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1.
Life Sci ; 273: 119263, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33636177

RESUMO

AIMS: Previous reports have found that STAT4 is involved in the epithelial-mesenchymal transition (EMT), thereby regulating the metastasis and invasion of ovarian cancer. However, the mechanisms underlying remain unclear. MAIN METHODS: We first established hypoxia-induced in vivo and in vitro models. The expression levels of signal transducer and activator of transcription 4 (STAT4), the markers of EMT and microRNA-200a (miR-200a) were assessed by western blot and qRT-PCR analysis, respectively. Through the bioinformatics analysis and luciferase assay, the relationship between miR-200a and SATA4 was performed. The gain- and loss-function experiments were performed to examine the role of miR-200a/STAT4 axis. KEY FINDINGS: The results showed that the protein level of STAT4 was significantly up-regulated in our hypoxia-exposed models, and contributed to the regulating of EMT. Besides, we found STAT4 was a direct target of miR-200a. Overexpression of miR-200a repressed the expression of STAT4, and inhibited EMT progress, whereas the silencing of miR-200a promoted the STAT4-mediated EMT regulation both in vitro and in vivo. SIGNIFICANCE: Our results provided a potential molecular mechanism by which miR-200a involved in hypoxia-induced metastasis and invasion in ovarian cancer, suggesting a possible target for the treatment of ovarian cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica , Hipóxia/fisiopatologia , MicroRNAs/genética , Neoplasias Ovarianas/patologia , Fator de Transcrição STAT4/metabolismo , Animais , Apoptose , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Movimento Celular , Proliferação de Células , Transição Epitelial-Mesenquimal , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Prognóstico , Fator de Transcrição STAT4/genética , Transdução de Sinais , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Cell Rep ; 30(4): 984-996.e4, 2020 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-31995767

RESUMO

The induction of broadly neutralizing antibodies (bnAbs) is highly desired for an effective vaccine against HIV-1. Typically, bnAbs develop in patients with high viremia, but they can also evolve in some untreated HIV-1 controllers with low viral loads. Here, we identify a subgroup of neutralizer-controllers characterized by myeloid DCs (mDCs) with a distinct inflammatory signature and a superior ability to prime T follicular helper (Tfh)-like cells in an STAT4-dependent fashion. This distinct immune profile is associated with a higher frequency of Tfh-like cells in peripheral blood (pTfh) and an enrichment for Tfh-defining genes in circulating CD4+ T cells. Correspondingly, monocytes from this neutralizer controller subgroup upregulate genes encoding for chemotaxis and inflammation, and they secrete high levels of IL-12 in response to TLR stimulation. Our results suggest the existence of multi-compartment immune networks between mDCs, Tfh, and monocytes that may facilitate the development of bnAbs in a subgroup of HIV-1 controllers.


Assuntos
Anticorpos Neutralizantes/imunologia , Linfócitos T CD4-Positivos/imunologia , Células Dendríticas/imunologia , Anticorpos Anti-HIV/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Monócitos/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Adulto , Idoso , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Linhagem Celular , Sobrevivência Celular/imunologia , Células Dendríticas/metabolismo , Feminino , Regulação da Expressão Gênica/imunologia , Humanos , Interleucina-12/metabolismo , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , RNA-Seq , Fator de Transcrição STAT4/genética , Fator de Transcrição STAT4/metabolismo , Linfócitos T Auxiliares-Indutores/metabolismo , Células Th1/imunologia , Células Th1/metabolismo
3.
Eur J Dermatol ; 29(5): 468-476, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31789272

RESUMO

Systemic sclerosis (SSc) is a predominantly T-cell-mediated autoimmune disorder with a characteristic sequence of Th1 and Th2 inflammation resulting in fibrosis. The contribution of differentiated memory T-cell subpopulations and methylation of CpG regions of Th1- or Th2-specific transcription factor genes on the inflammatory cytokine signature in SSc is not well understood. The study aimed to investigate phenotypic differentiation, the cytokine signature, sensitivity of memory T cells to in vitro suppression by autologous regulatory T cells (Tregs), and methylation of Th1- and Th2-specific transcription factor genes in patients with limited (lcSSc) and diffuse cutaneous SSc (dcSSc) compared to healthy donors (HD). Phenotype/intracellular cytokine production and methylation of Th1- and Th2-specific transcription factor genes were determined by flow cytometry and epigenetic analysis, respectively, and compared between patients with lcSSc, dcSSc and HD. Discrimination of CD4+ T cells that lack CCR7 expression revealed that CCR7- CD4+ memory T cells and effectors are producers of intracellular TNFα, IL-13 and IL-4, particularly in dcSSc. A proportional increase in CCR7- memory T cells was demonstrated by SSc-derived CD4+ T-cells after insufficient suppression by Tregs. A higher level of methylation of GATA3 or STAT4 (Th2- and Th1-specific transcription factor genes, respectively) was observed in dcSSc. An abundance of specific CD4+ memory T-cell subpopulations strongly contributes to the production of pro-inflammatory cytokines in dcSSc. Our results suggest that therapeutic concepts should focus more intensively on the memory phenotype to control T cell-mediated inflammation in SSc patients.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Citocinas/biossíntese , Receptores CCR7/genética , Escleroderma Sistêmico/imunologia , Ilhas de CpG/genética , Metilação de DNA , Fator de Transcrição GATA3/genética , Expressão Gênica , Humanos , Antígenos Comuns de Leucócito/imunologia , Linfopenia/imunologia , Fator de Transcrição STAT4/genética , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/metabolismo , Proteínas com Domínio T/genética , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th2/imunologia
4.
Biomed Res Int ; 2019: 1703842, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31871930

RESUMO

Systemic lupus erythematosus (SLE) is characterized by systemic end-organ damage. We investigated the involvement of IRF5, TLR-7, MECP2, STAT4, and TNFSF4 genes and TNF-α, IFN-γ, IL-2, IL-12, IL-6, and IL-10 cytokines in SLE pathogenesis and in organ damage in Jordanian patients. Blood was collected from 51 patients and 50 controls. Expression levels of SLE genes in PBMCs and cytokine levels were determined using RT-PCR and ELISA, respectively. Expression levels of all genes and levels of TNF-α, IL-12, IL-6, and IL-10 were higher in SLE patients than those in controls (p < 0.05), whereas IL-2 level was lower. High STAT4 (α), TNFSF4, and IL-10 levels correlated with cardiovascular damage, and high MECP2 (α) and TNF-α correlated with renal damage. Pulmonary and musculoskeletal damages correlated with high levels of TNFSF4. We concluded that STAT4 and TNFSF4 genes with TNF-α and IL-10 cytokines could be used as biomarkers to assess SLE activity and manage treatment.


Assuntos
Citocinas/metabolismo , Fatores Reguladores de Interferon/metabolismo , Lúpus Eritematoso Sistêmico/metabolismo , Proteína 2 de Ligação a Metil-CpG/metabolismo , Ligante OX40/metabolismo , Fator de Transcrição STAT4/metabolismo , Receptor 7 Toll-Like/metabolismo , Adulto , Biomarcadores/sangue , Citocinas/sangue , Feminino , Regulação da Expressão Gênica , Humanos , Fatores Reguladores de Interferon/genética , Interferon gama/metabolismo , Interleucina-10/metabolismo , Interleucina-12/metabolismo , Interleucina-2/metabolismo , Interleucina-6/metabolismo , Jordânia , Lúpus Eritematoso Sistêmico/genética , Masculino , Proteína 2 de Ligação a Metil-CpG/genética , Ligante OX40/genética , RNA Mensageiro/metabolismo , Fator de Transcrição STAT4/genética , Receptor 7 Toll-Like/genética , Fator de Necrose Tumoral alfa/metabolismo
5.
Immunol Res ; 67(4-5): 408-415, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31741236

RESUMO

The interleukin (IL)-12/interferon(IFN)γ axis plays an important role in the control of mycobacterial diseases as demonstrated by the increased susceptibility to mycobacterial species in patients with an inborn error of the IL-12-dependent IFNγ immunity. Here, we report a novel mutation in the IL-12Rß1 gene in a female Pakistani patient who was born in a consanguineous marriage and developed severe bacille Calmette-Guérin (BCG) infection and recurrent tuberculosis. After reviewing the patient's clinical records, she was investigated for IL-12/IFNγ defects using enzyme-linked immunosorbent assay (ELISA), flow cytometry, and DNA genetic Sanger sequencing. Quantification of secretory cytokines from the patient's peripheral blood mononuclear cells (PBMCs) revealed significantly reduced IFNγ production. Flow cytometric analysis revealed no surface expression of IL-12Rß1 on PHA-activated T lymphocytes. In addition, IL-12-induced impaired STAT4 phosphorylation in the patient's lymphocytes when compared with those from five healthy controls. The genetic analysis of IL-12Rß1 gene identified a novel nonsense mutation c.199G>T/p.E67* within exon 3, which encodes part of the cytokine-binding region (CBR). In silico analysis indicates that this novel nonsense mutation generates a truncated protein with an apparent inactivating effect. Our data expand the genetic spectrum of IL-12Rß1 deficiency. Moreover, our findings highlight the need for developing newborn screening for patients with primary immunodeficiency associated with mycobacterial infections in areas where BCG vaccination is mandatory in order to improve the treatment of patients, and consequently their quality of life.


Assuntos
Códon sem Sentido , Receptores de Interleucina-12 , Tuberculose , Adulto , Criança , Éxons , Feminino , Humanos , Fosforilação , Receptores de Interleucina-12/genética , Receptores de Interleucina-12/imunologia , Recidiva , Fator de Transcrição STAT4/genética , Fator de Transcrição STAT4/imunologia , Linfócitos T/imunologia , Linfócitos T/patologia , Tuberculose/genética , Tuberculose/imunologia , Tuberculose/patologia
6.
Int J Oncol ; 55(4): 805-822, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31485610

RESUMO

Hepatocellular carcinoma (HCC) is one the most common malignancies and has poor prognosis in patients. The aim of the present study is to explore the clinical significance of the main genes involved in the Janus kinase (JAK)­signal transducer and activator of transcription (STAT) pathway in HCC. GSE14520, a training cohort containing 212 hepatitis B virus­infected HCC patients from the Gene Expression Omnibus database, and data from The Cancer Genome Atlas as a validation cohort containing 370 HCC patients, were used to analyze the diagnostic and prognostic significance for HCC. Joint­effect analyses were performed to determine diagnostic and prognostic significance. Nomograms and risk score models were constructed to predict HCC prognosis using the two cohorts. Additionally, molecular mechanism analysis was performed for the two cohorts. Prognosis­associated genes in the two cohorts were further validated for differential expression using reverse transcription­quantitative polymerase chain reaction of 21 pairs of hepatitis B virus­infected HCC samples. JAK2, TYK2, STAT3, STAT4 and STAT5B had diagnostic significance in the two cohorts (all area under curves >0.5; P≤0.05). In addition, JAK2, STAT5A, STAT6 exhibited prognostic significance in both cohorts (all adjusted P≤0.05). Furthermore, joint­effect analysis had advantages over using one gene alone. Molecular mechanism analyses confirmed that STAT6 was enriched in pathways and terms associated with the cell cycle, cell division and lipid metabolism. Nomograms and risk score models had advantages for HCC prognosis prediction. When validated in 21 pairs of HCC and non­tumor tissue, STAT6 was differentially expressed, whereas JAK2 was not differentially expressed. In conclusion, JAK2, STAT5A and STAT6 may be potential prognostic biomarkers for HCC. JAK2, TYK2, STAT3, STAT4 and STAT5B may be potential diagnostic biomarkers for HCC. STAT6 has a role in HCC that may be mediated via effects on the cell cycle, cell division and lipid metabolism.


Assuntos
Carcinoma Hepatocelular/genética , Perfilação da Expressão Gênica/métodos , Hepatite B/genética , Janus Quinases/genética , Neoplasias Hepáticas/genética , Fatores de Transcrição STAT/genética , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/virologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Janus Quinase 2/genética , Neoplasias Hepáticas/virologia , Masculino , Nomogramas , Prognóstico , Estudos Prospectivos , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT4/genética , Fator de Transcrição STAT5/genética , Transdução de Sinais , Análise de Sobrevida , TYK2 Quinase/genética
7.
Mol Cell Endocrinol ; 498: 110541, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31415795

RESUMO

MicroRNAs (miRNAs) are small RNAs without protein-coding functions that negatively regulate target genes and play important roles in physiological and pathological processes. The aim of this work was to reveal a novel miRNA/gene pathway in diabetic retinopathy (DR). A microarray was used to screen miRNAs in samples from nondiabetic controls and patients with DR, and miR-223-3p was screened as a potential candidate. Quantitative real-time PCR (qRT-PCR) revealed that the level of miR-223-3p was frequently overexpressed in DR samples and human retinal endothelial cells (hRECs) in hyperglycemia, but it was decreased in hyperglycemia after the addition of transthyretin (TTR). In addition, according to cell proliferation, tube formation, and wound healing assays, the downregulation of miR-223-3p suppressed cell migration and proliferation, whereas miR-223-3p upregulation showed the opposite effects. Furthermore, luciferase assays identified F-box and WD repeat domain-containing 7 (FBXW7) as a target mRNA of miR-223-3p. High glucose conditions facilitated the recruitment of signal transducer and activator of transcription 4 (STAT4) and promoted the transcription of miR-223-3p. In hRECs, in a hyperglycemic environment, TTR inhibited STAT4 expression, downregulated the level of miR-223-3p, and finally promoted FBXW7 expression. This study found a novel mechanism whereby TTR might affect neovascularization through a newly identified STAT4/miR-223-3p/FBXW7 cascade in DR.


Assuntos
Retinopatia Diabética/complicações , Proteína 7 com Repetições F-Box-WD/metabolismo , Hiperglicemia/fisiopatologia , MicroRNAs/genética , Neovascularização Patológica/patologia , Pré-Albumina/metabolismo , Fator de Transcrição STAT4/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Movimento Celular , Proliferação de Células , Retinopatia Diabética/metabolismo , Retinopatia Diabética/patologia , Proteína 7 com Repetições F-Box-WD/genética , Feminino , Regulação da Expressão Gênica , Humanos , Hiperglicemia/metabolismo , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica/etiologia , Neovascularização Patológica/metabolismo , Pré-Albumina/genética , Retina/metabolismo , Retina/patologia , Fator de Transcrição STAT4/genética , Transdução de Sinais
8.
Dermatol Ther ; 32(5): e13029, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31330078

RESUMO

The aim of this study was to assess changes in the expression of STAT1, STAT3, STAT4, SOCS2, and IL17 in psoriatic patients under ustekinumab treatment and in healthy volunteers. The study group consisted of 14 patients suffering from psoriasis vulgaris qualified for ustekinumab therapy (4 women, 10 men) The control group consisted of 14 healthy volunteers (7 women, 7 men), their whole blood was used as a material in this study. A quantitative reverse transcription polymerase chain assay was used to amplify analyzed genes. To indicate the differences in expression of selected genes in the test and control groups, the Kruskal-Wallis and the post hoc Dunn's test was carried out. After 40 weeks of observation of the effectiveness of ustekinumab in patients with psoriasis, the expression of STAT1, STAT3, STAT4, IL17, and SOCS2 was silenced. Statistic differences in expression were observed for STAT3 (40 vs. 0 weeks, p < .05; 0 week vs. C, p < .05) and SOCS2 (0 week vs. C, p < .05). Patients with psoriasis vulgaris have higher levels of STAT1, STAT3, STAT4, SOCS2, and IL17 expression compared to healthy individuals. On the other hand, the treatment of ustekinumab lasting 40 weeks caused a decrease in the transcriptional activity of the analyzed genes.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Psoríase/genética , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT4/genética , Proteínas Supressoras da Sinalização de Citocina/genética , Ustekinumab/farmacologia , Adulto , Fármacos Dermatológicos/farmacologia , Feminino , Humanos , Interleucina-17/biossíntese , Interleucina-17/genética , Masculino , Pessoa de Meia-Idade , Psoríase/tratamento farmacológico , Psoríase/metabolismo , RNA/genética , Fator de Transcrição STAT1/biossíntese , Fator de Transcrição STAT4/biossíntese , Transdução de Sinais , Proteínas Supressoras da Sinalização de Citocina/biossíntese , Adulto Jovem
9.
Biosci Rep ; 39(6)2019 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-31160486

RESUMO

Background: It has been reported that polymorphisms of signal transducer and activator of transcription (STAT) 3 and STAT4 might be associated with susceptibility to hepatitis B virus (HBV) infection and risk of chronic hepatocellular carcinoma (HCC). Owing to limitation of sample size and inconclusive results, we conducted a meta-analysis to clarify the association. Methods: We identified relevant studies by a systematic search of Medline/PubMed, Embase, Web of Science and the Cochrane Library up to 20 February 2019. The strength of the association measured by odds ratios (OR) with 95% confidence intervals (CIs) was studied. All the statistical analyses were conducted based on Review Manager 5.3 software. Results: A total of 5242 cases and 2717 controls from five studies were included for the STAT3 polymorphism, 5902 cases and 7867 controls from nine studies for the STAT4 polymorphism. Our results suggested that STAT3 rs1053004 polymorphism was a significant risk factor of chronic HBV infection (C vs. T: OR = 1.17, 95% CI: 1.07-1.29, P A=0.0007; CC + CT vs. TT: OR = 1.38, 95% CI: 1.09-1.76, P A=0.008). Validation with all the genetic models revealed that rs7574865 polymorphism of STAT4 gene was closely associated with chronic HBV infection (P A<0.01) and chronic hepatitis B (CHB)-related HCC (P A<0.05). Meanwhile, the authenticity of the above meta-analysis results was confirmed by trial sequential analysis (TSA). Conclusions: The meta-analysis showed that STAT3 rs1053004 polymorphism may be the risk for developing chronic HBV infection but not associated with HCC. The present study also indicates that STAT4 rs7574865 polymorphism increased the risk of chronic HBV infection and HCC.


Assuntos
Carcinoma Hepatocelular/genética , Predisposição Genética para Doença , Vírus da Hepatite B , Hepatite B Crônica/genética , Neoplasias Hepáticas/genética , Proteínas de Neoplasias/genética , Polimorfismo Genético , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT4/genética , Carcinoma Hepatocelular/virologia , Humanos , Neoplasias Hepáticas/virologia
10.
Am J Physiol Heart Circ Physiol ; 317(3): H531-H540, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31225989

RESUMO

As an inflammatory disease afflicting the heart muscle, autoimmune myocarditis (AM) represents one of the foremost causes of heart failure. Accumulating evidence has implicated microRNAs (miRNAs) in the process of inflammation and autoimmunity. Hence, the current study aimed to investigate the mechanism by which miR-141-3p influences experimental AM (EAM). An EAM mouse model was established using 6-wk old male BALB/c mice, after which the expression of miR-141-3p and STAT4 was measured. Gain-of-function and loss-of-function investigations were performed to identify the functional role of miR-141-3p and STAT4 in EAM. Heart weight-to-body weight ratio, cardiac function, and degree of inflammation, as well as the levels of inflammation factors (IFN-γ, TNF-α, IL-2, IL-6, and IL-17) in the serum were detected. STAT4 was subsequently verified to be upregulated, and miR-141-3p was downregulated in the EAM mice. Furthermore, the overexpression of miR-141-3p or silencing of STAT4 was observed to reduce the heart weight-to-body weight ratio of EAM mice and improve cardiac function, while alleviating the degree of inflammatory cell infiltration in the myocardial tissue. Meanwhile, the overexpression of miR-141-3p was identified to diminish serum inflammatory factor levels by downregulating STAT4. Additionally, miR-141-3p could bind to STAT4 to downregulate its expression, ultimately mitigating inflammation and inducing an anti-inflammatory effect in EAM mice. Taken together, upregulation of miR-141-3p alleviates the inflammatory response in EAM mice by inhibiting STAT4, providing a promising intervention target for the molecular treatment of AM.NEW & NOTEWORTHY miR-141-3p is poorly expressed, and STAT4 is upregulated in experimental autoimmune myocarditis (EAM) mice. Overexpressing miR-141-3p inhibits EAM. miR-141-3p binds to and suppresses STAT4 expression. miR-141-3p overexpression inhibits inflammatory factors by downregulating STAT4. This study provides new insights into the treatment of autoimmune myocarditis.


Assuntos
Doenças Autoimunes/prevenção & controle , MicroRNAs/metabolismo , Miocardite/prevenção & controle , Miocárdio/metabolismo , RNA Interferente Pequeno/administração & dosagem , Terapêutica com RNAi , Fator de Transcrição STAT4/metabolismo , Animais , Antagomirs/administração & dosagem , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Citocinas/sangue , Citocinas/genética , Modelos Animais de Doenças , Redes Reguladoras de Genes , Mediadores da Inflamação/sangue , Masculino , Camundongos Endogâmicos BALB C , MicroRNAs/genética , Miocardite/genética , Miocardite/imunologia , Miocardite/metabolismo , Miocárdio/imunologia , Miosinas , Interferência de RNA , Fator de Transcrição STAT4/genética
11.
Gene ; 706: 181-187, 2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31082500

RESUMO

Systemic lupus erythematous (SEL) is a heterogeneous, systemic autoimmune disorder which is defined by its autoantibody pattern. Transcriptomic data analysis has shown pathways and immune system responses associated with SLE. Eight up-regulated genes (SOCE, MMP9, CXCL8, JUN, IL1B, NFKBIA, TNF and FOS) have been examined with four interactions among different pathways. These genes are associated with SNPs which have been identified through two datasets from SLE genome-wide association studies (GWAS). In this investigation, the GWAS results were integrated with pathway analysis of transcriptomes and several genes were detected with known SLE-related variations (TYK2, C5, SH2B, IRF5, IL2RA, STAT4, FCGR2A, IL7R, LYN, HLA-DRB and TNFAIP3). Pathway-based analysis on the Wikipathway Human Collection allowed the identification of prioritized variants in the relevant pathways, such as thymic stromal lymphopoietin (TSLP) signaling pathway linked to LYN, IL7R, STAT4 and rs7574865. Analysis of existing transcriptomes and GWAS data identified eight up-regulated candidate genes with more than four relationships among the different pathways associated with SNPs to pinpoint the relevant loci linked to SLE. The results of this investigation have expanded the number of candidate genes related to SLE and have highlighted possible pathways and GWAS-based methods for gene detection. Identification of the fundamental genes would assist in revealing the mechanisms responsible for SLE.


Assuntos
Perfilação da Expressão Gênica/métodos , Lúpus Eritematoso Sistêmico/genética , Estudos de Casos e Controles , Bases de Dados Genéticas , Ontologia Genética , Redes Reguladoras de Genes/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Fatores Reguladores de Interferon/genética , Lúpus Eritematoso Sistêmico/fisiopatologia , Polimorfismo de Nucleotídeo Único/genética , Receptores de IgG/genética , Fator de Transcrição STAT4/genética , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética
12.
J Immunol Res ; 2019: 7682827, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30882006

RESUMO

Sjögren's syndrome (SS) is a chronic autoimmune condition characterized by autoantibody production, sicca syndrome, and periepithelial lymphocytic lesions in target tissues. A predisposing genetic background is likely, and, to date, several polymorphisms in non-HLA genes have been explored with interesting results. We investigated the association between the STAT4, TRAF3IP2, HCP5, and IL10 polymorphisms and SS susceptibility and their possible role in the modulation of clinical and laboratory features. 195 consecutive patients with SS were enrolled and clinical and laboratory data were collected. 248 age- and sex-matched healthy subjects were used as controls. Genotyping was performed by allelic discrimination assays. A case-control association study and a phenotype-genotype correlation analysis were performed. A genetic risk profile was developed considering the risk alleles. Both the variant alleles of rs7574865 in the STAT4 gene and rs3099844 in the HCP5 gene were significantly more prevalent in patients than in controls (OR = 1.91 and OR = 2.44, respectively). The variant allele of rs3024505 of IL10 resulted to be a susceptibility allele (OR = 1.52), while the variant allele of rs1800872 seemed to confer a protective effect for the development of the disease (OR = 0.65). A risk genetic profile showed a higher probability to develop the disease in subjects with at least three risk alleles; subjects with 4 risk alleles were not observed in the controls. HCP5 rs3099844 was associated with anti-SSA (P = 0.006, OR = 3.07) and anti-SSB (P = 0.005, OR = 2.66) antibodies, severity of focus score (P = 0.03, OR = 12), and lymphoma development (P = 0.002, OR = 7.23). Patients carrying the STAT4 rs7574965 variant allele had a higher risk of monoclonal component and leukopenia (P = 0.002, OR = 7.6; P = 0.048, OR = 2.01, respectively). We confirmed the association of SS with the STAT4 and IL10 genes and we describe a novel association with HCP5. In particular, we describe an association of this specific SNP of HCP5 not only with disease development but also with autoantibody production and focus score suggesting a potential contribution of this variant to a more severe phenotype.


Assuntos
Predisposição Genética para Doença , Interleucina-10/genética , RNA Longo não Codificante/genética , Fator de Transcrição STAT4/genética , Síndrome de Sjogren/genética , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/genética , Proteínas Adaptadoras de Transdução de Sinal , Idoso , Alelos , Estudos de Casos e Controles , Feminino , Frequência do Gene , Estudos de Associação Genética , Genótipo , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único
13.
Ann Hum Genet ; 83(4): 249-255, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30887509

RESUMO

The STAT4 gene is vital to signaling pathways in the immune response. Immunological alterations are involved in the pathogenesis of endometriosis, and STAT4 polymorphisms may be linked to disease development. This study's aim is to evaluate the possible association between four STAT4 polymorphisms (rs7601754/G > A, rs11889341/C > T, rs7574865/T > G, and rs7582694/C > G) and the pathogenesis of endometriosis in Brazilian women. This case-control study's sample comprised 238 women with endometriosis and 201 healthy, fertile women without endometriosis (which was surgically confirmed). Genotyping was performed using the TaqMan system with a real-time polymerase chain reaction; the genotype, allele, and haplotype frequencies were then compared between groups. A single-polymorphism analysis revealed that the TT genotype of the rs7574865/T > G polymorphism was significantly more frequent in women with minimal or mild endometriosis than in the controls (10% vs. 5%, p = 0.047). The CGAC, GTAT, and GTAC haplotypes were significantly more frequent in the women with endometriosis-related infertility (5.8%, 4.1%, and 2.9%, respectively) than in the controls (2.4%, 1.1%, and 0.8%, respectively; p = 0.020, p = 0.011, and p = 0.032, respectively), but the GGGC and CTAT haplotypes were significantly more prevalent in the control group (34.7% and 13.9%, respectively) than among the infertile group (26.2% and 9.1%, respectively). In addition, the CGAC haplotype was more frequently found in those with minimal or mild endometriosis (6.8%) than in the controls (2.4%, p = 0.009), and the GTAT haplotype was more commonly found in those with moderate or severe disease (3.6%) than in the controls (1.1%, p = 0.028). These findings suggest that STAT4 polymorphisms can influence the pathogenesis of endometriosis.


Assuntos
Endometriose/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Fator de Transcrição STAT4/genética , Adulto , Alelos , Estudos de Casos e Controles , Endometriose/metabolismo , Endometriose/patologia , Feminino , Frequência do Gene , Estudos de Associação Genética , Genótipo , Haplótipos , Humanos , Fenótipo
14.
Iran J Immunol ; 16(1): 71-83, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30864557

RESUMO

BACKGROUND: STAT4 is a transcription factor that plays a role in various cytokine signaling pathways and in T cell subsets differentiation. Several studies have reported STAT4 gene polymorphism in association with various autoimmune diseases. OBJECTIVE: To evaluated the association between STAT4 rs7574865 SNP and RA risk by meta-analysis. METHODS: Two major databases, namely Scopus and PubMed, were searched to find studies investigating the STAT4 polymorphism and RA in different populations up to November 2017. Association between STAT4 polymorphism and RA were analyzed using pooled odds ratio (OR) and their corresponding 95% CI. RESULTS: In this meta-analysis, 21 population studies (16 papers) comprising 15,732 cases and 15641 healthy subjects evaluating the STAT4 gene rs7574865 SNP were included based on inclusion criteria. Herein, we found a significant positive association between minor T allele as well as different genotypes with the risk of RA. CONCLUSIONS: In summary, this study revealed an association between STAT4 gene rs7574865 SNP and risk of RA.


Assuntos
Artrite Reumatoide/etiologia , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Fator de Transcrição STAT4/genética , Alelos , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Frequência do Gene , Estudos de Associação Genética , Genótipo , Humanos , Razão de Chances , Viés de Publicação , Fator de Transcrição STAT4/metabolismo
15.
Curr Opin Rheumatol ; 31(3): 307-315, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30920455

RESUMO

PURPOSE OF REVIEW: Autoimmune diseases are of unknown origin, and they represent significant causes of morbidity and mortality. Here, we review new developments in the understanding of their pathogenesis that have led to development of well tolerated and effective treatments. RECENT FINDINGS: In addition to the long-recognized genetic impact of the HLA locus, interferon regulatory factors, PTPN22, STAT4, and NOX have been implicated in pathogenesis of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Smoking, ultraviolet light, diet, and microbiota exert strong environmental influence on development of RA and SLE. Metabolism has been recognized as a critical integrator of genetic and environmental factors, and it controls immune cell differentiation both under physiological and pathological conditions. SUMMARY: With the advent of high-throughput genetic, proteomic, and metabolomic technologies, the field of medicine has been shifting towards systems-based and personalized approaches to diagnose and treat common conditions, including rheumatic diseases. Regulatory checkpoints of metabolism and signal transduction, such as glucose utilization, mitochondrial electron transport, JAK, mTOR, and AMPK pathway activation, and production of pro-inflammatory cytokines IL-1, IL-6, and IL-17 have presented new targets for therapeutic intervention. This review amalgamates recent discoveries in genetics and metabolomics with immunological pathways of pathogenesis in rheumatic diseases.


Assuntos
Doenças Autoimunes/genética , Doenças Reumáticas/genética , Antirreumáticos/uso terapêutico , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Citocinas/imunologia , Humanos , Fatores Reguladores de Interferon/genética , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Proteômica , Doenças Reumáticas/tratamento farmacológico , Doenças Reumáticas/imunologia , Fator de Transcrição STAT4/genética , Transdução de Sinais
16.
Clin Exp Rheumatol ; 37(2): 333-337, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30620272

RESUMO

OBJECTIVES: Previous studies have demonstrated a potential role of STAT4 polymorphisms in increased juvenile idiopathic arthritis (JIA) risk in Caucasian populations; however, their role remains unclear in Han Chinese populations. We aimed to investigate single nucleotide polymorphisms (SNPs) of STAT4 and their role in JIA in Han Chinese populations. METHODS: This study included 205 JIA cases and 267 healthy controls. MassArray high-throughput DNA analyser and mass spectrometry were used to analyse 16 STAT4 SNP sites. The relationship between these SNPs and JIA risk was calculated using multiple logistic regressions. RESULTS: The G allele of rs11893432 was associated with an increased risk of JIA (odds ratio [OR]: 1.73; 95% confidence interval [CI]: 1.03-2.88; p=0.037). This relationship was observed in oligoarticular JIA (OR: 2.75; 95% CI: 1.29-5.83; p=0.026), and not in polyarticular JIA or systemic JIA. The GG motif was significantly correlated with oligoarticular JIA risk,compared to the CC+CG motif (OR: 1.88; 95% CI: 1.06-3.32; p=0.034). The C allele of rs1018981 and the A allele of rs10931481 were associated with a greater risk of polyarticular JIA (C allele: [OR: 7.82; 95% CI: 1.06-57.74; p=0.044]; A allele: [OR: 2.86; 95% CI: 1.23, 6.65; p=0.039). CONCLUSIONS: The G allele of rs11893432 was significantly associated with JIA risk, particularly oligoarticular JIA, in Han Chinese populations. SNPs at rs1018981 and rs10931481 were correlated with higher risk of polyarticular JIA.


Assuntos
Artrite Juvenil , Grupo com Ancestrais do Continente Asiático/genética , Polimorfismo de Nucleotídeo Único , Fator de Transcrição STAT4/genética , Adolescente , Alelos , Artrite Juvenil/genética , Estudos de Casos e Controles , Criança , Predisposição Genética para Doença/genética , Humanos
17.
Microb Pathog ; 128: 288-293, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30660736

RESUMO

The signal transducer and activator of transcription 4 (STAT4) gene encodes a transcription factor that transmits signals induced by several cytokines which play critical roles in the development of autoimmune and chronic inflammatory diseases. We performed an association study between STAT4 single nucleotide polymorphisms (SNPs) and tuberculosis (TB). 624 TB cases and 598 healthy controls were studied to compare allele/genotype frequencies of 4 SNPs in STAT4. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression. Genotyping was performed with the Sequenom MassARRAY SNP genotyping platform. Out of 4 SNPs tested in the study, rs4853542 allele A showed a 25% decreased risk of TB compared with allele G (P = 0.013, OR = 0.75, 95%CI: 0.60-0.94). However, it did not show significant differences under any genetic model after Bonferroni correction. No association was found for the other 3 SNPs with TB. In subgroup analyses, the protective effects of rs485342 allele A were stronger among younger subjects <25 years (P = 0.002, OR = 0.49, 95%CI: 0.31-0.76). Allele A of the rs4853542 polymorphism in STAT4 is not associated with TB susceptibility, but we demonstrated that rs4853542A allele decreased risk of TB in younger adults after Bonferroni correction.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Fator de Transcrição STAT4/genética , Tuberculose/genética , Adulto , Feminino , Frequência do Gene , Estudos de Associação Genética , Genótipo , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco , Adulto Jovem
18.
Am J Trop Med Hyg ; 100(2): 377-385, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30652669

RESUMO

Type 2 reaction (T2R) or erythema nodosum leprosum (ENL), a sudden episode of acute inflammation predominantly affecting lepromatous leprosy patients (LL), characterized by a reduced cellular immune response. This possibly indicates a close relationship between the onset of T2R and the altered frequency, and functional activity of T lymphocytes, particularly of memory subsets. This study performed ex vivo and in vitro characterizations of T cell blood subpopulations from LL patients with or without T2R. In addition, the evaluation of activity of these subpopulations was performed by analyzing the frequency of these cells producing IFN-γ, TNF, and IL-10 by flow cytometry. Furthermore, the expression of transcription factors, for the differentiation of T cells, were analyzed by quantitative real-time polymerase chain reaction. Our results showed an increased frequency of CD8+/TNF+ effector memory T cells (TEM) among T2Rs. Moreover, there was evidence of a reduced frequency of CD4 and CD8+ IFN-γ-producing cells in T2R, and a reduced expression of STAT4 and TBX21. Finally, a significant and positive correlation between bacteriological index (BI) of T2R patients and CD4+/TNF+ and CD4+/IFN-γ+ T cells was observed. Thus, negative correlation between BI and the frequency of CD4+/IL-10+ T cells was noted. These results suggest that CD8+/TNF+ TEM are primarily responsible for the transient alteration in the immune response to Mycobacterium leprae in ENL patients. Thus, our study improves our understanding of pathogenic mechanisms and might suggest new therapeutic approaches for leprosy.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Eritema Nodoso/imunologia , Hanseníase Virchowiana/imunologia , Mycobacterium leprae/patogenicidade , Fator de Necrose Tumoral alfa/imunologia , Adolescente , Adulto , Idoso , Linfócitos T CD4-Positivos/microbiologia , Linfócitos T CD8-Positivos/microbiologia , Estudos de Casos e Controles , Eritema Nodoso/genética , Eritema Nodoso/patologia , Feminino , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Memória Imunológica , Imunofenotipagem , Interferon gama/genética , Interferon gama/imunologia , Interleucina-10/genética , Interleucina-10/imunologia , Hanseníase Virchowiana/genética , Hanseníase Virchowiana/patologia , Masculino , Pessoa de Meia-Idade , Mycobacterium leprae/crescimento & desenvolvimento , Mycobacterium leprae/imunologia , Cultura Primária de Células , Fator de Transcrição STAT4/genética , Fator de Transcrição STAT4/imunologia , Transdução de Sinais , Proteínas com Domínio T/genética , Proteínas com Domínio T/imunologia , Fator de Necrose Tumoral alfa/genética
20.
Diagnosis (Berl) ; 6(3): 277-286, 2019 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-30511928

RESUMO

Background Clinical evidence indicates that genetic variations may interfere with the mechanism of drug action. Recently, it has been reported that the single nucleotide polymorphisms (SNPs) of STAT4, PTPN2, PSORS1C1 and TRAF3IP2RA genes are associated with the clinical efficacy of tumor necrosis factor (TNF) inhibitors in the treatment of rheumatoid arthritis (RA) patients. Therefore, the detection of the SNPs linked with TNF inhibitor efficacy may provide an important basis for the treatment of RA. This study intended to establish molecular diagnostic methods for genotyping the linked SNPs based on high resolution melting (HRM) curve analysis. Methods The polymerase chain reaction-HRM (PCR-HRM) curve analysis detecting systems were established by designing the primers of the four SNPs, rs7574865G>T, rs7234029A>G, rs2233945C>A and rs33980500C>T, and the performance and clinical applicability of which were evaluated by using the Sanger sequencing method and genotyping test for 208 clinical samples. Results The self-developed molecular diagnostic methods of PCR-HRM were confirmed to be able to correctly genotype the four SNPs, the sensitivity and specificity of which were 100% in this study. The repeatability and reproducibility tests showed that there is little variable in intra-assay and inter-assay (the coefficient of variation ranged from 0.01% to 0.07%). The slight changes of DNA template and primer concentrations, PCR cycle number and reaction system volume had no significant effect on the genotyping performance of the method. The PCR-HRM assays were also applied to other PCR thermocyclers with HRM function and use different saturation fluorescent dyes. Conclusions The PCR-HRM genotyping method established in this study can be applied to the routine molecular diagnosis of rs7574865, rs7234029, rs2233945 and rs33980500.


Assuntos
Técnicas de Genotipagem , Técnicas de Diagnóstico Molecular , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único , Inibidores do Fator de Necrose Tumoral , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Patologia Molecular , Proteína Tirosina Fosfatase não Receptora Tipo 2/genética , Proteínas/genética , Reprodutibilidade dos Testes , Fator de Transcrição STAT4/genética , Sensibilidade e Especificidade
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