Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 8 de 8
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Immunol ; 167(5): 2511-21, 2001 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-11509590

RESUMO

During embryogenesis, the Peyer's patch anlagen are induced by a cell population that produces lymphotoxin (LT) alpha(1)beta(2) following stimulation of IL-7Ralpha. In this study, we show that the LT-producing cell is localized within the IL-7Ralpha(+) and integrin alpha(4)beta(7) (alpha(4)beta(7))(+) population in the embryonic intestine. Lineage commitment to the LT producer phenotype in the fetal liver coincides with expression of alpha(4)beta(7). Before expression of alpha(4)beta(7), the potential of IL-7Ralpha(+) population to generate B cells is lost. However, the progenitors for T cells and LT producer cells reside in the IL-7Ralpha(+)alpha(4)beta(7)(+) cells, but during subsequent differentiation, the potential to give rise to T cells is lost. This IL-7Ralpha(+)alpha(4)beta(7)(+) population migrates to the intestine, where it induces the Peyer's patch anlagen. When stimulated with IL-15 or IL-3 and TNF, the intestinal IL-7Ralpha(+)alpha(4)beta(7)(+) population can differentiate into fully competent NK1.1(+) NK cells or CD11c(+) APCs. Expression of alpha(4)beta(7) is lost during differentiation of both lineages; IL-7Ralpha expression is lost during NK1.1(+) cells differentiation. A newly discovered lineage(-)IL-7Ralpha(+)c-Kit(+)alpha(4)beta(7)(+) population in the fetal liver is committed to T, NK, dendritic, and fetal intestinal LT producer lineage, the latter being an intermediate stage during differentiation of NK and dendritic cells.


Assuntos
Integrinas/metabolismo , Nódulos Linfáticos Agregados/embriologia , Nódulos Linfáticos Agregados/imunologia , Células-Tronco/citologia , Células-Tronco/imunologia , Animais , Diferenciação Celular , Movimento Celular , Células Dendríticas/citologia , Células Dendríticas/imunologia , Feminino , Integrinas/genética , Interleucina-15/farmacologia , Interleucina-3/farmacologia , Células Matadoras Naturais/citologia , Células Matadoras Naturais/imunologia , Linfotoxina-alfa/biossíntese , Camundongos , Camundongos Endogâmicos C57BL , Nódulos Linfáticos Agregados/citologia , Gravidez , Receptores de Interleucina-7/metabolismo , Transdução de Sinais , Linfócitos T/citologia , Linfócitos T/imunologia
2.
J Immunol ; 165(2): 671-9, 2000 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-10878339

RESUMO

The development of lymphoid organs requires membrane-bound lymphotoxin (LT), a heterotrimer containing LTalpha and LTbeta, but the effects of LT on T cell function have not been characterized extensively. Upon TCR cross-linking in vitro, splenocytes from both LTalpha-/- and LTbeta-/- mice failed to produce IL-4 and IL-10 due to a reduction in NK T cells. Concordantly, LTalpha-/- and LTbeta-/- mice did not respond to the lipoglycan alpha-galactosylceramide, which is presented by mouse CD1 to Valpha14+ NK T cells. Interestingly, both populations of NK T cells, including those that are mouse CD1 dependent and alpha-galactosylceramide reactive and those that are not, were affected by disruption of the LTalpha and LTbeta genes. NK T cells were not affected, however, in transgenic mice in which LT signaling is blocked, beginning on day 3 after birth, by expression of a soluble decoy LTbeta receptor. This suggests that membrane-bound LT is critical for NK T cells early in ontogeny, but not for the homeostasis of mature cells.


Assuntos
Células Matadoras Naturais/citologia , Células Matadoras Naturais/imunologia , Linfotoxina-alfa/fisiologia , Proteínas de Membrana/fisiologia , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/imunologia , Animais , Antígenos CD1/fisiologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Feminino , Galactosilceramidas/administração & dosagem , Galactosilceramidas/farmacologia , Homeostase/imunologia , Fragmentos Fc das Imunoglobulinas/genética , Injeções Intraperitoneais , Injeções Intravenosas , Interleucina-10/antagonistas & inibidores , Interleucina-10/biossíntese , Interleucina-4/antagonistas & inibidores , Interleucina-4/biossíntese , Células Matadoras Naturais/metabolismo , Linfopenia/genética , Linfopenia/imunologia , Receptor beta de Linfotoxina , Linfotoxina-alfa/genética , Linfotoxina-alfa/metabolismo , Linfotoxina-beta , Masculino , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Receptores do Fator de Necrose Tumoral/genética , Subpopulações de Linfócitos T/metabolismo
3.
Proc Natl Acad Sci U S A ; 96(17): 9803-8, 1999 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-10449775

RESUMO

TRAF5 [tumor necrosis factor (TNF) receptor-associated factor 5] is implicated in NF-kappaB and c-Jun NH(2)-terminal kinase/stress-activated protein kinase activation by members of the TNF receptor superfamily, including CD27, CD30, CD40, and lymphotoxin-beta receptor. To investigate the functional role of TRAF5 in vivo, we generated TRAF5-deficient mice by gene targeting. Activation of either NF-kappaB or c-Jun NH(2)-terminal kinase/stress-activated protein kinase by tumor necrosis factor, CD27, and CD40 was not abrogated in traf5(-/-) mice. However, traf5(-/-) B cells showed defects in proliferation and up-regulation of various surface molecules, including CD23, CD54, CD80, CD86, and Fas in response to CD40 stimulation. Moreover, in vitro Ig production of traf5(-/-) B cells stimulated with anti-CD40 plus IL-4 was reduced substantially. CD27-mediated costimulatory signal also was impaired in traf5(-/-) T cells. Collectively, these results demonstrate that TRAF5 is involved in CD40- and CD27-mediated signaling.


Assuntos
Antígenos CD40/imunologia , Ativação Linfocitária , Proteínas Quinases Ativadas por Mitógeno , Proteínas/genética , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia , Animais , Ligante de CD40 , Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo , Ativação Enzimática , Proteínas Quinases JNK Ativadas por Mitógeno , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Knockout , NF-kappa B/metabolismo , Fator 5 Associado a Receptor de TNF
4.
Genomics ; 42(1): 26-32, 1997 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-9177772

RESUMO

Tumor necrosis factor (TNF) receptor-associated factors (TRAFs) are signal transducers for members of the TNF receptor superfamily. We previously identified murine TRAF5 (mTRAF5) and showed that it specifically interacts with the lymphotoxin-beta receptor (LT-beta R) and activates the transcription factor NF-kappa B. Here we have cloned the human TRAF5 homologue (hTRAF5) by cross hybridization with mTRAF5 cDNA. hTRAF5 cDNA is composed of 2894 nucleotides with a 557-amino-acid open reading frame that exhibits 77.5 and 80% identity to mTRAF5 at the nucleotide and amino acid levels, respectively. Northern blot analysis revealed that hTRAF5 mRNA is expressed in all visceral organs. Western blotting revealed that hTRAF5 protein was abundantly expressed in the human follicular dentritic cell line, FDC-1, and to a much lesser degree in several tumor cell lines. Interspecific backcross mapping revealed that Traf5 is located in the distal region of mouse chromosome 1, which shares a region of homology with human chromosome 1q. Fluorescence in situ hybridization confirmed regional localization to human chromosome 1q32.


Assuntos
Proteínas de Transporte/genética , Cromossomos Humanos Par 1/genética , DNA Complementar/genética , Proteínas , Sequência de Aminoácidos , Animais , Linhagem Celular , Mapeamento Cromossômico , Clonagem Molecular , Cruzamentos Genéticos , Células Dendríticas/metabolismo , Feminino , Expressão Gênica , Humanos , Hibridização in Situ Fluorescente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Muridae , Hibridização de Ácido Nucleico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Homologia de Sequência de Aminoácidos , Fator 5 Associado a Receptor de TNF , Distribuição Tecidual , Fator de Necrose Tumoral alfa/metabolismo
5.
J Biol Chem ; 271(35): 21151-9, 1996 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-8702885

RESUMO

Tumor necrosis factor receptor p75 (TNF-R p75) is a 75-kDa type I transmembrane protein expressed predominantly on cells of hematopoietic lineage. TNF-R p75 belongs to the TNF receptor superfamily characterized by cysteine-rich extracellular regions composed of three to six disulfide-linked domains. In the present report we have characterized, for the first time, the complete gene structure for human TNF-R p75, which spans approximately 43 kbp. The gene consists of 10 exons (ranging from 34 base pairs to 2.5 kilobase pairs) and nine introns (343 base pairs to 19 kilobase pairs). Consensus elements for transcription factors involved in T cell development and activation were noted in the 5'-flanking region including T cell factor-1, Ikaros, AP-1, CK-2, interleukin-6 receptor E (IL-6RE), ISRE, GAS, NF-kappaB, and Sp1. The unusual (GATA)n and (GAA)(GGA) repeats found within intron 1 may prove useful for further genome analysis within the 1p36 chromosomal locus. Characterization of the human TNF-R p75 gene structure will permit further assessment of its involvement in normal hematopoietic cell development and function, autoimmune disease, and nonrandom translocations in hematopoietic malignancies.


Assuntos
Antígenos CD/genética , Regiões Promotoras Genéticas , Receptores do Fator de Necrose Tumoral/genética , Sequência de Aminoácidos , Sequência de Bases , Linhagem Celular , Clonagem Molecular , DNA Complementar , Éxons , Humanos , Íntrons , Dados de Sequência Molecular , Polimorfismo Genético , Receptores Tipo II do Fator de Necrose Tumoral , Sequências Repetitivas de Ácido Nucleico , Transcrição Gênica
6.
Mol Cell Biol ; 15(6): 3032-40, 1995 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-7539102

RESUMO

Fas/APO-1 is a cell surface protein known to trigger apoptosis upon specific antibody engagement. Because wild-type p53 can activate transcription as well as induce apoptosis, we queried whether p53 might upregulate Fas/APO-1. To explore this possibility, we examined human p53-null (H358 non-small-cell lung adenocarcinoma and K562 erythroleukemia) and wild-type p53-containing (H460 non-small-cell lung adenocarcinoma) cell lines. When H358 or H460 cells were transduced with a replication-deficient adenovirus expression construct containing the human wild-type p53 gene but not with vector alone, a marked upregulation (approximately a three-to fourfold increase) of cell surface Fas/APO-1 was observed by flow cytometry. Similarly, K562, cells stably transfected with a plasmid vector containing the temperature-sensitive human p53 mutant Ala-143 demonstrated a four- to sixfold upregulation of Fas/APO-1 by flow-cytometric analysis at the permissive temperature of 32.5 degrees C. Temperature-sensitive upregulation of Fas/APO-1 in K562 Ala-143 cells was verified by immunoprecipitation and demonstrated to result from enhanced mRNA production by nuclear run-on and Northern (RNA) analyses. Stably transfected K562 cells expressing temperature-insensitive, transcriptionally inactive p53 mutants (His-175, Trp-248, His-273, or Gly-281) failed to upregulate Fas/APO-1 at either 32.5 degrees or 37.5 degrees C. The temperature-sensitive transcription of Fas/APO-1 occurred in the presence of cycloheximide, indicating that de novo protein synthesis was not required and suggested a direct involvement of p53. Collectively, these observations argue that Fas/APO-1 is a target gene for transcriptional activation by p53.


Assuntos
Antígenos de Superfície/biossíntese , Proteína Supressora de Tumor p53/genética , Adenocarcinoma/metabolismo , Apoptose , Humanos , Leucemia Eritroblástica Aguda/metabolismo , Neoplasias Pulmonares/metabolismo , Mutação , RNA Mensageiro/análise , Temperatura , Transcrição Gênica , Células Tumorais Cultivadas , Regulação para Cima , Receptor fas
7.
J Appl Physiol (1985) ; 76(3): 1130-7, 1994 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-8005855

RESUMO

The effects of NG-methyl-L-arginine (L-NMA), an inhibitor of nitric oxide formation, were studied in dogs treated with interleukin-2 (IL-2). The administration of IL-2 to dogs resulted in hypotension within 3 days of treatment. The development of hypotension correlated with accumulation in the serum of nitrate, which is a stable breakdown product of nitric oxide. Administration of L-NMA decreased serum nitrate levels and increased the mean arterial pressure. The antihypotensive effect was dose dependent with a maximum effect observed at a dose of 20 mg/kg. Administration of a continuous infusion of L-NMA (5 mg.kg-1.h-1) maintained the mean arterial pressure for 48 h with concurrent administration of IL-2. Evaluation of IL-2-induced lymphokine-activated killer cell proliferation and tumoricidal activity toward a canine glioblastoma target cell line was unaffected by L-NMA. These studies imply that L-NMA may effectively ameliorate the dose-limiting hypotension associated with administration of IL-2 without adversely affecting the antitumor effects.


Assuntos
Arginina/análogos & derivados , Hipotensão/prevenção & controle , Interleucina-2/antagonistas & inibidores , Óxido Nítrico/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Arginina/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Nitrogênio da Ureia Sanguínea , Divisão Celular/efeitos dos fármacos , Creatinina/sangue , Cães , Enzimas/sangue , Glioma/metabolismo , Glioma/fisiopatologia , Hipotensão/induzido quimicamente , Interleucina-2/farmacologia , Células Matadoras Ativadas por Linfocina/efeitos dos fármacos , Contagem de Leucócitos/efeitos dos fármacos , Linfócitos/efeitos dos fármacos , Masculino , Monócitos/efeitos dos fármacos , Óxido Nítrico/biossíntese , Óxido Nítrico/sangue , Trombocitopenia/induzido quimicamente , Células Tumorais Cultivadas , ômega-N-Metilarginina
8.
J Immunother Emphasis Tumor Immunol ; 15(1): 1-10, 1994 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-8110725

RESUMO

We previously demonstrated that recombinant human tumor necrosis factor (hTNF) is synergistic with human interleukin-2 (hIL-2) for in vivo regression of murine tumors. In mice, the timing of cytokine administration is critical in achieving synergy. Because hTNF exhibits negligible binding to the type II murine TNF receptor (TNF-R), we questioned whether murine TNF (mTNF) would have therapeutic benefits, scheduling requirements, and toxic effects similar to those of the hIL-2-hTNF combination. To evaluate the biological effects of TNF-R types I and II interaction, we directly compared the effects of mTNF and hTNF in combination with hIL-2 on in vivo tumor regression and in vitro activation of murine splenocytes. Our results demonstrate for the first time that (a) the cytokine combination hTNF-hIL-2 is consistently more efficacious than mTNF-hIL-2 in in vivo murine immunotherapy models; (b) the in vivo antitumor effects of hTNF-hIL-2 and not mTNF-hIL-2 are critically dependent upon cytokine scheduling; and (c) in vitro culture of splenocytes with mTNF-hIL-2 enhances cellular proliferation, Lyt 2, and TNF-RI expression compared with hTNF-hIL-2. Collectively, these studies extend the previous findings of species-specific mTNF-R responses and reveal that optimal scheduling and efficacy of TNF-hIL-2 combination therapy in murine tumor models is critically dependent upon the TNF species employed.


Assuntos
Interleucina-2/uso terapêutico , Fator de Necrose Tumoral alfa/uso terapêutico , Animais , Especificidade de Anticorpos , Esquema de Medicação , Sinergismo Farmacológico , Feminino , Imunoterapia , Técnicas In Vitro , Interleucina-2/metabolismo , Leucemia L1210/terapia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Receptores do Fator de Necrose Tumoral/metabolismo , Especificidade da Espécie , Células Tumorais Cultivadas , Fator de Necrose Tumoral alfa/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...