Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 2 de 2
Filtrar
Mais filtros











Base de dados
Intervalo de ano de publicação
1.
J Virol ; 86(9): 5165-78, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22357270

RESUMO

Epstein-Barr virus (EBV) establishes a persistent latent infection in B lymphocytes and is associated with the development of numerous human tumors. Epstein-Barr nuclear antigen 3C (EBNA 3C) is essential for B-cell immortalization, has potent cell cycle deregulation capabilities, and functions as a regulator of both viral- and cellular-gene expression. We performed transcription profiling on EBNA 3C-expressing B cells and identified several chemokines and members of integrin receptor-signaling pathways, including CCL3, CCL4, CXCL10, CXCL11, ITGA4, ITGB1, ADAM28, and ADAMDEC1, as cellular target genes that could be repressed by the action of EBNA 3C alone. Chemotaxis assays demonstrated that downregulation of CXCL10 and -11 by EBNA 3C is sufficient to reduce the migration of cells expressing the CXCL10 and -11 receptor CXCR3. Gene repression by EBNA 3C was accompanied by decreased histone H3 lysine 9/14 acetylation and increased histone H3 lysine 27 trimethylation. In an EBV-positive cell line expressing all latent genes, we identified binding sites for EBNA 3C at ITGB1 and ITGA4 and in a distal regulatory region between ADAMDEC1 and ADAM28, providing the first demonstration of EBNA 3C association with cellular-gene control regions. Our data implicate indirect mechanisms in CXCL10 and CXCL11 repression by EBNA 3C. In summary, we have unveiled key cellular pathways repressed by EBNA 3C that are likely to contribute to the ability of EBV-immortalized cells to modulate immune responses, adhesion, and B-lymphocyte migration to facilitate persistence in the host.


Assuntos
Antígenos Virais/metabolismo , Regulação para Baixo/genética , Integrinas/genética , Regiões Promotoras Genéticas , Transdução de Sinais , Proteínas ADAM/genética , Animais , Sítios de Ligação , Adesão Celular/genética , Linhagem Celular , Inibição de Migração Celular/genética , Quimiocinas/genética , Quimiotaxia/genética , Antígenos Nucleares do Vírus Epstein-Barr , Regulação da Expressão Gênica , Humanos , Camundongos , Receptores CXCR3/metabolismo , Elementos Reguladores de Transcrição
2.
J Immunol ; 187(7): 3721-9, 2011 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-21876034

RESUMO

Blockade of IL-2R with humanized anti-CD25 Abs, such as daclizumab, inhibits Th2 responses in human T cells. Recent murine studies have shown that IL-2 also plays a significant role in regulating Th2 cell differentiation by activated STAT5. To explore the role of activated STAT5 in the Th2 differentiation of primary human T cells, we studied the mechanisms underlying IL-2 regulation of C-MAF expression. Chromatin immunoprecipitation studies revealed that IL-2 induced STAT5 binding to specific sites in the C-MAF promoter. These sites corresponded to regions enriched for markers of chromatin architectural features in both resting CD4 and differentiated Th2 cells. Unlike IL-6, IL-2 induced C-MAF expression in CD4 T cells with or without prior TCR stimulation. TCR-induced C-MAF expression was significantly inhibited by treatment with daclizumab or a JAK3 inhibitor, R333. Furthermore, IL-2 and IL-6 synergistically induced C-MAF expression in TCR-activated T cells, suggesting functional cooperation between these cytokines. Finally, both TCR-induced early IL4 mRNA expression and IL-4 cytokine expression in differentiated Th2 cells were significantly inhibited by IL-2R blockade. Thus, our findings demonstrate the importance of IL-2 in Th2 differentiation in human T cells and support the notion that IL-2R-directed therapies may have utility in the treatment of allergic disorders.


Assuntos
Diferenciação Celular/imunologia , Interleucina-2/metabolismo , Proteínas Proto-Oncogênicas c-maf/biossíntese , Transdução de Sinais/imunologia , Células Th2/metabolismo , Western Blotting , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Diferenciação Celular/genética , Separação Celular , Imunoprecipitação da Cromatina , Citometria de Fluxo , Expressão Gênica , Regulação da Expressão Gênica/imunologia , Humanos , Interleucina-2/imunologia , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Proto-Oncogênicas c-maf/genética , Proteínas Proto-Oncogênicas c-maf/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição STAT5/imunologia , Fator de Transcrição STAT5/metabolismo , Células Th2/imunologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA