Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 26
Filtrar
Mais filtros

Base de dados
Tipo de documento
Intervalo de ano de publicação
1.
Int Arch Allergy Immunol ; 185(9): 910-920, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38781935

RESUMO

INTRODUCTION: The occurrence and progression of lung adenocarcinoma (LUAD) impair T-cell immune responses, causing immune escape and subsequently affecting the efficacy of immunotherapy in patients. Aurora kinase A (AURKA) is upregulated in varying cancers, but its role in LUAD immune escape is elusive. This work attempted to explore molecular mechanisms of AURKA regulation in LUAD immune escape. METHODS: Through bioinformatics analysis, AURKA level in LUAD was evaluated, and potential upstream transcription factors of AURKA were predicted using hTFtarget. ETS variant transcription factor 4 (ETV4) expression in LUAD was analyzed through The Cancer Genome Atlas. Pearson's correlation analysis was then utilized to test the correlation between AURKA and ETV4. Interaction and binding between AURKA and ETV4 were validated through dual-luciferase assay and chromatin immunoprecipitation. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) tested relative mRNA expression of AURKA and ETV4 in LUAD cells, cell counting kit-8 assayed cell viability, and Western blot analysis was conducted to determine the protein level of programmed death-ligand 1 (PD-L1). Coculture of LUAD cells with activated CD8+ T cells was carried out, and an LDH assay was used to assess the cytotoxicity of CD8+ T cells against LUAD cells. Interferon-γ (IFN-γ), interleukin-2 (IL-2), and tumor necrosis factor-α (TNF-α) levels in the coculture system were assessed by enzyme-linked immunosorbent assay (ELISA). Western blot assessed protein levels of JAK2, p-JAK2, STAT3, and p-STAT3. RESULTS: Compared to normal tissues, AURKA and ETV4 were upregulated in tumor tissues, and AURKA presented a negative association with CD8+ T-cell immune infiltration but a positive association with PD-L1. qRT-PCR unveiled significantly upregulated mRNA of AURKA and ETV4 in LUAD cells compared to normal lung epithelial cells. Knockdown of AURKA significantly decreased cell viability and PD-L1 protein level in LUAD cells, enhanced cytotoxicity of CD8+ T cells against LUAD cells and IFN-γ, IL-2, and TNF-α expression, while overexpression of AURKA yielded opposite results. Furthermore, the knockdown of ETV4 could reverse the oncogenic characteristics of cells caused by AURKA overexpression. CONCLUSION: Our study illustrated that ETV4/AURKA axis promoted PD-L1 expression, suppressed CD8+ T-cell activity, and mediated immune escape in LUAD by regulating the JAK2/STAT3 signaling pathway.


Assuntos
Adenocarcinoma de Pulmão , Aurora Quinase A , Antígeno B7-H1 , Neoplasias Pulmonares , Proteínas Proto-Oncogênicas c-ets , Evasão Tumoral , Humanos , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/genética , Proteínas E1A de Adenovirus/metabolismo , Proteínas E1A de Adenovirus/genética , Aurora Quinase A/metabolismo , Aurora Quinase A/genética , Aurora Quinase A/imunologia , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/imunologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Proto-Oncogênicas c-ets/metabolismo , Proteínas Proto-Oncogênicas c-ets/imunologia , Evasão Tumoral/imunologia
2.
Proc Natl Acad Sci U S A ; 118(9)2021 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-33622787

RESUMO

HLA-C arose during evolution of pregnancy in the great apes 10 to 15 million years ago. It has a dual function on placental extravillous trophoblasts (EVTs) as it contributes to both tolerance and immunity at the maternal-fetal interface. The mode of its regulation is of considerable interest in connection with the biology of pregnancy and pregnancy abnormalities. First-trimester primary EVTs in which HLA-C is highly expressed, as well as JEG3, an EVT model cell line, were employed. Single-cell RNA-seq data and quantitative PCR identified high expression of the transcription factor ELF3 in those cells. Chromatin immunoprecipitation (ChIP)-PCR confirmed that both ELF3 and MED1 bound to the proximal HLA-C promoter region. However, binding of RFX5 to this region was absent or severely reduced, and the adjacent HLA-B locus remained closed. Expression of HLA-C was inhibited by ELF3 small interfering RNAs (siRNAs) and by wrenchnolol treatment. Wrenchnolol is a cell-permeable synthetic organic molecule that mimics ELF3 and is relatively specific for binding to ELF3's coactivator, MED23, as our data also showed in JEG3. Moreover, the ELF3 gene is regulated by a superenhancer that spans more than 5 Mb, identified by assay for transposase-accessible chromatin using sequencing (ATAC-seq), as well as by its sensitivity to (+)-JQ1 (inhibitor of BRD4). ELF3 bound to its own promoter, thus creating an autoregulatory feedback loop that establishes expression of ELF3 and HLA-C in trophoblasts. Wrenchnolol blocked binding of MED23 to ELF3, thus disrupting the positive-feedback loop that drives ELF3 expression, with down-regulation of HLA-C expression as a consequence.


Assuntos
Proteínas de Ligação a DNA/genética , Elementos Facilitadores Genéticos , Retroalimentação Fisiológica , Antígenos HLA-C/genética , Proteínas Proto-Oncogênicas c-ets/genética , Fatores de Transcrição/genética , Trofoblastos/imunologia , Aborto Legal , Adamantano/farmacologia , Azepinas/farmacologia , Linhagem Celular , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/imunologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento/imunologia , Antígenos HLA-B/genética , Antígenos HLA-B/imunologia , Antígenos HLA-C/imunologia , Humanos , Imunidade Materno-Adquirida , Indóis/farmacologia , Complexo Mediador/genética , Complexo Mediador/imunologia , Subunidade 1 do Complexo Mediador/genética , Subunidade 1 do Complexo Mediador/imunologia , Gravidez , Primeiro Trimestre da Gravidez , Cultura Primária de Células , Regiões Promotoras Genéticas , Ligação Proteica , Proteínas Proto-Oncogênicas c-ets/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-ets/imunologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/imunologia , Fatores de Transcrição de Fator Regulador X/genética , Fatores de Transcrição de Fator Regulador X/imunologia , Transdução de Sinais , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/imunologia , Triazóis/farmacologia , Trofoblastos/citologia , Trofoblastos/efeitos dos fármacos
3.
Inflamm Res ; 70(1): 89-98, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33185705

RESUMO

OBJECTIVE: The dysfunction of pulmonary microvascular endothelial cells (PMVECs) is one of the critical characteristics of acute lung injury/acute respiratory distress syndrome (ALI/ARDS) induced by severe infection. PIM1 is a constitutively active serine/threonine kinase that is involved in multiple biological processes. However, the underlying correlation between PIM1 and PMVECs injury remains unclear. The main purpose of this study was to reveal roles of PIM1 and explore the potential mechanisms during the development of endotoxin-induced ALI induced by intraperitoneal LPS administration. MATERIALS AND METHODS: PIM1 level in the lung tissues of endotoxin-induced ALI mice or plasma derived from cardiopulmonary bypass (CPB)-induced ALI patients were measured. The protective roles of PIM1 specific inhibitor SMI-4a on endotoxin-induced lung injuries were evaluated through histological, permeability, neutrophil infiltration and survival assessment. The relationship between PIM1 and ELK3/ICAM-1 axis was validated in vivo and vitro. The correlation between plasma PIM1 and indicative vascular endothelium injury biomarkers (PaO2/FiO2 ratio, Ang-II, E-selectin and PAI-1) levels derived from CPB-induced ALI patient were analyzed. RESULTS: PIM1 expression in the lung tissues was increased in the mice of endotoxin-induced ALI. The PIM1 specific inhibitor SMI-4a administration relieved the severity of endotoxin-induced ALI. More importantly, PIM1 modulates ICAM1 expression through regulating transcription factor ELK3 expression in vitro. Eventually, plasma PIM1 level was positively correlated with Ang-II and PAI-1 levels but negatively correlated with SpO2/FiO2 ratio among CPB induced ALI patients. CONCLUSION: Our results indicated that PIM1 inhibition carried a protective role against endotoxin-induced ALI by modulating the ELK3/ICAM1 axis on PMVECs. PIM1 may be a potential therapeutic target for endotoxin-induced ALI.


Assuntos
Lesão Pulmonar Aguda/imunologia , Células Endoteliais/imunologia , Molécula 1 de Adesão Intercelular/imunologia , Pulmão/imunologia , Proteínas Proto-Oncogênicas c-ets/imunologia , Proteínas Proto-Oncogênicas c-pim-1/imunologia , Lesão Pulmonar Aguda/induzido quimicamente , Animais , Ponte Cardiopulmonar/efeitos adversos , Células Cultivadas , Humanos , Lipopolissacarídeos , Pulmão/citologia , Masculino , Camundongos Endogâmicos C57BL , Microvasos/citologia , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-pim-1/sangue
4.
Blood ; 129(4): 509-519, 2017 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-27940477

RESUMO

Macrophages are key components of the innate immune system and play pivotal roles in immune response, organ development, and tissue homeostasis. Studies in mice and zebrafish have shown that tissue-resident macrophages derived from different hematopoietic origins manifest distinct developmental kinetics and colonization potential, yet the genetic programs controlling the development of macrophages of different origins remain incompletely defined. In this study, we use zebrafish, where tissue-resident macrophages arise from the rostral blood island (RBI) and ventral wall of dorsal aorta (VDA), the zebrafish hematopoietic tissue equivalents to the mouse yolk sac and aorta-gonad-mesonephros for myelopoiesis, to address this issue. We show that RBI- and VDA-born macrophages are orchestrated by distinctive regulatory networks formed by the E-twenty-six (Ets) transcription factors Pu.1 and Spi-b, the zebrafish ortholog of mouse spleen focus forming virus proviral integration oncogene B (SPI-B), and the helix-turn-helix DNA-binding domain containing protein Irf8. Epistatic studies document that during RBI macrophage development, Pu.1 acts upstream of Spi-b, which, upon induction by Pu.1, partially compensates the function of Pu.1. In contrast, Pu.1 and Spi-b act in parallel and cooperatively to regulate the development of VDA-derived macrophages. Interestingly, these two distinct regulatory networks orchestrate the RBI- and VDA-born macrophage development largely by regulating a common downstream gene, Irf8. Our study indicates that macrophages derived from different origins are governed by distinct genetic networks formed by the same repertoire of myeloid-specific transcription factors.


Assuntos
Linhagem da Célula/imunologia , Regulação da Expressão Gênica no Desenvolvimento , Redes Reguladoras de Genes , Macrófagos/imunologia , Proteínas Proto-Oncogênicas/imunologia , Transativadores/imunologia , Peixe-Zebra/imunologia , Sequência de Aminoácidos , Animais , Aorta/citologia , Aorta/crescimento & desenvolvimento , Aorta/imunologia , Diferenciação Celular , Linhagem da Célula/genética , Embrião não Mamífero , Humanos , Imunidade Inata , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/imunologia , Macrófagos/citologia , Mesonefro/citologia , Mesonefro/crescimento & desenvolvimento , Mesonefro/imunologia , Camundongos , Especificidade de Órgãos , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Proto-Oncogênicas c-ets/imunologia , Transdução de Sinais , Transativadores/genética , Saco Vitelino/citologia , Saco Vitelino/crescimento & desenvolvimento , Saco Vitelino/imunologia , Peixe-Zebra/genética , Peixe-Zebra/crescimento & desenvolvimento
5.
Int J Mol Sci ; 20(15)2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31370265

RESUMO

Osteosarcoma and Ewing sarcoma are the most common malignant primary bone tumors mainly occurring in children, adolescents and young adults. Current standard therapy includes multidrug chemotherapy and/or radiation specifically for Ewing sarcoma, associated with tumor resection. However, patient survival has not evolved for the past decade and remains closely related to the response of tumor cells to chemotherapy, reaching around 75% at 5 years for patients with localized forms of osteosarcoma or Ewing sarcoma but less than 30% in metastatic diseases and patients resistant to initial chemotherapy. Despite Ewing sarcoma being characterized by specific EWSR1-ETS gene fusions resulting in oncogenic transcription factors, currently, no targeted therapy could be implemented. It seems even more difficult to develop a targeted therapeutic strategy in osteosarcoma which is characterized by high complexity and heterogeneity in genomic alterations. Nevertheless, the common point between these different bone tumors is their ability to deregulate bone homeostasis and remodeling and divert them to their benefit. Therefore, targeting different actors of the bone tumor microenvironment has been hypothesized to develop new therapeutic strategies. In this context, it is well known that the Wnt/ß-catenin signaling pathway plays a key role in cancer development, including osteosarcoma and Ewing sarcoma as well as in bone remodeling. Moreover, recent studies highlight the implication of the Wnt/ß-catenin pathway in angiogenesis and immuno-surveillance, two key mechanisms involved in metastatic dissemination. This review focuses on the role played by this signaling pathway in the development of primary bone tumors and the modulation of their specific microenvironment.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica , Osteossarcoma/tratamento farmacológico , Sarcoma de Ewing/tratamento farmacológico , Microambiente Tumoral/efeitos dos fármacos , Adolescente , Neoplasias Ósseas/genética , Neoplasias Ósseas/imunologia , Neoplasias Ósseas/mortalidade , Osso e Ossos , Criança , Humanos , Metástase Linfática , Terapia de Alvo Molecular/métodos , Neovascularização Patológica/genética , Neovascularização Patológica/imunologia , Neovascularização Patológica/mortalidade , Neovascularização Patológica/prevenção & controle , Proteínas de Fusão Oncogênica/antagonistas & inibidores , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/imunologia , Osteossarcoma/genética , Osteossarcoma/imunologia , Osteossarcoma/mortalidade , Proteínas Proto-Oncogênicas c-ets/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Proto-Oncogênicas c-ets/imunologia , Proteína EWS de Ligação a RNA/antagonistas & inibidores , Proteína EWS de Ligação a RNA/genética , Proteína EWS de Ligação a RNA/imunologia , Sarcoma de Ewing/genética , Sarcoma de Ewing/imunologia , Sarcoma de Ewing/mortalidade , Análise de Sobrevida , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Via de Sinalização Wnt/efeitos dos fármacos , Adulto Jovem , beta Catenina/antagonistas & inibidores , beta Catenina/genética , beta Catenina/imunologia
6.
Cell Physiol Biochem ; 45(6): 2401-2410, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29550824

RESUMO

BACKGROUND/AIMS: The E74-like factor 3 (ELF3) is an inflammatory mediator that participates in cartilage destruction in osteoarthritis. Leptin and other adipokines negatively impact articular cartilage, triggering catabolic and inflammatory responses in chondrocytes. Here, we investigated whether leptin induces ELF3 expression in chondrocytes and the signaling pathway involved in this process. METHODS: We determined mRNA and protein levels of ELF3 by RT-qPCR and Western blotting using cultured human primary chondrocytes and the human T/C-28a2 chondrocyte cell line. Further, we measured luciferase activities of different reporter constructs, and we assessed the contribution of leptin to the induction of ELF3 mRNA by knocking down hLEPR gene expression using siRNA technology. RESULTS: Leptin synergizes with IL-1ß in inducing ELF3 expression in chondrocytes. We also found that PI3K, p38, and JAK2 signaling pathways are at play in the leptin-driven induction of ELF3. Moreover, we confirm the participation of NFΚB in the leptin/IL-1ß synergistic induction of ELF3. CONCLUSION: Here we show, for the first time, the regulation of ELF3 expression by leptin, suggesting that this transcription factor likely mediates the inflammatory responses triggered by leptin in articular chondrocytes.


Assuntos
Condrócitos/metabolismo , Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica , Inflamação/genética , Leptina/imunologia , Obesidade/genética , Proteínas Proto-Oncogênicas c-ets/genética , Fatores de Transcrição/genética , Cartilagem/imunologia , Cartilagem/metabolismo , Linhagem Celular , Células Cultivadas , Condrócitos/imunologia , Proteínas de Ligação a DNA/imunologia , Humanos , Inflamação/imunologia , Interleucina-1beta/imunologia , Leptina/genética , Obesidade/imunologia , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-ets/imunologia , Interferência de RNA , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Receptores para Leptina/genética , Receptores para Leptina/imunologia , Fatores de Transcrição/imunologia , Ativação Transcricional
7.
J Immunol ; 194(8): 3798-807, 2015 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-25769919

RESUMO

Spi-C is an E26 transformation-specific family transcription factor that is highly related to PU.1 and Spi-B. Spi-C is expressed in developing B cells, but its function in B cell development and function is not well characterized. To determine whether Spi-C functions as a negative regulator of Spi-B (encoded by Spib), mice were generated that were germline knockout for Spib and heterozygous for Spic (Spib(-/-)Spic(+/-)). Interestingly, loss of one Spic allele substantially rescued B cell frequencies and absolute numbers in Spib(-/-) mouse spleens. Spib(-/-)Spic(+/-) B cells had restored proliferation compared with Spib(-/-) B cells in response to anti-IgM or LPS stimulation. Investigation of a potential mechanism for the Spib(-/-)Spic(+/-) phenotype revealed that steady-state levels of Nfkb1, encoding p50, were elevated in Spib(-/-)Spic(+/-) B cells compared with Spib(-/-) B cells. Spi-B was shown to directly activate the Nfkb1 gene, whereas Spi-C was shown to repress this gene. These results indicate a novel role for Spi-C as a negative regulator of B cell development and function.


Assuntos
Linfócitos B/imunologia , Proliferação de Células , Proteínas de Ligação a DNA/imunologia , Regulação da Expressão Gênica/imunologia , Animais , Proteínas de Ligação a DNA/genética , Camundongos , Camundongos Knockout , Subunidade p50 de NF-kappa B/genética , Subunidade p50 de NF-kappa B/imunologia , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Proto-Oncogênicas c-ets/imunologia , Baço/imunologia
8.
Cell Mol Biol (Noisy-le-grand) ; 63(8): 19-22, 2017 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-28886309

RESUMO

Despite advances in treatment, children with acute lymphoblastic leukemia (ALL) still experience drug resistance and relapse. Several gene mutations are involved in the onset of this disease and resistance to therapy. The present study examines the incidence of IKZF1, CDKN2A/B, PAX5, EBF1, ETV6, BTG1, RB1, JAK2, and Xp22.33 gene deletions/duplications associated with pediatric ALL in Iran and investigates the possible effect of these mutations on drug resistance. Three-year disease-free survival (3DFS) was evaluated for children diagnosed with Philadelphia negative precursor-B-cell ALL hospitalized at Sayed-al-Shohada Hospital, Isfahan-Iran, from January 2009 until December 2012. DNA was extracted from bone marrow slides, and ALL correlated gene deletions and duplications were measured using Multiplex Ligation-dependent Probe Amplification (MLPA) method. The correlation between gene mutations and 3DFS was then assessed. Among the nine aforementioned investigated genes, 63% of samples showed at least one gene mutation. At least two concomitant genomic mutations were observed in 42% of samples. Pax5 deletion was the most prevalent gene mutation observed in 45% of cases, and showed significant negative impact on response to treatment. CDKN2A/B (9p21.3) gene deletion, and ETV6 (12p13.2) gene duplication also demonstrated negative effect on patient survival and contributed to a worse prognosis if concomitant with Pax5 gene deletion. ALL patients with one of the gene deletions including Pax5  and CDKN2A/B (9p21.3) or ETV6 (12p13.2) gene duplication are classified as high-risk patients and need more intensified protocols of treatment to improve their chance of survival.


Assuntos
Inibidor de Quinase Dependente de Ciclina p15/genética , Inibidor de Quinase Dependente de Ciclina p18/genética , Deleção de Genes , Regulação Leucêmica da Expressão Gênica , Fator de Transcrição PAX5/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Repressoras/genética , Adolescente , Antineoplásicos/uso terapêutico , Criança , Pré-Escolar , Inibidor de Quinase Dependente de Ciclina p15/imunologia , Inibidor p16 de Quinase Dependente de Ciclina , Inibidor de Quinase Dependente de Ciclina p18/imunologia , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Duplicação Gênica , Humanos , Lactente , Irã (Geográfico) , Masculino , Fator de Transcrição PAX5/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Células Precursoras de Linfócitos B/imunologia , Células Precursoras de Linfócitos B/metabolismo , Células Precursoras de Linfócitos B/patologia , Prognóstico , Proteínas Proto-Oncogênicas c-ets/imunologia , Proteínas Repressoras/imunologia , Análise de Sobrevida , Variante 6 da Proteína do Fator de Translocação ETS
9.
Clin Exp Allergy ; 45(9): 1447-58, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25772331

RESUMO

BACKGROUND: Increased mucus production is a critical factor impairing lung function in patients suffering from bronchial asthma, the most common chronic inflammatory lung disease worldwide. OBJECTIVE: This study aimed at investigating whether goblet cell (GC) metaplasia and mucus production are differentially regulated in proximal and distal airways. METHODS: Female Balb/c mice were sensitized to ovalbumin (OVA) and challenged with an OVA-aerosol on two consecutive days for 1 week (acute) or 12 weeks (chronic). Real-time RT-PCR analysis was applied on microdissected airways. RESULTS: In acutely and chronically OVA-challenged mice, GC metaplasia and mucus production were observed in proximal but not in distal airways. In contrast, inflammation reflected by the infiltration of eosinophils and expression of the TH2-type cytokines IL-4 and IL-13 was increased in both proximal and distal airways. Abundance of IL-13Rα1 was lower in distal airways of healthy control mice. Under acute and chronic OVA-exposure, activation of IL-13Rα1-dependent signalling cascade, reflected by Spdef and Foxo3A transcription factors, was attenuated in distal compared to proximal airways. CONCLUSION AND CLINICAL RELEVANCE: These data indicate that distal airways might be less sensitive to IL-13-induced GC metaplasia and mucus production through lower expression of IL-13Rα1 and attenuated activation of downstream signalling. This might represent a protective strategy to prevent mucus plugging of distal airways and thus impaired ventilation of attached alveoli.


Assuntos
Asma/imunologia , Regulação da Expressão Gênica/imunologia , Células Caliciformes/imunologia , Interleucina-13/imunologia , Pulmão/imunologia , Transdução de Sinais/imunologia , Animais , Asma/metabolismo , Asma/patologia , Feminino , Proteína Forkhead Box O3 , Fatores de Transcrição Forkhead/biossíntese , Fatores de Transcrição Forkhead/imunologia , Células Caliciformes/metabolismo , Células Caliciformes/patologia , Interleucina-13/biossíntese , Subunidade alfa1 de Receptor de Interleucina-13/biossíntese , Subunidade alfa1 de Receptor de Interleucina-13/imunologia , Interleucina-4/biossíntese , Interleucina-4/imunologia , Pulmão/metabolismo , Pulmão/patologia , Metaplasia , Camundongos , Camundongos Endogâmicos BALB C , Muco/imunologia , Muco/metabolismo , Proteínas Proto-Oncogênicas c-ets/biossíntese , Proteínas Proto-Oncogênicas c-ets/imunologia , Células Th2/imunologia , Células Th2/metabolismo , Células Th2/patologia
10.
Blood ; 115(2): 265-73, 2010 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-19965651

RESUMO

Activation of the T cell-mediated immune response has been associated with changes in the expression of specific microRNAs (miRNAs). However, the role of miRNAs in the development of an effective immune response is just beginning to be explored. This study focuses on the functional role of miR-146a in T lymphocyte-mediated immune response and provides interesting clues on the transcriptional regulation of miR-146a during T-cell activation. We show that miR-146a is low in human naive T cells and is abundantly expressed in human memory T cells; consistently, miR-146a is induced in human primary T lymphocytes upon T-cell receptor (TCR) stimulation. Moreover, we identified NF-kB and c-ETS binding sites as required for the induction of miR-146a transcription upon TCR engagement. Our results demonstrate that several signaling pathways, other than inflammation, are influenced by miR-146a. In particular, we provide experimental evidence that miR-146a modulates activation-induced cell death (AICD), acting as an antiapoptotic factor, and that Fas-associated death domain (FADD) is a target of miR-146a. Furthermore, miR-146a enforced expression impairs both activator protein 1 (AP-1) activity and interleukin-2 (IL-2) production induced by TCR engagement, thus suggesting a role of this miRNA in the modulation of adaptive immunity.


Assuntos
Imunidade Adaptativa/fisiologia , Regulação da Expressão Gênica/fisiologia , Interleucina-2/biossíntese , Ativação Linfocitária/fisiologia , MicroRNAs/metabolismo , Linfócitos T/metabolismo , Morte Celular/fisiologia , Proteína de Domínio de Morte Associada a Fas/imunologia , Proteína de Domínio de Morte Associada a Fas/metabolismo , Humanos , Interleucina-2/imunologia , Células Jurkat , MicroRNAs/imunologia , Proteínas Proto-Oncogênicas c-ets/imunologia , Proteínas Proto-Oncogênicas c-ets/metabolismo , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Elementos de Resposta/fisiologia , Transdução de Sinais/fisiologia , Linfócitos T/citologia , Linfócitos T/imunologia , Fator de Transcrição AP-1/imunologia , Fator de Transcrição AP-1/metabolismo , Transcrição Gênica/fisiologia
11.
J Immunol ; 185(12): 7374-84, 2010 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-21057087

RESUMO

Splenic B-2 cells can be divided into two major subsets: follicular (FO) and marginal zone (MZ) B cells. FO and MZ B cells are generated from immature transitional B cells. Few transcription factors have been identified that regulate FO B cell differentiation. The highly related proteins PU.1, Spi-B, and Spi-C are transcription factors of the E26-transformation-specific family and are important for B cell differentiation and function. To determine whether these proteins play a role in the differentiation of FO B cells, we performed a detailed analysis of splenic B cells in mice with inactivating mutations in the genes encoding PU.1 (Sfpi1) or Spi-B (Spib). Sfpi1(+/-) Spib(-/-) (PUB) mice had a 9-fold reduction in the frequency of CD23(+) FO B cells compared with that of wild-type mice. In contrast, PUB mice had a 2-fold increase in the frequency of MZ B cells that was confirmed by immunofluorescence staining. Expression of Spi-C in Eµ-Spi-C transgenic PUB mice partially rescued frequencies of CD23(+) B cells. Gene expression analysis, in vitro reporter assays, and chromatin immunoprecipitation experiments showed that transcription of the Fcer2a gene encoding CD23 is activated by PU.1, Spi-B, and Spi-C. These results demonstrate that FO B cell differentiation is regulated by the E26-transformation-specific transcription factors PU.1, Spi-B, and Spi-C.


Assuntos
Linfócitos B/imunologia , Diferenciação Celular/imunologia , Proteínas de Ligação a DNA/imunologia , Proteínas Proto-Oncogênicas c-ets/imunologia , Proteínas Proto-Oncogênicas/imunologia , Transativadores/imunologia , Animais , Linfócitos B/metabolismo , Diferenciação Celular/genética , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Masculino , Camundongos , Camundongos Knockout , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Proto-Oncogênicas c-ets/metabolismo , Receptores de IgE/genética , Receptores de IgE/imunologia , Receptores de IgE/metabolismo , Transativadores/genética , Transativadores/metabolismo
12.
J Immunol ; 185(2): 1082-92, 2010 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-20554967

RESUMO

The ternary complex factors (TCFs; SAP-1, Elk-1, and Net) are serum response factor cofactors that share many functional properties and are coexpressed in many tissues. SAP-1, the predominant thymus TCF, is required for thymocyte positive selection. In this study, we assessed whether the different TCFs are functionally equivalent. Elk-1 deletion, but not the hypomorphic Net(delta) mutation, exacerbated the SAP-1 positive selection phenotype, but triply deficient thymocytes were no more defective than SAP-1(-/-) Elk-1(-/-) cells. Inactivation of the other TCFs did not affect SAP-1-independent processes, including beta-selection, regulatory T cell selection, and negative selection, although reduced marginal zone B cells were observed in SAP-1(-/-) Elk-1(-/-) animals. Ectopic expression of Elk-1, but not Net, rescued positive selection of SAP-1(-/-) thymocytes; thus, SAP-1 and Elk-1 are functionally equivalent in this system, and the SAP-1 null selection phenotype reflects only its high expression in the thymus. Array analysis of TCR-stimulated double-positive cells identified SAP-1-dependent inducible genes whose transcription was further impaired in SAP-1(-/-) Elk-1(-/-) cells; thus, these genes, which include Egr-1 and Egr-2, represent candidate mediators of positive selection. Chromatin immunoprecipitation revealed subtly different promoter targeting between the different TCFs. Ectopic expression of Egr-1 restored positive selection in SAP-1 null thymocytes, establishing it (and possibly other Egr family members) as the major effector for ERK-SAP-1 signaling in thymocyte positive selection.


Assuntos
Proteínas Proto-Oncogênicas c-ets/imunologia , Timo/imunologia , Proteínas Elk-1 do Domínio ets/imunologia , Proteínas Elk-4 do Domínio ets/imunologia , Animais , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Células Cultivadas , Imunoprecipitação da Cromatina , Feminino , Citometria de Fluxo , Perfilação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Proto-Oncogênicas c-ets/metabolismo , Retroviridae/genética , Timo/citologia , Timo/metabolismo , Transdução Genética , Proteínas Elk-1 do Domínio ets/genética , Proteínas Elk-1 do Domínio ets/metabolismo , Proteínas Elk-4 do Domínio ets/genética , Proteínas Elk-4 do Domínio ets/metabolismo
13.
J Allergy Clin Immunol ; 127(1): 254-61, 261.e1-6, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21126757

RESUMO

BACKGROUND: Asthma is a major public health burden worldwide. Studies from our group and others have demonstrated that SERPINB3 and SERPINB4 are induced in patients with asthma; however, their mechanistic role in asthma has yet to be determined. OBJECTIVE: To evaluate the role of Serpin3a, the murine homolog of SERPINB3 and SERPINB4, in asthma. METHODS: We studied wild-type Balb/c and Serpinb3a-null mice in house dust mite or IL-13-induced asthma models and evaluated airway hyperresponsiveness, inflammation, and goblet cell hyperplasia. RESULTS: Airway hyperresponsiveness and goblet cell hyperplasia were markedly attenuated in the Serpinb3a-null mice compared with the wild-type mice after allergen challenge, with minimal effects on inflammation. Expression of sterile alpha motif pointed domain containing v-ets avian erythroblastosis virus E26 oncogene homolog transcription factor (SPDEF), a transcription factor that mediates goblet cell hyperplasia, was decreased in the absence of Serpinb3a. IL-13-treated Serpinb3a-null mice showed attenuated airway hyperresponsiveness, inflammation, and mucus production. CONCLUSION: Excessive mucus production and mucus plugging are key pathologic features of asthma, yet the mechanisms responsible for mucus production are not well understood. Our data reveal a novel nonredundant role for Serpinb3a in mediating mucus production through regulation of SPDEF expression. This pathway may be used to target mucus hypersecretion effectively.


Assuntos
Asma/imunologia , Muco/imunologia , Proteínas Proto-Oncogênicas c-ets/imunologia , Serpinas/imunologia , Animais , Asma/metabolismo , Asma/patologia , Líquido da Lavagem Broncoalveolar , Separação Celular , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Expressão Gênica , Regulação da Expressão Gênica/imunologia , Células Caliciformes/imunologia , Células Caliciformes/metabolismo , Imunoglobulina E/sangue , Imunoglobulina G/sangue , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Muco/metabolismo , Proteínas Proto-Oncogênicas c-ets/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Serpinas/metabolismo
14.
Nat Commun ; 11(1): 4225, 2020 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-32839463

RESUMO

Gallbladder cancer (GBC) is an aggressive gastrointestinal malignancy with no approved targeted therapy. Here, we analyze exomes (n = 160), transcriptomes (n = 115), and low pass whole genomes (n = 146) from 167 gallbladder cancers (GBCs) from patients in Korea, India and Chile. In addition, we also sequence samples from 39 GBC high-risk patients and detect evidence of early cancer-related genomic lesions. Among the several significantly mutated genes not previously linked to GBC are ETS domain genes ELF3 and EHF, CTNNB1, APC, NSD1, KAT8, STK11 and NFE2L2. A majority of ELF3 alterations are frame-shift mutations that result in several cancer-specific neoantigens that activate T-cells indicating that they are cancer vaccine candidates. In addition, we identify recurrent alterations in KEAP1/NFE2L2 and WNT pathway in GBC. Taken together, these define multiple targetable therapeutic interventions opportunities for GBC treatment and management.


Assuntos
Proteínas de Ligação a DNA/genética , Mutação da Fase de Leitura , Neoplasias da Vesícula Biliar/genética , Predisposição Genética para Doença/genética , Proteínas Proto-Oncogênicas c-ets/genética , Fatores de Transcrição/genética , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Chile , Proteínas de Ligação a DNA/imunologia , Proteínas de Ligação a DNA/metabolismo , Neoplasias da Vesícula Biliar/diagnóstico , Neoplasias da Vesícula Biliar/metabolismo , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Genômica/métodos , Humanos , Índia , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas Proto-Oncogênicas c-ets/imunologia , Proteínas Proto-Oncogênicas c-ets/metabolismo , República da Coreia , Fatores de Transcrição/imunologia , Fatores de Transcrição/metabolismo , Via de Sinalização Wnt/genética , beta Catenina/genética , beta Catenina/metabolismo
15.
Front Immunol ; 9: 497, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29593737

RESUMO

This study was designed to define gene expression and H3K4me3 histone modifications in T cells, B cells, and monocytes in systemic lupus erythematosus (SLE). Array studies of total peripheral blood mononuclear cells have demonstrated gene expression signatures related to neutrophils, interferon, and other inflammatory pathways. It is not clear how consistent these effects are across different cell types. In this study, RNA-seq and chromatin immunoprecipitation-seq were utilized to identify gene expression patterns and H3K4me3 histone modifications related to promoter activation in SLE. Across the three cell types, there was 55% concordance for gene expression changes related to SLE. Key conserved pathways were ribosome biogenesis among upregulated genes and heat shock response among downregulated genes. ETS family transcription factors (TFs) and STAT1 were revealed as common regulators by position weight matrices. When epigenetic changes were leveraged with gene expression, the pivotal TFs ATF3 and FOS were defined with ATF3 also cross-referencing with gene expression-identified TFs. Genome-wide association study (GWAS) single nucleotide polymorphisms associated with SLE were cross-referenced with both mRNA and H3K4me3 changes in SLE. Baseline mRNA expression and H3K4me3 peak height was higher at sites that cross-referenced with GWAS signals, however, all three cell types exhibited an overall decrease in expression of GWAS-associated RNAs differentially expressed in SLE. H3K4me3 changes in SLE were also enriched in GWAS-associated sites. In summary, the SLE disease process is associated with both shared and cell-specific changes in gene expression and epigenetics. Surprisingly, GWAS-associated RNAs were overall markedly decreased across all three cell types. TF analysis identified ATF3, FOS, STAT1, and ETS family members as critical, all pathways with a recognized relationship to the SLE disease process. GWAS signals clearly mark both cell-type specific changes in SLE as well as concordant changes across all three cell types. Interpretation of single nucleotide polymorphism effects in SLE will require tissue-specific mechanistic studies and therapeutics will require mechanistic studies in multiple cell types.


Assuntos
Regulação para Baixo/imunologia , Histonas/imunologia , Lúpus Eritematoso Sistêmico/imunologia , RNA Mensageiro/imunologia , Transdução de Sinais/imunologia , Fator 3 Ativador da Transcrição/genética , Fator 3 Ativador da Transcrição/imunologia , Feminino , Estudo de Associação Genômica Ampla , Histonas/genética , Humanos , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/patologia , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Proto-Oncogênicas c-ets/imunologia , RNA Mensageiro/genética , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/imunologia , Transdução de Sinais/genética
16.
J Exp Med ; 215(9): 2265-2278, 2018 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-30087163

RESUMO

An IRF8-dependent subset of conventional dendritic cells (cDCs), termed cDC1, effectively cross-primes CD8+ T cells and facilitates tumor-specific T cell responses. Etv6 is an ETS family transcription factor that controls hematopoietic stem and progenitor cell (HSPC) function and thrombopoiesis. We report that like HSPCs, cDCs express Etv6, but not its antagonist, ETS1, whereas interferon-producing plasmacytoid dendritic cells (pDCs) express both factors. Deletion of Etv6 in the bone marrow impaired the generation of cDC1-like cells in vitro and abolished the expression of signature marker CD8α on cDC1 in vivo. Moreover, Etv6-deficient primary cDC1 showed a partial reduction of cDC-specific and cDC1-specific gene expression and chromatin signatures and an aberrant up-regulation of pDC-specific signatures. Accordingly, DC-specific Etv6 deletion impaired CD8+ T cell cross-priming and the generation of tumor antigen-specific CD8+ T cells. Thus, Etv6 optimizes the resolution of cDC1 and pDC expression programs and the functional fitness of cDC1, thereby facilitating T cell cross-priming and tumor-specific responses.


Assuntos
Antígenos de Neoplasias/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Regulação da Expressão Gênica/imunologia , Imunidade Celular , Neoplasias/imunologia , Proteínas Proto-Oncogênicas c-ets/imunologia , Proteínas Repressoras/imunologia , Animais , Antígenos de Neoplasias/genética , Antígenos CD8/genética , Antígenos CD8/imunologia , Linfócitos T CD8-Positivos/patologia , Células Dendríticas/patologia , Deleção de Genes , Células-Tronco Hematopoéticas/imunologia , Células-Tronco Hematopoéticas/patologia , Camundongos , Camundongos Knockout , Neoplasias/genética , Neoplasias/patologia , Proteína Proto-Oncogênica c-ets-1/genética , Proteína Proto-Oncogênica c-ets-1/imunologia , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Repressoras/genética , Trombopoese/genética , Trombopoese/imunologia , Variante 6 da Proteína do Fator de Translocação ETS
17.
Hum Pathol ; 38(11): 1628-38, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17521701

RESUMO

The purpose of this study was to understand the characteristics of prostate-derived Ets factor (PDEF) protein expression in breast and prostate cancer progression. A polyclonal antibody specific to PDEF was raised and reacted with tissue microarrays consisting of benign breast, in situ ductal, invasive ductal, and invasive lobular breast carcinomas. The antibody was also reacted with tissue microarrays, including benign prostate, prostate intraepithelial neoplasias (PINs), and prostate carcinomas. Increased expression of PDEF was identified in 18%, 50%, 46%, and 51% of benign breast tissues, intraductal, invasive ductal, and invasive lobular carcinomas, respectively. Importantly, in matched samples of benign breast vs tumor, 90% showed higher expression of PDEF in the tumor tissue. Moreover, in invasive breast carcinomas, increased PDEF expression tended to correlate with Her2/neu overexpression. Increased expression of PDEF was also found in 27%, 33%, and 40% of benign prostate tissues, PIN samples, and prostate adenocarcinomas, respectively. Again, in matching samples of cancer vs benign and cancer vs PIN, 68% and 70%, respectively, showed increased expression in the malignant tissue. Moreover, PDEF was found to be more highly expressed in tumors with intermediate or high Gleason score compared with low-grade tumors (P < .01). In addition, R1881 treatment induced PDEF expression in the LNCaP prostate tumor cell line, suggesting regulation of PDEF by androgens in vivo. Together, these results for the first time show frequent increased expression of PDEF protein in breast and prostate tumors and support a role for PDEF in breast and prostate cancer progression.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Próstata/metabolismo , Proteínas Proto-Oncogênicas c-ets/biossíntese , Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/fisiopatologia , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Células HeLa , Humanos , Masculino , Metribolona/farmacologia , Próstata/metabolismo , Neoplasias da Próstata/patologia , Neoplasias da Próstata/fisiopatologia , Proteínas Proto-Oncogênicas c-ets/imunologia , Células U937
18.
Sci Signal ; 10(475)2017 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-28420758

RESUMO

Goblet cell metaplasia and excessive mucus secretion associated with asthma, cystic fibrosis, and chronic obstructive pulmonary disease contribute to morbidity and mortality worldwide. We performed a high-throughput screen to identify small molecules targeting a transcriptional network critical for the differentiation of goblet cells in response to allergens. We identified RCM-1, a nontoxic small molecule that inhibited goblet cell metaplasia and excessive mucus production in mice after exposure to allergens. RCM-1 blocked the nuclear localization and increased the proteasomal degradation of Forkhead box M1 (FOXM1), a transcription factor critical for the differentiation of goblet cells from airway progenitor cells. RCM-1 reduced airway resistance, increased lung compliance, and decreased proinflammatory cytokine production in mice exposed to the house dust mite and interleukin-13 (IL-13), which triggers goblet cell metaplasia. In cultured airway epithelial cells and in mice, RCM-1 reduced IL-13 and STAT6 (signal transducer and activator of transcription 6) signaling and prevented the expression of the STAT6 target genes Spdef and Foxa3, which are key transcriptional regulators of goblet cell differentiation. These results suggest that RCM-1 is an inhibitor of goblet cell metaplasia and IL-13 signaling, providing a new therapeutic candidate to treat patients with asthma and other chronic airway diseases.


Assuntos
Alérgenos/toxicidade , Proteína Forkhead Box M1/antagonistas & inibidores , Células Caliciformes/imunologia , Interleucina-13/imunologia , Fator de Transcrição STAT6/imunologia , Animais , Proteína Forkhead Box M1/genética , Proteína Forkhead Box M1/imunologia , Células Caliciformes/patologia , Fator 3-gama Nuclear de Hepatócito/genética , Fator 3-gama Nuclear de Hepatócito/imunologia , Interleucina-13/genética , Metaplasia/induzido quimicamente , Metaplasia/genética , Metaplasia/imunologia , Metaplasia/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Proto-Oncogênicas c-ets/imunologia , Fator de Transcrição STAT6/genética
19.
J Leukoc Biol ; 101(5): 1109-1117, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28235774

RESUMO

Megakaryocytes (MK) are the sole source of platelets in the body. They develop from lineage-committed hematopoietic stem and progenitor cells (HSPCs) via intermediate cells, which differ in morphology, size, ploidy, and surface phenotype. Development and maturation of MKs is governed by different transcription factors, including GATA-1, E26 transformation-specific transcription factor (ETS) family members, nuclear factor erythroid 2 transcription factor (NF-E2), and STAT3. During such challenges as acute inflammation, platelets are consumed in high numbers and must be replenished to secure survival of the host. This is achieved by integration of inflammatory signals into early MK development and depends on the STAT1-mediated enhanced translation of transcripts in stem cell-like megakaryocyte progenitors. Here, we review recent developments, which highlight the impact of inflammation on the development of platelets from HSPCs.


Assuntos
Plaquetas/imunologia , Citocinas/imunologia , Regulação da Expressão Gênica no Desenvolvimento/imunologia , Células-Tronco Hematopoéticas/imunologia , Inflamação/imunologia , Megacariócitos/imunologia , Animais , Plaquetas/citologia , Diferenciação Celular , Linhagem da Célula/imunologia , Proliferação de Células , Citocinas/genética , Fator de Transcrição GATA1/genética , Fator de Transcrição GATA1/imunologia , Células-Tronco Hematopoéticas/citologia , Humanos , Inflamação/genética , Inflamação/patologia , Megacariócitos/citologia , Camundongos , Subunidade p45 do Fator de Transcrição NF-E2/genética , Subunidade p45 do Fator de Transcrição NF-E2/imunologia , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Proto-Oncogênicas c-ets/imunologia , Fatores de Transcrição STAT/genética , Fatores de Transcrição STAT/imunologia , Transdução de Sinais
20.
Nat Commun ; 8(1): 1426, 2017 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-29127283

RESUMO

Humoral immunity requires B cells to respond to multiple stimuli, including antigen, membrane and soluble ligands, and microbial products. Ets family transcription factors regulate many aspects of haematopoiesis, although their functions in humoral immunity are difficult to decipher as a result of redundancy between the family members. Here we show that mice lacking both PU.1 and SpiB in mature B cells do not generate germinal centers and high-affinity antibody after protein immunization. PU.1 and SpiB double-deficient B cells have a survival defect after engagement of CD40 or Toll-like receptors (TLR), despite paradoxically enhanced plasma cell differentiation. PU.1 and SpiB regulate the expression of many components of the B cell receptor signaling pathway and the receptors for CD40L, BAFF and TLR ligands. Thus, PU.1 and SpiB enable B cells to appropriately respond to environmental cues.


Assuntos
Linfócitos B/imunologia , Linfócitos B/metabolismo , Proteínas Proto-Oncogênicas c-ets/imunologia , Proteínas Proto-Oncogênicas/imunologia , Transativadores/imunologia , Animais , Linfócitos B/citologia , Antígenos CD40/metabolismo , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Feminino , Centro Germinativo/citologia , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Imunidade Humoral/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Plasmócitos/citologia , Plasmócitos/imunologia , Plasmócitos/metabolismo , Proteínas Proto-Oncogênicas/deficiência , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-ets/deficiência , Proteínas Proto-Oncogênicas c-ets/genética , Transdução de Sinais , Receptores Toll-Like/metabolismo , Transativadores/deficiência , Transativadores/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA