive. Here, we investigate the regulatory effect of MAZ on interferon-gamma (IFN-γ)-stimulated genes via STAT1, a protein that plays an essential role in immune responses to viral, fungal, and mycobacterial pathogens. We demonstrate that about 80% of occupied STAT1-binding sites colocalize with occupied MAZ-binding sites in HAP1/K562 cells after IFN-γ stimulation. MAZ depletion significantly reduces STAT1 binding in the genome. By analyzing genome-wide gene expression profiles in the RNA-Seq data, we show that MAZ depletion significantly suppresses a subset of the immune response genes, which include the IFN-stimulated genes IRF8 and Absent in Melanoma 2. Furthermore, we find that MAZ controls expression of the immunity-related genes by changing the epigenetic landscape in chromatin. Our study reveals an important role for MAZ in regulating immune-related gene expression.


Asunto(s)
Cromatina , Interferón gamma , Masculino , Humanos , Interferón gamma/genética , Interferón gamma/farmacología , Cromatina/genética , Regulación de la Expresión Génica , Unión Proteica , Dedos de Zinc/genética , Factor de Transcripción STAT1/genética
4.
Sci Rep ; 14(1): 8046, 2024 04 05.
Artículo en Inglés | MEDLINE | ID: mdl-38580748

RESUMEN

Osteoarthritis is a common chronic disease and major cause of disability and chronic pain in ageing populations. In this pathology, the entire joint is involved, and the regeneration of articular cartilage still remains one of the main challenges. Here, we investigated the molecular mechanisms underlying cartilage regeneration in young mice using a full-thickness cartilage injury (FTCI) model. FTCI-induced cartilage defects were created in the femoral trochlea of young and adult C57BL/6 mice. To identify key molecules and pathways involved in the early response to cartilage injury, we performed RNA sequencing (RNA-seq) analysis of cartilage RNA at 3 days after injury. Young mice showed superior cartilage regeneration compared to adult mice after cartilage injury. RNA-seq analysis revealed significant upregulation of genes associated with the immune response, particularly in the IFN-γ signaling pathway and qRT-PCR analysis showed macrophage polarization in the early phase of cartilage regeneration (3 days) in young mice after injury, which might promote the removal of damaged or necrotic cells and initiate cartilage regeneration in response to injury. IFN-γR1- and IFN-γ-deficient mice exhibited impaired cartilage regeneration following cartilage injury. DMM-induced and spontaneous OA phenotypes were exacerbated in IFN-γR1-/- mice than in wild-type mice. Our data support the hypothesis that IFN-γ signaling is necessary for cartilage regeneration, as well as for the amelioration of post-traumatic and age-induced OA.


Asunto(s)
Cartílago Articular , Osteoartritis , Animales , Ratones , Cartílago Articular/patología , Modelos Animales de Enfermedad , Interferón gamma/genética , Ratones Endogámicos C57BL , Osteoartritis/metabolismo , Regeneración , Transducción de Señal
5.
Artículo en Chino | MEDLINE | ID: mdl-38604686

RESUMEN

OBJECTIVE: To investigate the effect of LAG-3 deficiency (LAG3-/-) on natural killer (NK) cell function and hepatic fibrosis in mice infected with Echinococcus multilocularis. METHODS: C57BL/6 mice, each weighing (20 ± 2) g, were divided into the LAG3-/- and wild type (WT) groups, and each mouse in both groups was inoculated with 3 000 E. multilocularis protoscoleces via the hepatic portal vein. Mouse liver and spleen specimens were collected 12 weeks post-infection, sectioned and stained with sirius red, and the hepatic lesions and fibrosis were observed. Mouse hepatic and splenic lymphocytes were isolated, and flow cytometry was performed to detect the proportions of hepatic and splenic NK cells, the expression of CD44, CD25 and CD69 molecules on NK cell surface, and the secretion of interferon γ (IFN-γ), tumor necrosis factor α (TNF-α), interleukin (IL)-4, IL-10 and IL-17A. RESULTS: Sirius red staining showed widening of inflammatory cell bands and hyperplasia of fibrotic connective tissues around mouse hepatic lesions, as well as increased deposition of collagen fibers in the LAG3-/-group relative to the WT group. Flow cytometry revealed lower proportions of mouse hepatic (6.29% ± 1.06% vs. 11.91% ± 1.85%, P < 0.000 1) and splenic NK cells (4.44% ± 1.22% vs. 5.85% ± 1.10%, P > 0.05) in the LAG3-/- group than in the WT group, and the mean fluorescence intensity of CD44 was higher on the surface of mouse hepatic NK cells in the LAG3-/- group than in the WT group (t = -3.234, P < 0.01), while no significant differences were found in the mean fluorescence intensity of CD25 or CD69 on the surface of mouse hepaticNK cells between the LAG3-/- and WT groups (both P values > 0.05). There were significant differences between the LAG3-/- and WT groups in terms of the percentages of IFN-γ (t = -0.723, P > 0.05), TNF-α (t = -0.659, P > 0.05), IL-4 (t = -0.263, P > 0.05), IL-10 (t = -0.455, P > 0.05) or IL-17A secreted by mouse hepatic NK cells (t = 0.091, P > 0.05), and the percentage of IFN-γ secreted by mouse splenic NK cells was higher in the LAG3-/- group than in the WT group (58.40% ± 1.64% vs. 50.40% ± 4.13%; t = -4.042, P < 0.01); however, there were no significant differences between the two groups in terms of the proportions of TNF-α (t = -1.902, P > 0.05), IL-4 (t = -1.333, P > 0.05), IL-10 (t = -1.356, P > 0.05) or IL-17A secreted by mouse splenic NK cells (t = 0.529, P > 0.05). CONCLUSIONS: During the course of E. multilocularis infections, LAG3-/- promotes high-level secretion of IFN-γ by splenic NK cells, which may participate in the reversal the immune function of NK cells, resulting in aggravation of hepatic fibrosis.


Asunto(s)
Echinococcus multilocularis , Interleucina-10 , Animales , Ratones , Interleucina-10/metabolismo , Interleucina-17/metabolismo , Interleucina-17/farmacología , Interleucina-4/metabolismo , Interleucina-4/farmacología , Echinococcus multilocularis/genética , Factor de Necrosis Tumoral alfa/metabolismo , Ratones Endogámicos C57BL , Interferón gamma/genética , Interferón gamma/metabolismo , Células Asesinas Naturales/metabolismo , Cirrosis Hepática/genética
6.
Viruses ; 16(4)2024 Apr 22.
Artículo en Inglés | MEDLINE | ID: mdl-38675991

RESUMEN

Tumor necrosis factor (TNF) and interferon-gamma (IFNγ) are important inflammatory mediators in the development of cytokine storm syndrome (CSS). Single nucleotide polymorphisms (SNPs) regulate the expression of these cytokines, making host genetics a key factor in the prognosis of COVID-19. In this study, we investigated the associations of the TNF -308G/A and IFNG +874T/A polymorphisms with COVID-19. We analyzed the frequencies of the two polymorphisms in the control groups (CG: TNF -308G/A, n = 497; IFNG +874T/A, n = 397), a group of patients with COVID-19 (CoV, n = 222) and among the subgroups of patients with nonsevere (n = 150) and severe (n = 72) COVID-19. We found no significant difference between the genotypic and allelic frequencies of TNF -308G/A in the groups analyzed; however, both the frequencies of the high expression genotype (TT) (CoV: 13.51% vs. CG: 6.30%; p = 0.003) and the *T allele (CoV: 33.56% vs. CG: 24. 81%; p = 0.001) of the IFNG +874T/A polymorphism were higher in the COVID-19 group than in the control group, with no differences between the subgroups of patients with nonsevere and severe COVID-19. The *T allele of IFNG +874T/A (rs2430561) is associated with susceptibility to symptomatic COVID-19. These SNPs provided valuables clues about the potential mechanism involved in the susceptibility to developing symptomatic COVID-19.


Asunto(s)
COVID-19 , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Interferón gamma , Polimorfismo de Nucleótido Simple , SARS-CoV-2 , Factor de Necrosis Tumoral alfa , Humanos , COVID-19/genética , COVID-19/virología , Interferón gamma/genética , Femenino , Masculino , Persona de Mediana Edad , SARS-CoV-2/genética , Factor de Necrosis Tumoral alfa/genética , Anciano , Adulto , Alelos , Síndrome de Liberación de Citoquinas/genética
7.
Cytokine ; 178: 156569, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38484620

RESUMEN

Inflammation is associated with thoracic aortic aneurysm (TAA) but the effects of each circulating inflammatory factor on TAA remain unclear. In this study, we explored the relationship between circulating inflammatory factors and TAA risk using Mendelian randomization (MR) approach based on summary statistics from the latest genome-wide association study (GWAS) of 41 circulating inflammatory factors in 8293 Finns and a GWAS involving 1351 TAA cases and 18,295 controls of European ancestry. In univariable MR, higher interferon gamma-induced protein 10 (IP-10) levels, higher interferon gamma (IFNγ) levels and higher stem cell growth factor beta (SCGFß) levels were associated with an increased risk of TAA (OR = 1.37, 95 % CI = 1.17-1.59, p = 7.42 × 10-5; OR = 1.43, 95 % CI = 1.19-1.74, p = 2.04 × 10-4; OR = 1.27, 95 % CI = 1.09-1.48, p = 2.40 × 10-3, respectively). In multivariable MR, the patterns of associations for the three cytokines remained adjusting for each other or smoking, but were attenuated differently with adjustment for other cardiovascular risk factors, especially for lipids and body mass index. Bidirectional MR approach did not identify any significant associations between cytokines and risk factors. Our results indicated that circulating cytokines may play mediation roles in the pathogenesis of TAA. Further studies are needed to determine whether these biomarkers can be used to prevent and treat TAA.


Asunto(s)
Aneurisma de la Aorta Torácica , Interferón gamma , Humanos , Interferón gamma/genética , Quimiocina CXCL10 , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Citocinas , Aneurisma de la Aorta Torácica/genética
8.
J Cell Biol ; 223(3)2024 03 04.
Artículo en Inglés | MEDLINE | ID: mdl-38319288

RESUMEN

TNFα and IFNγ (TNF/IFNγ) synergistically induce caspase-8 activation and cancer cell death. However, the mechanism of IFNγ in promoting TNF-initiated caspase-8 activation in cancer cells is poorly understood. Here, we found that in addition to CASP8, CYLD is transcriptionally upregulated by IFNγ-induced transcription factor IRF1. IRF1-mediated CASP8 and CYLD upregulation additively mediates TNF/IFNγ-induced cancer cell death. Clinically, the expression levels of TNF, IFNγ, CYLD, and CASP8 in melanoma tumors are increased in patients responsive to immune checkpoint blockade (ICB) therapy after anti-PD-1 treatment. Accordingly, our genetic screen revealed that ELAVL1 (HuR) is required for TNF/IFNγ-induced caspase-8 activation. Mechanistically, ELAVL1 binds CASP8 mRNA and extends its stability to sustain caspase-8 expression both in IFNγ-stimulated and in basal conditions. Consequently, ELAVL1 determines death receptors-initiated caspase-8-dependent cell death triggered from stimuli including TNF and TRAIL by regulating basal/stimulated caspase-8 levels. As caspase-8 is a master regulator in cell death and inflammation, these results provide valuable clues for tumor immunotherapy and inflammatory diseases.


Asunto(s)
Inmunoterapia , Factor 1 Regulador del Interferón , Interferón gamma , Melanoma , Humanos , Caspasa 8/genética , Muerte Celular , Proteína 1 Similar a ELAV/genética , Inflamación , Factor 1 Regulador del Interferón/genética , Melanoma/genética , Interferón gamma/genética , Factor de Necrosis Tumoral alfa/genética , Enzima Desubiquitinante CYLD/genética , Animales , Ratones
9.
Am J Physiol Cell Physiol ; 326(5): C1494-C1504, 2024 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-38406824

RESUMEN

Primary Sjögren's syndrome (pSS) is characterized by its autoimmune nature. This study investigates the role of the IFNγ SNP rs2069705 in modulating the susceptibility to pSS. Differential expression of IFNγ and BAFF was analyzed using the GEO database's mRNA microarray GSE84844. Genotyping of the IFNγ SNP rs2069705 was conducted via the dbSNP website. The JASPAR tool was used for predicting transcription factor bindings. Techniques such as dual-luciferase reporter assays, Chromatin immunoprecipitation, and analysis of a pSS mouse model were applied to study gene and protein interactions. A notable increase in the mutation frequency of IFNγ SNP rs2069705 was observed in MNCs from the exocrine glands of pSS mouse models. Bioinformatics analysis revealed elevated levels of IFNγ and BAFF in pSS samples. The model exhibited an increase in both CD20+ B cells and cells expressing IFNγ and BAFF. Knocking down IFNγ resulted in lowered BAFF expression and less lymphocyte infiltration, with BAFF overexpression reversing this suppression. Activation of the Janus kinase (JAK)/STAT1 pathway was found to enhance transcription in the BAFF promoter region, highlighting IFNγ's involvement in pSS. In addition, rs2069705 was shown to boost IFNγ transcription by promoting interaction between its promoter and STAT4. SNP rs2069705 in the IFNγ gene emerges as a pivotal element in pSS susceptibility, primarily by augmenting IFNγ transcription, activating the JAK/STAT1 pathway, and leading to B-lymphocyte infiltration in the exocrine glands.NEW & NOTEWORTHY The research employed a combination of bioinformatics analysis, genotyping, and experimental models, providing a multifaceted approach to understanding the complex interactions in pSS. We have uncovered that the rs2069705 SNP significantly affects the transcription of IFNγ, leading to altered immune responses and B-lymphocyte activity in pSS.


Asunto(s)
Factor Activador de Células B , Linfocitos B , Interferón gamma , Polimorfismo de Nucleótido Simple , Síndrome de Sjögren , Activación Transcripcional , Síndrome de Sjögren/genética , Síndrome de Sjögren/inmunología , Síndrome de Sjögren/metabolismo , Síndrome de Sjögren/patología , Interferón gamma/genética , Interferón gamma/metabolismo , Polimorfismo de Nucleótido Simple/genética , Animales , Linfocitos B/inmunología , Linfocitos B/metabolismo , Factor Activador de Células B/genética , Factor Activador de Células B/metabolismo , Ratones , Humanos , Factor de Transcripción STAT1/genética , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT4/genética , Factor de Transcripción STAT4/metabolismo , Femenino , Modelos Animales de Enfermedad , Predisposición Genética a la Enfermedad , Quinasas Janus/metabolismo , Quinasas Janus/genética , Transducción de Señal/genética
10.
Sheng Wu Gong Cheng Xue Bao ; 40(2): 573-584, 2024 Feb 25.
Artículo en Chino | MEDLINE | ID: mdl-38369842

RESUMEN

Signal peptides (SP) are involved in regulating the secretion level and transmembrane translocation of chimeric antigen receptors (CAR), which is crucial for CAR-T cells. This study aimed to optimize the SP sequence by site-directed mutagenesis and investigate its impact on the killing function of CD19-CAR-T. Firstly, CAR vectors targeting CD19 containing wild-type SP (SP-wtY) or two mutant SP (SP-muK or SP-muR) were constructed using gene synthesis and molecular cloning techniques. The successfully constructed vector was packaged with lentivirus, and T cells were infected. The transfection efficiency of T cells was detected by flow cytometry, while the killing effect on target cells was assessed using the calcein release method. The secretion levels of cytokines interferon-γ (IFN-γ) and interferon-α (TNF-α) were measured using enzyme linked immunosorbent assay (ELISA). The results showed that successful construction of recombinant lentivirus plasmids with wild type and signal peptide mutation. After the transferring the lentivirus into T cells, the transfection efficiency of CD19-CAR carrying three signal peptides (SP-wtY, SP-muK, or SP-muR) were 33.9%, 35.5%, and 36.8%, respectively. Further killing assay showed that the tumor-killing effect of SP-muR cells was significantly higher than that of SP-muK and SP-wtY cells. When the ratio of effector to target was 10:1, the secretion levels of cytokines IFN-γ and TNF-α of CAR-T cells of the SP-muR group were significantly higher than those in SP-muK and SP-wtY groups. In summary, this study revealed that increasing the N-terminal positive charge of the signal peptide can improve the expression efficiency of CAR and promote the killing of CD19+ target cells. These findings provide a scientific basis the optimization and clinical application of CAR structure.


Asunto(s)
Receptores Quiméricos de Antígenos , Receptores Quiméricos de Antígenos/genética , Receptores Quiméricos de Antígenos/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Señales de Clasificación de Proteína/genética , Linfocitos T/metabolismo , Lentivirus/genética , Citocinas/metabolismo , Interferón gamma/genética , Interferón gamma/metabolismo , Mutagénesis Sitio-Dirigida
11.
Nat Nanotechnol ; 19(4): 565-575, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38212521

RESUMEN

Lung carcinoma is one of the most common cancers and has one of the lowest survival rates in the world. Cytokines such as interleukin-12 (IL-12) have demonstrated considerable potential as robust tumour suppressors. However, their applications are limited due to off-target toxicity. Here we report on a strategy involving the inhalation of IL-12 messenger RNA, encapsulated within extracellular vesicles. Inhalation and preferential uptake by cancer cells results in targeted delivery and fewer systemic side effects. The IL-12 messenger RNA generates interferon-γ production in both innate and adaptive immune-cell populations. This activation consequently incites an intense activation state in the tumour microenvironment and augments its immunogenicity. The increased immune response results in the expansion of tumour cytotoxic immune effector cells, the formation of immune memory, improved antigen presentation and tumour-specific T cell priming. The strategy is demonstrated against primary neoplastic lesions and provides profound protection against subsequent tumour rechallenge. This shows the potential for locally delivered cytokine-based immunotherapies to address orthotopic and metastatic lung tumours.


Asunto(s)
Vesículas Extracelulares , Neoplasias Pulmonares , Humanos , Interleucina-12/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , ARN Mensajero/genética , Interferón gamma/genética , Citocinas , Microambiente Tumoral
12.
Immunobiology ; 229(2): 152787, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38271857

RESUMEN

Increased susceptibility to bacterial infections like tuberculosis (TB) is one of the complications of type 2 diabetes, however the underlying mechanisms remains poorly characterized. To explore how chronic hyperglycemia in diabetes affects progression of active TB, we examined mRNA expression of M1 (proinflammatory) and M2 (anti-inflammatory) cytokines/markers, in monocyte-derived macrophages obtained from patients with PTB + DM (pulmonary TB + diabetes mellitus type 2), patients with DM alone, patients with PTB alone, and healthy individuals (controls). Our findings indicate a dysregulated cytokine response in patients with both PTB and DM, characterized by decreased expression levels of interferon-gamma (IFN-γ) and inducible nitric oxide synthase (iNOS), along with increased expression levels of interleukin-1 beta (IL-1ß) and CD206. Furthermore, we observed a positive correlation of IL-1ß and CD206 expression with levels of glycosylated hemoglobin (HbA1c) in both PTB + DM and DM groups, while IFN-γ showed a positive correlation with HbA1c levels, specifically in the PTB + DM group. Additionally, M1 cytokines/markers, IL-1ß and iNOS were found to be significantly associated with the extent of sputum positivity in both PTB and PTB + DM groups, suggesting it to be a function of increased bacterial load and hence severity of infection. Our data demonstrates that tuberculosis in individuals with PTB + DM is characterized by altered M1/M2 cytokine responses, indicating that chronic inflammation associated with type 2 diabetes may contribute to increased immune pathology and inadequate control of tuberculosis infection.


Asunto(s)
Diabetes Mellitus Tipo 2 , Hiperglucemia , Tuberculosis Pulmonar , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Hemoglobina Glucada , Tuberculosis Pulmonar/complicaciones , Macrófagos , Citocinas , Interferón gamma/genética
13.
Gene ; 903: 148224, 2024 Apr 20.
Artículo en Inglés | MEDLINE | ID: mdl-38286270

RESUMEN

BACKGROUND: Cutaneous leishmaniasis (CL) is a complex, multifactorial disease that results from environmental factors such as parasite polymorphism, phlebotomine vectors, and host genetic factors. Some studies have identified specific genetic factors that may be associated with cutaneous leishmaniasis. The objective of this research was to resolve the association of 8 cytokine polymorphisms, including TNF-α -308 A/G (rs 1800629), TNF-α -238 A/G (rs 361525), TGF-ß1 -509 T/C (rs 1800469), TGF-ß1+ 915 G/C (rs 1800471), IFN-γ -874 T/A (rs 2430561), IFN-γ -179 G/A (rs 2069709), IL-10 -819 C/T (rs 1800871), and IL-10 -592 A/C (rs 1800872) with susceptibility to CL. METHODS: A total of 152 patients with designated CL and 100 healthy controls were selected from those referred to Sistan and Baluchestan hospitals. CL was diagnosed by microscopic examination of Giemsa-stained samples and culture. Leishmania species were identified using ITS2 gene PCR amplification with universal primers. Genetic polymorphism was determined by the ARMS PCR method on extracted genomic DNA of individuals. Eight SNPs cytokines were genotyped. RESULTS: Most of the Genotypic and allelic frequency comparisons between patients with CL and healthy subjects showed no difference, except 3. Individual SNP analysis showed highest association of TGF-ß1 -509 (rs1800469) -CC genotype (P = 0.03, OR = 7.05, 95 % CI = 3.3-15) with 5.7-fold increase, IFN-γ -874 (rs 2430561) -AA genotype (P = 0.04, OR = 4.72, 95 % CI = 1.6-14) with 4.2-fold increase, and IL10 -819 (rs1800871) -CC genotype (P = 0.05, OR = 3.63, 95 % CI = 2.5-5.3) with 1.9-fold increase, with CL. Odds ratios (ORs) and 95 % confidence intervals (CIs) were evaluated to assess the association power. CONCLUSION: Our results conclude that rs1800469 (TGF-ß1), rs2430561 (INF-γ), and rs1800872 (IL10) polymorphisms are associated with CL in southeastern Iranian people.


Asunto(s)
Citocinas , Leishmaniasis Cutánea , Pueblos de Medio Oriente , Humanos , Citocinas/genética , Predisposición Genética a la Enfermedad , Genotipo , Interferón gamma/genética , Interleucina-10/genética , Irán , Leishmaniasis Cutánea/genética , Pueblos de Medio Oriente/genética , Polimorfismo de Nucleótido Simple , Factor de Crecimiento Transformador beta1/genética , Factor de Necrosis Tumoral alfa/genética
14.
Free Radic Biol Med ; 212: 360-374, 2024 02 20.
Artículo en Inglés | MEDLINE | ID: mdl-38171407

RESUMEN

Evidence recently showed that pleiotropic cytokine interferon-gamma (IFN-γ) in the tumor microenvironment (TME) plays a positive role in hepatocellular carcinoma (HCC) progression through the regulation of liver cancer stem cells (LCSCs) in HCC. The present study explored the role and potential mechanism of mitochondrial programmed cell death-ligand 1 (PD-L1) and its regulation of ferroptosis in modulating the cancer stemness of LCSCs. It was shown that mimicking TME IFN-γ exposure increased the LCSCs ratio and cancer stemness phenotypes in HCC cells. IFN-γ exposure inhibited sorafenib (Sora)-induced ferroptosis by enhancing glutathione peroxidase 4 (GPX4) expression as well reactive oxygen species (ROS) and lipid peroxidation (LPO) generation in LCSCs. Furthermore, IFN-γ exposure upregulated PD-L1 expression and its mitochondrial translocation, inducing dynamin-related protein 1 (Drp1)-dependent mitochondrial fission and correlating with glycolytic metabolism reprogramming in LCSCs. The genetic intervention of PD-L1 promoted ferroptosis-dependent anti-tumor effects of Sora, reduced glycolytic metabolism reprogramming, and inhibited cancer stemness of HCC in vitro and in vivo. Our results revealed a novel mechanism that IFN-γ exposure-induced mitochondrial translocation of PD-L1 enhanced glycolytic reprogramming to mediate the GPX4-dependent ferroptosis resistance and cancer stemness in LCSCs. This study provided new insights into the role of mitochondrial PD-L1-Drp1-GPX4 signal axis in regulating IFN-γ exposure-associated cancer stemness in LCSCs and verified that PD-L1-targeted intervention in combination with Sora might achieve promising synergistic anti-HCC effects.


Asunto(s)
Carcinoma Hepatocelular , Ferroptosis , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Sorafenib/farmacología , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Interferón gamma/genética , Interferón gamma/metabolismo , Ferroptosis/genética , Línea Celular Tumoral , Microambiente Tumoral
15.
Fish Shellfish Immunol ; 146: 109402, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38281613

RESUMEN

Type II interferons (IFNs) are a key class of molecules regulating innate and adaptive immunity in vertebrates. In the present study, two members of the type II IFNs, IFN-γ and IFNγ-rel, were identified in the blunt snout bream (Megalobrama amblycephala). The open reading frame (ORF) of IFN-γ and IFNγ-rel was found to have 564 bp and 492 bp, encoding 187 and 163 amino acids, with the first 26 and 24 amino acids being the signal peptide, respectively. IFN-γ and IFNγ-rel genes showed a high degree of similarity to their zebrafish homologues, being 76.9 % and 58.9 %, respectively. In the phylogenetic tree, IFN-γ and IFNγ-rel were clustered with homologous genes in cyprinids. In blunt snout bream, IFN-γ and IFNγ-rel were constitutively expressed in trunk kidney, head kidney, spleen, liver, heart, muscle, gill, intestine and brain and were significantly up-regulated by poly (I:C) induction in head kidney, spleen, liver, gill and intestine. Using recombinant proteins of IFN-γ and IFNγ-rel, the surface plasmon resonance (SPR) results showed that IFN-γ was bound to CRFB6, CRFB13 and CRFB17, but mainly to CRFB6 and CRFB13, whereas IFN-γrel bound mainly to CRFB17 and had no affinity with CRFB6. These results contribute to a better understanding on type II IFNs and their receptor usage in teleost fish.


Asunto(s)
Cyprinidae , Pez Cebra , Animales , Pez Cebra/metabolismo , Filogenia , Interferón gamma/genética , Interferón gamma/metabolismo , Secuencia de Aminoácidos , Proteínas de Peces/química , Proteínas Recombinantes/genética , Aminoácidos/genética
16.
Biol Pharm Bull ; 47(1): 175-186, 2024 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-38092386

RESUMEN

Autophagy and M1 macrophage polarization play important roles in the regulation of inflammation in atopic dermatitis (AD). Dictamnine is one of the main ingredients in Cortex Dictamni, a widely used traditional Chinese medicine for the treatment of dermatitis. In the present study, we investigated the anti-inflammatory effects of dictamnine on AD like skin lesions and M1 macrophage polarization. A 2,4-dinitrofluorobenzene (DNFB) triggered AD like skin lesions models in mice was established to identify the ameliorative effects of dictamnine on AD in vivo. In addition, an M1 macrophage polarization model was co-stimulated by lipopolysaccharide (LPS) and interferon-γ (IFN-γ) using phorbol myristate acetate (PMA) differentiated THP-1 cells, to investigate the effect of dictamnine on promoting autophagy and inhibiting inflammatory factor release. Dictamnine suppressed DNFB-induced skin inflammation by inhibiting M1 macrophage polarization, up-regulating the expression of microtubule-associated protein 1A/1B-light chain 3 (LC3) expression, and promoting macrophage autophagy at inflammatory sites. Dictamnine also could reduce the release of interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP-1), and interleukin-8 (IL-8), and down-regulate the mRNA expression of these genes in LPS-IFN-γ triggered M1 polarized macrophages. Dictamnine ameliorates AD like skin lesions by inhibiting M1 macrophage polarization and promoting autophagy. Hence, dictamnine is expected to be a potential therapeutic candidate for AD.


Asunto(s)
Dermatitis Atópica , Quinolinas , Ratones , Animales , Dermatitis Atópica/inducido químicamente , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/metabolismo , Dinitrofluorobenceno , Lipopolisacáridos , Inflamación/metabolismo , Macrófagos/metabolismo , Autofagia , Interferón gamma/genética , Interferón gamma/metabolismo
17.
Int Immunopharmacol ; 126: 111152, 2024 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-37977066

RESUMEN

OBJECTIVE: This study aimed to analyze the differences in the expression of Toll-like receptors (TLRs) and nuclear factor erythroid 2-related factor 2 (Nrf2) in ear effusion in children with different types of otitis media (OM), to elaborate the relationship between the expression of TLRs and Nrf2 in ear effusion and the pathogenesis of OM, and to explore the relationship between the two indicators and pro-inflammatory cytokines in children with OM, thereby laying a scientific foundation for revealing the underlying molecular mechanisms of the progression of different types of OM. METHODS: A total of 73 children with OM who were treated in our hospital from March 2019 to July 2021 were selected as the study subjects. By using the cross-sectional investigation method, participants were divided into three groups according to the different pathological types, including the secretory OM group (30 cases), the chronic suppurative OM group (27 cases), and the cystic lesional OM group (16 cases). The levels of Nrf2, TLR2, TLR4 and proinflammatory cytokines [interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), transforming growth factor-ß 1(TGF-ß1), procalcitonin (PCT) and interleukin-1ß (IL-1ß)] were detected in ear effusion of children with different types of OM. Linear regression was used to analyze the correlation between the Nrf2, TLR2 and TLR4 expression levels and pro-inflammatory cytokines in ear effusion. RESULTS: The expression levels of TNF-α and PCT in the ear effusion of the children under 3 years old were significantly higher than that of the children between 3 and 5 years old and that of the children between 6 and 8 years old (all P < 0.001). The mRNA levels of Nrf2, TLR2 and TLR4 in the ear effusion of the children from the chronic suppurative OM group were higher than these from the secretory OM group (P < 0.001, P = 0.008 and P = 0.021). The mRNA levels of Nrf2, TLR2, and TLR4 in the ear effusion of the children from the cystic lesional OM group were higher than those from the chronic suppurative OM group (P < 0.001, P = 0.029 and P = 0.018). A prominent increase in the concentrations of IFN-γ, TNF-α, TGF-ß1, PCT and IL-1ß was found in the ear effusion of children from the chronic suppurative OM group compared to these from the secretory OM group (P = 0.021, P = 0.044, P = 0.048, P = 0.004 and P = 0.001). The concentrations of IFN-γ, TNF-α, TGF-ß1, PCT and IL-1ß in the ear effusion of the children from the cystic lesional OM group were markedly increased as compared with these from the chronic suppurative OM group (P < 0.001, P = 0.004, P = 0.003, P < 0.001 and P < 0.001). Nrf2, TLR2 and TLR4 were taken as independent variables, and inflammatory indexes, including IFN-γ, TNF-α, TGF-ß1, PCT and IL-1ß were used as dependent variables for the linear regression analysis. The results showed that Nrf2, TLR2 and TLR4 were positively correlated with the secretion levels of pro-inflammatory cytokines after adjusting for age, sex, course and the OM classification (all P < 0.05). CONCLUSION: The expressions of Nrf2, TLR2 and TLR4 in the ear effusion of children with different types of OM gradually increased with the severity of the disease, these were significantly positively correlated with the pro-inflammatory cytokines of the children. Nrf2/TLR signaling pathway maintained chronic inflammation in OM, induced damage of middle ear tissue, and promoted the transition from acute OM to chronic OM.


Asunto(s)
Otitis Media , Factor de Crecimiento Transformador beta1 , Niño , Preescolar , Humanos , Estudios Transversales , Citocinas/metabolismo , Interferón gamma/genética , Factor 2 Relacionado con NF-E2/genética , Otitis Media/genética , ARN Mensajero/metabolismo , Receptor Toll-Like 2/genética , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismo , Receptores Toll-Like/genética , Factor de Necrosis Tumoral alfa/metabolismo
18.
Biol Trace Elem Res ; 202(5): 2052-2061, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-37540448

RESUMEN

This study was conducted to evaluate the effects of different doses of selenium (Se) from Sel-Plex© (selenium-enriched Saccharomyces cerevisiae yeast) supplement on the antioxidant status, the antibody titers against the foot-and-mouth disease virus, and the expression of interleukin-2 (IL-2) and interferon-γ (IFN-γ) genes in ewes during the hot season. Six ewes were kept at 25 °C and received basal diet (the negative control group), and 24 ewes were kept at 38 °C for 5 h per day and received no supplement (the positive control), 0.15, 0.30, and 0.45 mg Se/kg. Ewes in the positive control had higher (P<0.001) liver enzyme activity, malondialdehyde (MDA), and cortisol levels, and lower antibody titer than the negative control. The liver enzymes' lowest (P<0.001) activities were observed in ewes receiving 0.30 and 0.45 mg Se/kg. Ewes receiving 0.30 and 0.45 mg Se/kg had lower MDA levels than other treatments. Ewes receiving 0.30 and 0.45 mg Se/kg had higher (P<0.001) total antioxidant capacity levels than those receiving 0.15 mg Se/kg and the positive control. Se-supplemented groups had lower (P<0.001) relative expression of IL-2 and higher (P<0.04) expression of IFN-γ than the positive control. The antibody titer was the same in the positive control and the group receiving 0.15 mg Se/kg. Ewes fed a diet with 0.30 and 0.45 mg Se/kg had higher (P<0.011) antibody titer than the positive control. The Se supplementation can reverse the decrease of antioxidant capacity and immune function caused by heat stress, and 0.3 mg Se/kg from Sel-Plex©is the best dose.


Asunto(s)
Antioxidantes , Selenio , Animales , Ovinos , Femenino , Antioxidantes/farmacología , Selenio/farmacología , Selenio/fisiología , Interleucina-2/genética , Interferón gamma/genética , Estaciones del Año , Suplementos Dietéticos , Dieta , Saccharomyces cerevisiae , Inmunidad , Alimentación Animal/análisis
19.
Clin Infect Dis ; 78(1): 94-97, 2024 01 25.
Artículo en Inglés | MEDLINE | ID: mdl-37647624

RESUMEN

We describe bedside-to-bench immunological and genetic elucidation of defective pyroptosis attributable to novel caspase 4 defect mediating pathogen-triggered inflammatory programmed cell death, in the setting of severe pneumonia and abscess-forming melioidosis in an overtly healthy host failing to clear Burkholderia pseudomallei infection, and how targeted adjunctive biological therapy led to a successful outcome.


Asunto(s)
Burkholderia pseudomallei , Oxigenación por Membrana Extracorpórea , Melioidosis , Humanos , Melioidosis/tratamiento farmacológico , Burkholderia pseudomallei/genética , Interferón gamma/genética , Mutación
20.
Artículo en Inglés | MEDLINE | ID: mdl-37874649

RESUMEN

Interferon-gamma (IFN-γ) has been established to play a pivotal role in the pathogenesis of tuberculosis (TB). Existing evidence suggests a potential association between the genetic poly-morphisms of IFN-γ and the susceptibility to TB. However, this association remains a topic of controversy. To address this knowledge gap, a meta-analysis was conducted to provide more accurate results regarding their relationship. The pooled odds ratio along with its corresponding 95% confidence interval was calculated using four different gene models. This analytical approach served to evaluate the strength of the association between single nucleotide polymorphisms (SNPs) and TB susceptibility. Additionally, we determined whether a fixed effect model or a random effect model should be applied based on the extent of heterogeneity. Egger's test was used to evaluate publication bias. This study included a total of nine studies, involving 4509 patients with TB and 4378 healthy controls. In non-Asian populations, a C > T mutation at polymorphic variant rs2069705 and a T > C mutation at rs2069718 was associated with an increased risk of TB. Conversely, among Asians, the variants rs2069705, rs2069718, and rs1861494 were not significantly associated with the risk of TB. Importantly, our investigation did not reveal any significant publication bias in the pooled results of the four gene models. In conclusion, this meta-analysis suggests that two SNPs in IFN-γ may be associated with TB susceptibility in non-Asian populations. However, for Asians, there is no evidence to support a conclusive relationship between these SNPs and the risk of TB.


Asunto(s)
Predisposición Genética a la Enfermedad , Tuberculosis , Humanos , Interferón gamma/genética , Tuberculosis/genética , Polimorfismo de Nucleótido Simple
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