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1.
Immunity ; 50(4): 778-795, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30995499

RESUMO

Forty years after its naming, interleukin-1 (IL-1) is experiencing a renaissance brought on by the growing understanding of its context-dependent roles and advances in the clinic. Recent studies have identified important roles for members of the IL-1 family-IL-18, IL-33, IL-36, IL-37, and IL-38-in inflammation and immunity. Here, we review the complex functions of IL-1 family members in the orchestration of innate and adaptive immune responses and their diversity and plasticity. We discuss the varied roles of IL-1 family members in immune homeostasis and their contribution to pathologies, including autoimmunity and auto-inflammation, dysmetabolism, cardiovascular disorders, and cancer. The trans-disease therapeutic activity of anti-IL-1 strategies argues for immunity and inflammation as a metanarrative of modern medicine.


Assuntos
Imunidade Adaptativa/imunologia , Citocinas/fisiologia , Imunidade Inata/imunologia , Inflamação/imunologia , Interleucina-1/fisiologia , Animais , Doenças Cardiovasculares/imunologia , Citocinas/genética , Citocinas/imunologia , Gastroenteropatias/imunologia , Hematopoese/imunologia , Humanos , Interleucina-1/imunologia , Linfócitos/imunologia , Camundongos , Camundongos Knockout , Família Multigênica , Neoplasias/imunologia , Doenças Neurodegenerativas/imunologia , Receptores de Citocinas/genética , Receptores de Citocinas/imunologia
2.
Cancer Sci ; 110(6): 1931-1946, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30974024

RESUMO

Activating mutations in cytokine receptors and transcriptional regulators govern aberrant signal transduction in T-cell lineage acute lymphoblastic leukemia (T-ALL). However, the roles played by suppressors of cytokine signaling remain incompletely understood. We examined the regulatory roles of suppressor of cytokine signaling 5 (SOCS5) in T-ALL cellular signaling networks and leukemia progression. We found that SOCS5 was differentially expressed in primary T-ALL and its expression levels were lowered in HOXA-deregulated leukemia harboring KMT2A gene rearrangements. Here, we report that SOCS5 expression is epigenetically regulated by DNA methyltransferase-3A-mediated DNA methylation and methyl CpG binding protein-2-mediated histone deacetylation. We show that SOCS5 negatively regulates T-ALL cell growth and cell cycle progression but has no effect on apoptotic cell death. Mechanistically, SOCS5 silencing induces activation of JAK-STAT signaling, and negatively regulates interleukin-7 and interleukin-4 receptors. Using a human T-ALL murine xenograft model, we show that genetic inactivation of SOCS5 accelerates leukemia engraftment and progression, and leukemia burden. We postulate that SOCS5 is epigenetically deregulated in T-ALL and serves as an important regulator of T-ALL cell proliferation and leukemic progression. Our results link aberrant downregulation of SOCS5 expression to the enhanced activation of the JAK-STAT and cytokine receptor-signaling cascade in T-ALL.


Assuntos
Epigênese Genética , Janus Quinases/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Fatores de Transcrição STAT/genética , Proteínas Supressoras da Sinalização de Citocina/genética , Animais , Linhagem Celular , Linhagem Celular Tumoral , DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , Progressão da Doença , Perfilação da Expressão Gênica , Humanos , Janus Quinases/metabolismo , Células Jurkat , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Terapêutica com RNAi/métodos , Receptores de Citocinas/genética , Receptores de Citocinas/metabolismo , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/genética , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Análise de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
3.
Genes Chromosomes Cancer ; 58(9): 619-626, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30859636

RESUMO

The germline variant at rs3824662 in GATA3 is a risk locus for Philadelphia-like acute lymphoblastic leukemia (Ph-like ALL), the biological subtype of B-cell precursor (BCP)-ALL defined by a distinct gene expression profile and the presence of specific somatic aberrations including rearrangements of CRLF2. In this study, we investigated whether rs3824662 in GATA3 associates with CRLF2 expression in leukemic cells and predicts prognosis in pediatric BCP-ALL patients treated according to the ALL Intercontinental Berlin-Frankfurt-Münster (IC BFM) 2009 (n = 645) and the ALL IC BFM 2002 (n = 216) protocols. High expression of CRLF2 was observed at both protein and mRNA levels (fourfold higher in AA than in CA + CC) among GATA3 AA variant carriers, independent of the presence of P2RY8-CRLF2 fusion. Additionally, the AA variant at rs3824662 was a significant factor affecting minimal residual disease level at the end of induction phase and overall survival regardless of the risk group and the protocol. The germline variant at rs3824662 in GATA3 is a prognostic factor which associates with CRLF2 expression in leukemic cells supporting the hypothesis that GATA3 may have a regulatory effect on the CRLF2 pathway in pediatric BCP-ALL.


Assuntos
Fator de Transcrição GATA3/genética , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Receptores de Citocinas/genética , Células Cultivadas , Criança , Pré-Escolar , Feminino , Mutação em Linhagem Germinativa , Humanos , Masculino , Fusão Oncogênica , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Receptores de Citocinas/metabolismo , Receptores Purinérgicos P2Y/genética , Análise de Sobrevida
4.
Arterioscler Thromb Vasc Biol ; 39(4): 787-798, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30760013

RESUMO

Objective- Psoriasis is an inflammatory skin disease which heightens the risk of cardiovascular disease. This study directly investigated vascular endothelial health and systemically altered pathways in psoriasis and matched controls. Approach and Results- Twenty patients (mean age, 40 years; 50% male) with active psoriasis and 10 age-, sex-matched controls were recruited. To investigate systemically alerted pathways, a deep sequencing omics approach was applied, including unbiased blood transcriptomic and targeted proteomic analysis. Vascular endothelial health was assessed by transcriptomic profiling of endothelial cells obtained from the brachial veins of recruited participants. Blood transcriptomic profiling identified inflammasome signaling as the highest differentially expressed canonical pathway ( Z score 1.6; P=1×10-7) including upregulation of CASP5 and interleukin ( IL) -1ß. Proteomic panels revealed IL-6 as a top differentially expressed cytokine in psoriasis with pathway analysis highlighting IL-1ß ( Z score 3.7; P=1.02×10-23) as an upstream activator of the observed upregulated proteins. Direct profiling of harvested brachial vein endothelial cells demonstrated inflammatory transcript (eg, IL-1ß, CXCL10, VCAM-1, IL-8, CXCL1, Lymphotoxin beta, ICAM-1, COX-2, and CCL3) upregulation between psoriasis versus controls. A linear relationship was seen between differentially expressed endothelial inflammatory transcripts and psoriasis disease severity. IL-6 levels correlated with inflammatory endothelial cell transcripts and whole blood inflammasome-associated transcripts, including CASP5 and IL-1ß. Conclusions- An unbiased sequencing approach demonstrated the inflammasome as the most differentially altered pathway in psoriasis versus controls. Inflammasome signaling correlated with psoriasis disease severity, circulating IL-6, and proinflammatory endothelial transcripts. These findings help better explain the heightened risk of cardiovascular disease in psoriasis. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT03228017.


Assuntos
Células Endoteliais/fisiologia , Inflamassomos/fisiologia , Psoríase/fisiopatologia , Adulto , Aorta/citologia , Moléculas de Adesão Celular/biossíntese , Moléculas de Adesão Celular/genética , Células Cultivadas , Citocinas/biossíntese , Citocinas/genética , Células Endoteliais/efeitos dos fármacos , Feminino , Perfilação da Expressão Gênica , Humanos , Inflamassomos/metabolismo , Masculino , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Proteoma , Psoríase/sangue , RNA Mensageiro/biossíntese , Receptores de Citocinas/biossíntese , Receptores de Citocinas/genética , Transdução de Sinais , Transcrição Genética , Transcriptoma
5.
Innate Immun ; 25(1): 60-72, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30782046

RESUMO

Here, the potential mechanisms of the protective effects of fish oil against LPS-induced liver injury in a piglet model were investigated by using RNA sequencing. Twenty-four piglets were used in a 2 × 2 factorial design, and the main factors included diet (5% corn oil or 5% fish oil) and immunological challenge (LPS or saline, on d 19). All piglets were slaughtered at 4 h after challenge, and liver samples were collected. Fish oil improved liver morphology and reduced TNF-α, IL-1ß and IL-6 productions after LPS challenge. RNA sequencing analysis showed fish oil had significant effect on the expressions of genes involved in immune response during LPS-induced inflammation. Selected gene expression changes were validated using quantitative RT-PCR. Fish oil reduced the expressions of pro-inflammatory genes IL1R1, IL1RAP, CEBPB and CRP, and increased that of anti-inflammatory genes IL-18BP, NFKBIA, IFIT1, IFIT2 and ATF3. Moreover, fish oil restored the expressions of some lipid metabolism-related genes, such as ACAA1, ACACA, ACADS and ACADM, which were only decreased in pigs fed a corn oil diet after LPS challenge. Our RNA sequencing reveals novel gene-nutrient interactions following fish oil supplementation and evoked inflammation, which add to the current understanding of the benefits of n-3 polyunsaturated fatty acids against liver injury.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Suplementos Nutricionais , Óleos de Peixe/administração & dosagem , Fígado/metabolismo , Animais , Citocinas/genética , Citocinas/metabolismo , Dieta , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Mediadores da Inflamação/metabolismo , Metabolismo dos Lipídeos/genética , Lipopolissacarídeos/imunologia , Fígado/patologia , Inibidor de NF-kappaB alfa/genética , Inibidor de NF-kappaB alfa/metabolismo , Receptores de Citocinas/genética , Receptores de Citocinas/metabolismo , Suínos , Desmame
6.
Acta Derm Venereol ; 99(6): 579-586, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30809683

RESUMO

Prurigo nodularis is a highly pruritic and hyperplastic chronic dermatosis with unknown pathogenesis. Many pruritogenic mediators, including nerve growth factor, interleukin (IL)-31, thymic stromal lymphopoietin, and endothelin-1, are implicated in chronic itch and inflammation. This study investigated the mRNA levels and immunoreactivity of the nerve growth factor, IL-31, thymic stromal lymphopoietin, and endothelin axes in both lesional and perilesional skin in prurigo nodularis by using quantitative real-time PCR and immunohistochemistry studies. The nerve growth factor high-affinity receptor tyrosine kinase receptor A was upregulated while the low affinity receptor p75 neurotrophin receptor was downregulated in prurigo nodularis lesions. Downregulated expression of IL-31/IL-31 receptor A and endothelin-3/endothelin receptor B and upregulation of thymic stromal lymphopoietin receptor were found in prurigo nodularis lesions. Aberrant expression of nerve growth factor, IL-31, thymic stromal lymphopoietin and endothelin axes was found in prurigo nodularis lesions, especially in the epidermis, indicating the importance of keratinocytes in prurigo nodularis pathogenesis.


Assuntos
Epiderme/metabolismo , Queratinócitos/metabolismo , Prurigo/genética , Prurigo/metabolismo , Adulto , Citocinas/genética , Citocinas/metabolismo , Regulação para Baixo , Endotelina-3/genética , Endotelina-3/metabolismo , Feminino , Expressão Gênica , Humanos , Hipersensibilidade/complicações , Hipersensibilidade/genética , Hipersensibilidade/metabolismo , Subunidade alfa de Receptor de Interleucina-7/genética , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Masculino , Pessoa de Meia-Idade , Fator de Crescimento Neural/genética , Fator de Crescimento Neural/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Prurigo/complicações , RNA Mensageiro/metabolismo , Receptor de Endotelina B/genética , Receptor de Endotelina B/metabolismo , Receptor trkA/genética , Receptor trkA/metabolismo , Receptores de Citocinas/genética , Receptores de Citocinas/metabolismo , Receptores de Interleucina/genética , Receptores de Interleucina/metabolismo , Receptores de Fator de Crescimento Neural/genética , Receptores de Fator de Crescimento Neural/metabolismo , Regulação para Cima
7.
BMC Infect Dis ; 19(1): 56, 2019 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-30651082

RESUMO

BACKGROUND: The mechanism behind HIV mediated immune activation remains debated, although the role of virus replication in this process is increasingly evident. Toll like Receptor 9 (TLR9) has been implicated in HIV mediated immune activation via sensing of viral CpG DNA. Polymorphisms in the TLR9 gene and promoter region including TLR9 1635A/G and 1486C/T have been found to be associated with multiple infectious diseases and cancers. METHODS: In the current study, we looked at the correlation of TLR9 polymorphisms 1635A/G and 1486C/T with key hallmarks of HIV disease in a cohort of 50 HIV infected patients. We analyzed CD4 counts, T cell immune activation characterized by upregulation of CD38 and HLA-DR and upregulation of plasma biomarkers of inflammation like LPS, sCD14, IL-6 and IP10 in the HIV patient cohort and compared it to healthy controls. RESULTS: We found that TLR9 1635AA genotype was associated with lower CD4 counts and significantly higher immune activation in both CD4+ and CD8+ T cells. Analysis of HIV associated plasma biomarkers including LPS, sCD14, IL-6 and IP10 revealed a strong correlation between IP10 and immune activation. Interestingly, IP10 levels were also found to be higher in HIV patients with the 1635AA genotype. Furthermore, the TLR9 1486C/T polymorphism that is in linkage disequilibrium with 1635A/G was weakly associated with lower CD4 counts, higher CD8 immune activation and higher IP10 levels. CONCLUSIONS: As TLR9 stimulation is known to induce IP10 production by dendritic cells, our findings provide new insights into HIV mediated immune activation and CD4 loss. TLR9 stimulation by viral CpG DNA may be important to HIV immunopathogenesis and the TLR9 polymorphisms 1635A/G and 1486C/T may be associated with disease progression.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/imunologia , Polimorfismo Genético , Receptores de Citocinas/sangue , Receptor Toll-Like 9/genética , Adulto , Linfócitos T CD8-Positivos/imunologia , Estudos de Coortes , Estudos Transversais , DNA Viral , Feminino , Infecções por HIV/genética , Infecções por HIV/virologia , Antígenos HLA-DR/genética , Antígenos HLA-DR/imunologia , Humanos , Interleucina-6/sangue , Ativação Linfocitária/imunologia , Masculino , Receptores de Citocinas/genética , Replicação Viral
8.
Genes Chromosomes Cancer ; 58(6): 396-401, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30578688

RESUMO

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic malignancy with few molecular alterations showing a consensual prognostic value. CRLF2 overexpression was recently identified in high-risk T-ALL patients. For these cases, no genomic abnormality was found to be associated with CRLF2 overexpression. IKZF1 has been recently shown to be a direct transcriptional regulator of CRLF2 expression. Moreover, it is known that NOTCH1 antagonizes IKZF1 in T-ALL. In light of these pieces of evidence, we reasoned that IKZF1 binding perturbation and CRLF2 upregulation could be associated in T-ALL. We evaluated two independent series of pediatric T-ALL cases (PHOP, n = 57 and TARGET, n = 264) for the presence of common T-ALL molecular abnormalities, such as NOTCH1/FBXW7 mutations. We also assessed CRLF2 and IKZF1 gene expression. CRLF2 overexpression was observed in 14% (PHOP) and 16% (TARGET) of T-ALL patients. No correlation was found between mRNA expression of CRLF2 and IKZF1 in both cohorts. Interestingly, we show that patients with mutations affecting NOTCH1-PEST domain and/or FBXW7 had higher CRLF2 expression (P = .04). In summary, we demonstrate for the first time that only mutations resulting in ICN1 (intracellular domain of NOTCH1) stabilization are associated with CRLF2 overexpression.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Receptor Notch1/genética , Receptores de Citocinas/genética , Humanos , Fator de Transcrição Ikaros/genética , Fator de Transcrição Ikaros/metabolismo , Mutação , Ligação Proteica , Domínios Proteicos , Estabilidade Proteica , Receptor Notch1/química , Receptor Notch1/metabolismo , Receptores de Citocinas/metabolismo
9.
Br J Haematol ; 184(3): 418-423, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30484860

RESUMO

Our study aimed to determine the expression pattern and clinical relevance of CD99 in paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). Our findings demonstrate that high expression levels of CD99 are mainly found in high-risk BCP-ALL, e.g. BCR-ABL1 and CRLF2Re/Hi , and that high CD99 mRNA levels are strongly associated with a high frequency of relapse, high proportion of positive for minimal residual disease at day 29 and poor overall survival in paediatric cohorts, which indicate that CD99 is a potential biomarker for BCP-ALL.


Assuntos
Antígeno 12E7/biossíntese , Biomarcadores Tumorais/biossíntese , Regulação Leucêmica da Expressão Gênica , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Antígeno 12E7/genética , Adolescente , Biomarcadores Tumorais/genética , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/metabolismo , Humanos , Lactente , Masculino , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Receptores de Citocinas/genética , Receptores de Citocinas/metabolismo , Taxa de Sobrevida , Adulto Jovem
10.
Oncol Rep ; 41(2): 885-894, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30535452

RESUMO

Acute B­cell lymphoblastic leukemia (B­ALL) is a common type of blood cancer, which is associated with aberrant gene expression. Cytokine receptor­like factor 2 (CRLF2) serves a crucial role in the growth and allergic and inflammatory responses of dendritic cells and T cells. The purpose of the present study was to investigate the potential therapeutic and prognostic effect of silencing the CRLF2­mediated RAC­α serine/threonine­protein kinase (AKT)/serine/threonine­protein kinase mTOR (mTOR) pathway in B­ALL. In our study, bone marrow specimens were collected from 128 children with B­ALL and 26 healthy children. The expression of CRLF2 in bone marrow tissue was detected using immunohistochemistry. The survival rates were compared among the children with high and low CRLF2 expression levels. BaF3 leukemia cells were treated with CRLF2 short hairpin RNA knockdown and/or the AKT/mTOR pathway specific inhibitor LY294002. mRNA and protein expression associated with CRLF2 and the AKT/mTOR pathway in each group was detected by reverse transcription­quantitative polymerase chain reaction analysis and western blotting. The viability of BaF3 cells in all the groups was assessed by Cell Counting Kit­8 assay; the migration and invasion of BaF3 cells were determined by wound healing and Transwell invasion assays; and the sensitivity of BaF3 cells to the chemotherapeutic drug imatinib was detected using flow cytometry. The results demonstrated that CRLF2 overexpression is associated with a poor prognosis in B­ALL, and the CRLF2/AKT/mTOR pathway is involved in the migration, invasion and chemotherapeutic agent­induced apoptosis of BaF3 cells.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Receptores de Citocinas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Medula Óssea/patologia , Movimento Celular/efeitos dos fármacos , Criança , Cromonas/farmacologia , Feminino , Técnicas de Silenciamento de Genes , Humanos , Masculino , Morfolinas/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Prognóstico , Intervalo Livre de Progressão , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Receptores de Citocinas/genética , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo
11.
Leukemia ; 33(4): 893-904, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30487598

RESUMO

Deregulated expression of the type I cytokine receptor, CRLF2, is observed in 5-15% of precursor B-cell acute lymphoblastic leukaemia (B-ALL). We have previously reported the genomic landscape of patients with CRLF2 rearrangements (CRLF2-r) using both whole genome and exome sequencing, which identified a number of potential clonal and sub-clonal genomic alterations. In this study, we aimed to assess when the CRLF2-r; IGH-CRLF2 or P2RY8-CRLF2, arose during the evolution of both Down syndrome-ALL (DS-ALL) and non-DS-ALL. Using fluorescence in situ hybridisation, we were able to track up to four structural variants in single cells from 47 CRLF2-r B-ALL patients, which in association with our multiplex single-cell analysis of a further four patients, permitted simultaneous tracking of copy number alterations, structural and single nucleotide variants within individual cells. We observed CRLF2-r arising as both early and late events in DS and non-DS-ALL patients. Parallel evolution of discrete clones was observed in the development of CRLF2-r B-ALL, either involving the CRLF2-r or one of the other tracked abnormalities. In-depth single-cell analysis identified both linear and branching evolution with early clones harbouring a multitude of abnormalities, including the CRLF2-r in DS-ALL patients.


Assuntos
Síndrome de Down/genética , Rearranjo Gênico , Leucemia Mieloide Aguda/genética , Receptores de Citocinas/genética , Análise de Célula Única/métodos , Adolescente , Adulto , Animais , Estudos de Casos e Controles , Criança , Pré-Escolar , Síndrome de Down/complicações , Síndrome de Down/patologia , Feminino , Humanos , Hibridização in Situ Fluorescente , Lactente , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/patologia , Masculino , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Mutação , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto Jovem
12.
Int Endod J ; 52(1): 5-12, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29904933

RESUMO

AIM: To investigate the DNA methylation profiles of immune response-related genes in apical periodontitis (AP) lesions. METHODOLOGY: The methylation profiles on the cytosine-phosphate-guanine (CpG) regions of 22 gene promoters involved in inflammation and autoimmunity were assessed in 60 human AP lesions and 24 healthy periodontal ligaments (controls) using a pathway-specific real-time polymerase chain reaction array (EpiTect® Methyl Signature PCR Array Human Inflammatory Response). Differentially methylated genes were subsequently assessed for their mRNA expression. Data analyses (One-way anova, Tukey's multiple comparisons tests and Mann-Whitney tests) were performed using GraphPad Prism 6 software. P values ≤ 0.05 were considered statistically significant. RESULTS: Significant DNA hypermethylation was observed for CXCL3 and FADD gene promoters in AP lesions when compared to control tissues (P < 0.001) and among other genes (P < 0.05). In contrast, IL12B and IL4R were associated with significant hypomethylation in comparison to other genes (P < 0.05). IL12B, IL4R, CXCL3 and FADD had differential mRNA expression in AP lesions and controls (P < 0.001). CONCLUSIONS: Differential methylation profiles of immune response-related genes, such as FADD, CXCL3, IL12B and IL4R, may have an influence on individual AP susceptibility and patient treatment outcomes, through their potential contributions to altered expression of disease-relevant genes. Methylation and/or genetic variations in additional genes may also contribute to the dynamics of AP development and should be considered in future studies.


Assuntos
Metilação de DNA , Periodontite Periapical/genética , Periodontite Periapical/imunologia , Periodontite Periapical/metabolismo , Transcriptoma , Adolescente , Adulto , Idoso , Autoimunidade/genética , Brasil , Quimiocinas/genética , Quimiocinas CXC/genética , Citocinas/genética , Proteína de Domínio de Morte Associada a Fas/genética , Regulação da Expressão Gênica , Humanos , Inflamação , Subunidade p40 da Interleucina-12/genética , Subunidade alfa de Receptor de Interleucina-4/genética , Pessoa de Meia-Idade , Ligamento Periodontal , Regiões Promotoras Genéticas , RNA Mensageiro/biossíntese , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Citocinas/genética , Adulto Jovem
13.
Genes Immun ; 20(1): 10-22, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29217828

RESUMO

We selected two sets of naturally occurring human missense allelic variants within innate immune genes. The first set represented eleven non-synonymous variants in six different genes involved in interferon (IFN) induction, present in a cohort of patients suffering from herpes simplex encephalitis (HSE) and the second set represented sixteen allelic variants of the IFNLR1 gene. We recreated the variants in vitro and tested their effect on protein function in a HEK293T cell based assay. We then used an array of 14 available bioinformatics tools to predict the effect of these variants upon protein function. To our surprise two of the most commonly used tools, CADD and SIFT, produced a high rate of false positives, whereas SNPs&GO exhibited the lowest rate of false positives in our test. As the problem in our test in general was false positive variants, inclusion of mutation significance cutoff (MSC) did not improve accuracy.


Assuntos
Biologia Computacional/normas , Encefalite por Herpes Simples/genética , Testes Genéticos/normas , Estudo de Associação Genômica Ampla/normas , Software/normas , Criança , Reações Falso-Positivas , Feminino , Células HEK293 , Humanos , Masculino , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo Único , Receptores de Citocinas/genética , Receptores de Citocinas/metabolismo
14.
Arthritis Rheumatol ; 71(4): 561-570, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30298554

RESUMO

OBJECTIVE: Multiple single-nucleotide polymorphisms (SNPs) conferring susceptibility to osteoarthritis (OA) mark imbalanced expression of positional genes in articular cartilage, reflected by unequally expressed alleles among heterozygotes (allelic imbalance [AI]). We undertook this study to explore the articular cartilage transcriptome from OA patients for AI events to identify putative disease-driving genetic variation. METHODS: AI was assessed in 42 preserved and 5 lesioned OA cartilage samples (from the Research Arthritis and Articular Cartilage study) for which RNA sequencing data were available. The count fraction of the alternative alleles among the alternative and reference alleles together (φ) was determined for heterozygous individuals. A meta-analysis was performed to generate a meta-φ and P value for each SNP with a false discovery rate (FDR) correction for multiple comparisons. To further validate AI events, we explored them as a function of multiple additional OA features. RESULTS: We observed a total of 2,070 SNPs that consistently marked AI of 1,031 unique genes in articular cartilage. Of these genes, 49 were found to be significantly differentially expressed (fold change <0.5 or >2, FDR <0.05) between preserved and paired lesioned cartilage, and 18 had previously been reported to confer susceptibility to OA and/or related phenotypes. Moreover, we identified notable highly significant AI SNPs in the CRLF1, WWP2, and RPS3 genes that were related to multiple OA features. CONCLUSION: We present a framework and resulting data set for researchers in the OA research field to probe for disease-relevant genetic variation that affects gene expression in pivotal disease-affected tissue. This likely includes putative novel compelling OA risk genes such as CRLF1, WWP2, and RPS3.


Assuntos
Desequilíbrio Alélico/genética , Cartilagem Articular/metabolismo , Osteoartrite/genética , Polimorfismo de Nucleotídeo Único , Transcriptoma/genética , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptores de Citocinas/genética , Proteínas Ribossômicas/genética , Fatores de Risco , Análise de Sequência de RNA , Ubiquitina-Proteína Ligases/genética
15.
J Immunol ; 201(8): 2392-2402, 2018 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-30224514

RESUMO

IFN-λ is a cytokine expressed in epithelial tissues and plays a central role in antiviral mucosal immune response. The expression of IFN-λ in the airway is impaired in chronic airway diseases (e.g., asthma, chronic obstructive pulmonary disease), which renders patients susceptible to viral infection. IL-17A is associated with asthma and chronic obstructive pulmonary disease pathogenesis; however, IL-17A regulation of IFN-λ expression remains unclear. The aim of the current study is to clarify IL-17A-mediated regulatory mechanisms of IFN-λ expression in human airway epithelial cells. In this study, we have shown that polyinosinic:polycytidylic acid (polyI:C) and influenza A virus (IAV) infection increased IFN-λ expression at mRNA and protein levels in primary cultures of normal human bronchial epithelial cells, whereas IL-17A attenuated polyI:C- or IAV-induced IFN-λ expression. IFN-λ receptor 1 knockdown and a JAK inhibitor, ruxolitinib, attenuated polyI:C-induced IFN-λ expression, confirming that a positive autocrine feedback loop, the IFN-λ receptor-JAK-STAT pathway, was involved in IFN-λ expression. In Western blotting analysis, we demonstrated that polyI:C and IAV infection induced STAT1 phosphorylation in normal human bronchial epithelial cells, whereas IL-17A suppressed polyI:C- or IAV-mediated STAT1 phosphorylation. Furthermore, we found that cotreatment with IL-17A and polyI:C or IAV infection synergistically increased suppressor of cytokine signaling (SOCS)1 and SOCS3 expression. SOCS1 small interfering RNA and SOCS3 small interfering RNA negated the inhibitory effect of IL-17A in polyI:C-induced IFN-λ expression by restoring attenuated STAT1 phosphorylation. Taken together, these findings indicate that IL-17A attenuates virus-induced IFN-λ expression by enhancing SOCS1 and SOCS3 expression to inhibit autocrine signaling loops in human airway epithelial cells.


Assuntos
Vírus da Influenza A Subtipo H3N2/fisiologia , Influenza Humana/imunologia , Interferons/metabolismo , Interleucina-17/metabolismo , Mucosa Respiratória/fisiologia , Brônquios/patologia , Células Cultivadas , Regulação da Expressão Gênica , Humanos , Fator Regulador 3 de Interferon/genética , Fator Regulador 3 de Interferon/metabolismo , Interferons/genética , NF-kappa B/genética , NF-kappa B/metabolismo , RNA Interferente Pequeno/genética , Receptores de Citocinas/genética , Transdução de Sinais , Proteína 1 Supressora da Sinalização de Citocina/genética , Proteína 1 Supressora da Sinalização de Citocina/metabolismo
16.
Front Immunol ; 9: 1775, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30123216

RESUMO

The thymic stromal lymphopoietin (TSLP)/TSLP receptor (TSLPR) axis is involved in multiple inflammatory immune diseases, including coronary artery disease (CAD). To explore the causal relationship between this axis and CAD, we performed a three-stage case-control association analysis with 3,628 CAD cases and 3,776 controls using common variants in the genes TSLP, interleukin 7 receptor (IL7R), and TSLPR. Three common variants in the TSLP/TSLPR axis were significantly associated with CAD in a Chinese Han population [rs3806933T in TSLP, Padj = 4.35 × 10-5, odds ratio (OR) = 1.18; rs6897932T in IL7R, Padj = 1.13 × 10-7, OR = 1.31; g.19646A>GA in TSLPR, Padj = 2.04 × 10-6, OR = 1.20]. Reporter gene analysis demonstrated that rs3806933 and rs6897932 could influence TSLP and IL7R expression, respectively. Furthermore, the "T" allele of rs3806933 might increase plasma TSLP levels (R2 = 0.175, P < 0.01). In a stepwise procedure, the risk for CAD increased by nearly fivefold compared with the maximum effect of any single variant (Padj = 6.99 × 10-4, OR = 4.85). In addition, the epistatic interaction between TSLP and IL33 produced a nearly threefold increase in the risk of CAD in the combined model of rs3806933TT-rs7025417TT (Padj = 3.67 × 10-4, OR = 2.98). Our study illustrates that the TSLP/TSLPR axis might be involved in the pathogenesis of CAD through upregulation of mRNA or protein expression of the referenced genes and might have additive effects on the CAD risk when combined with IL-33 signaling.


Assuntos
Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/metabolismo , Citocinas/genética , Epistasia Genética , Regulação da Expressão Gênica , Interleucina-33/genética , Receptores de Citocinas/genética , Idoso , Alelos , Estudos de Casos e Controles , China , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/mortalidade , Citocinas/sangue , Citocinas/metabolismo , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Interleucina-33/metabolismo , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo Único , Modelos de Riscos Proporcionais , Receptores de Citocinas/metabolismo , Receptores de Interleucina-7/genética , Transdução de Sinais
17.
J Leukoc Biol ; 104(6): 1147-1157, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30117603

RESUMO

IL-10 and IL-35 suppress excessive immune responses and therapeutic strategies are being developed to increase their levels in autoimmune diseases. In this study, we sought to identify major cell types that produce both cytokines in-vivo and to characterize mechanisms that regulate their production. Experimental autoimmune uveitis (EAU) is a CNS autoimmune disease that serves as model of human uveitis. We induced EAU in C57BL/6J mice and investigated whether T cells, B lymphocytes, or myeloid cells are the major producers of IL-10 or IL-35 in blood, lymph nodes (LNs), spleen, and at the site of ocular inflammation, the neuroretina. Analysis of these tissues identified B cells as the major producers of IL-10 and IL-35 in-vivo. Compared to regulatory T cells (Tregs), IL-10- or IL-35-producing regulatory B cells (Bregs) are substantially expanded in blood, LNs, spleen, and retina of mice with EAU. We performed EMSA and chromatin immunoprecipitation (ChIP) assays on activated B cells stimulated with IL-35 or TLR agonists. We found that BATF, IFN regulatory factor (IRF)-4, and IRF-8 transcription factors were recruited and bound to AP1-IRF-composite elements (AICEs) of il12a, ebi3, and/or il10 loci, suggesting their involvement in regulating IL-10 and IL-35 transcriptional programs of B cells. Showing that B cells are major source of IL-10 and IL-35 in-vivo and identifying transcription factors that contribute to IL-10 and IL-35 expression in the activated B-cell, suggest that the BATF/IRF-4/IRF-8 axis can be exploited therapeutically to regulate physiological levels of IL-10/IL-35-Bregs and that adoptive transfer of autologous Bregs might be an effective therapy for autoimmune and neurodegenerative diseases.


Assuntos
Doenças Autoimunes/imunologia , Linfócitos B Reguladores/metabolismo , Fatores de Transcrição de Zíper de Leucina Básica/fisiologia , Fatores Reguladores de Interferon/fisiologia , Interleucina-10/genética , Subunidade p35 da Interleucina-12/genética , Interleucinas/biossíntese , Antígenos de Histocompatibilidade Menor/genética , Receptores de Citocinas/genética , Uveíte/imunologia , Animais , Doenças Autoimunes/metabolismo , Feminino , Interleucina-10/biossíntese , Subunidade p35 da Interleucina-12/biossíntese , Interleucinas/agonistas , Interleucinas/genética , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Distribuição Aleatória , Retina/imunologia , Retina/metabolismo , Retina/patologia , Linfócitos T Reguladores/imunologia , Transcrição Genética , Uveíte/metabolismo
18.
Biochem Biophys Res Commun ; 503(4): 2666-2672, 2018 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-30086883

RESUMO

The molecular repertoire of porcine alveolar macrophages (PAMs) is greatly affected by the microenvironment they are exposed to, and specifically by inflammatory cytokines, such as interferon gamma (IFN-γ) released by activated lymphocytes, and microbial products, such as lipopolysaccharide (LPS). In our previous study, we found that IFN-γ- and LPS-activated PAMs (M1) could inhibit porcine reproductive and respiratory syndrome virus (PRRSV) replication. In this study, comprehensive analysis of the expression profiles of the genes associated with the polarization of M0-type PAMs (resting) toward M1 phenotypes (activated by IFN-γ and LPS) led to the following main results: 1) 1551 and 1823 genes were upregulated or downregulated in M1-type PAMs, respectively, compared with M0-type PAMs; 2) Among these, genes encoding ASS1 and CRTAM were the most upregulated and downregulated, respectively; 3) Genes involved in cytokine-cytokine receptor interaction and the JAK/STAT signaling pathway were significantly upregulated, suggesting their critical role in cellular activation; and 4) Genes involved in antigen proteolysis and presentation (immunoproteasome subunits), and inhibition of virus replication (host restriction factors) were significantly upregulated, emphasizing the critical role of these cytokines in immunity. Thus, our results provide important information for future studies on the role of PAM polarization in modulation of infection.


Assuntos
Argininossuccinato Sintase/genética , Imunoglobulinas/genética , Interferon gama/farmacologia , Lipopolissacarídeos/farmacologia , Macrófagos Alveolares/efeitos dos fármacos , Vírus da Síndrome Respiratória e Reprodutiva Suína/genética , Transcriptoma/imunologia , Animais , Argininossuccinato Sintase/imunologia , Diferenciação Celular/efeitos dos fármacos , Linhagem da Célula/efeitos dos fármacos , Ontologia Genética , Imunoglobulinas/imunologia , Janus Quinase 1/genética , Janus Quinase 1/imunologia , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/virologia , Anotação de Sequência Molecular , Vírus da Síndrome Respiratória e Reprodutiva Suína/imunologia , Cultura Primária de Células , Receptores de Citocinas/genética , Receptores de Citocinas/imunologia , Fatores de Transcrição STAT/genética , Fatores de Transcrição STAT/imunologia , Suínos , Replicação Viral/efeitos dos fármacos
19.
Exp Hematol ; 67: 1-9, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30075295

RESUMO

Acute lymphoblastic leukemia (ALL) is an aggressive hematologic malignancy characterized by suboptimal outcomes in the adult age group. Recently, a new subtype called Philadelphia (Ph)-like ALL has been described. This subgroup is characterized by high cytokine receptor and tyrosine kinase signaling expression, resulting in kinase activation through stimulation of two main pathways, the ABL and JAK/STAT pathways. The diagnostic method or approach for Ph-like ALL is still not standardized and efforts are ongoing to identify an easy and applicable diagnostic method. Accurate and standard testing approaches are much needed and this will facilitate better understanding of this subgroup, including better estimation of the prevalence and incidence in different age groups and the clinical outcomes of such new entity. Here, we review the currently available diagnostic tools, activated pathways, and different therapeutic approaches used to target this subgroup.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Adolescente , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Criança , Pré-Escolar , Ensaios Clínicos como Assunto , Gerenciamento Clínico , Drogas em Investigação/uso terapêutico , Ativação Enzimática , Feminino , Previsões , Perfilação da Expressão Gênica/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Proteínas de Fusão Oncogênica/efeitos dos fármacos , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/fisiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/classificação , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Prognóstico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Quinases/efeitos dos fármacos , Proteínas Quinases/genética , Proteínas Quinases/fisiologia , Receptores de Citocinas/efeitos dos fármacos , Receptores de Citocinas/genética , Receptores de Citocinas/fisiologia , Distribuição por Sexo , Transdução de Sinais/efeitos dos fármacos , Adulto Jovem
20.
Gigascience ; 7(7)2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29982439

RESUMO

Background: Genomic profiling efforts have revealed a rich diversity of oncogenic fusion genes. While there are many methods for identifying fusion genes from RNA-sequencing (RNA-seq) data, visualizing these transcripts and their supporting reads remains challenging. Findings: Clinker is a bioinformatics tool written in Python, R, and Bpipe that leverages the superTranscript method to visualize fusion genes. We demonstrate the use of Clinker to obtain interpretable visualizations of the RNA-seq data that lead to fusion calls. In addition, we use Clinker to explore multiple fusion transcripts with novel breakpoints within the P2RY8-CRLF2 fusion gene in B-cell acute lymphoblastic leukemia. Conclusions: Clinker is freely available software that allows visualization of fusion genes and the RNA-seq data used in their discovery.


Assuntos
Biologia Computacional/métodos , Proteínas de Fusão Oncogênica/genética , Análise de Sequência de RNA/métodos , Software , Processamento Alternativo , Mutação da Fase de Leitura , Perfilação da Expressão Gênica , Genômica , Humanos , Leucemia de Células B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Linguagens de Programação , Domínios Proteicos , Isoformas de Proteínas , RNA/genética , Receptores de Citocinas/genética , Receptores Purinérgicos P2Y/genética
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