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1.
Cell Death Differ ; 21(2): 226-33, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24270406

RESUMO

The thymus is the primary organ responsible for de novo generation of immunocompetent T cells that have a diverse repertoire of antigen recognition. During the developmental process, 98% of thymocytes die by apoptosis. Thus apoptosis is a dominant process in the thymus and occurs through either death by neglect or negative selection or through induction by stress/aging. Caspase activation is an essential part of the general apoptosis mechanism, and data suggest that caspases may have a role in negative selection; however, it seems more probable that caspase-8 activation is involved in death by neglect, particularly in glucocorticoid-induced thymocyte apoptosis. Caspase-8 is active in double-positive (DP) thymocytes in vivo and can be activated in vitro in DP thymocytes by T-cell receptor (TCR) crosslinking to induce apoptosis. Caspase-8 is a proapoptotic member of the caspase family and is considered an initiator caspase, which is activated upon stimulation of a death receptor (e.g., Fas), recruitment of the adaptor molecule FADD, and recruitment and subsequent processing of procaspase-8. The main role of caspase-8 seems to be pro-apoptotic and, in this review, we will discuss about the involvement of caspase-8 in (1) TCR-triggered thymic apoptosis; (2) death receptor-mediated thymic apoptosis; and (3) glucocorticoid-induced thymic apoptosis. Regarding TCR triggering, caspase-8 is active in medullary, semi-mature heat-stable antigen(hi) (HAS(hi) SP) thymocytes as a consequence of strong TCR stimulation. The death receptors Fas, FADD, and FLIP are involved upstream of caspase-8 activation in apoptosis; whereas, Bid and HDAC7 are involved downstream of caspase-8. Finally, caspase-8 is involved in glucocortocoid-induced thymocyte apoptosis through an activation loop with the protein GILZ. GILZ activates caspase-8, promoting GILZ sumoylation and its protection from proteasomal degradation.


Assuntos
Caspase 8/metabolismo , Timo/enzimologia , Timo/fisiologia , Animais , Humanos
2.
J Chemother ; 23(3): 150-7, 2011 06.
Artigo em Inglês | MEDLINE | ID: mdl-21742584

RESUMO

The leaves of Artocarpus tonkinensis are used in Vietnamese traditional medicine for treatment of arthritis, and the compound maesopsin 4-O-ß-D-glucoside (TAT-2), isolated from them, inhibits the proliferation of activated T cells. Our goal was to test the anti-proliferative activity of TAT-2 on the T-cell leukemia, Jurkat, and on the acute myeloid leukemia, OCI-AML. TAT-2 inhibited the growth of OCI-AML (and additional acute myeloid leukemia cells) but not Jurkat cells. Growth inhibition was shown to be due to inhibition of proliferation rather than increase in cell death. Analysis of cytokine release showed that TAT-2 stimulated the release of TGF-ß, yet TGF-ß neutralization did not reverse the maesopsin-dependent effect. Gene expression profiling determined that maesopsin modulated 19 identifiable genes. Transcription factor CP2 was the gene most significantly modulated. Real-time PCR validated that up-regulation of sulphiredoxin 1 homolog (SRXN1), hemeoxygenase 1 (HMOX1), and breast carcinoma amplified sequence 3 (BCAS3) were consistently modulated.


Assuntos
Benzofuranos/farmacologia , Glucosídeos/farmacologia , Heme Oxigenase-1/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Proteínas de Neoplasias/genética , Oxirredutases atuantes sobre Doadores de Grupo Enxofre/genética , Artocarpus/química , Morte Celular/efeitos dos fármacos , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Relação Dose-Resposta a Droga , Expressão Gênica/efeitos dos fármacos , Perfilação da Expressão Gênica/métodos , Células HL-60 , Heme Oxigenase-1/biossíntese , Humanos , Células Jurkat , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Leucemia de Células T/tratamento farmacológico , Leucemia de Células T/genética , Leucemia de Células T/metabolismo , Leucemia de Células T/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/biossíntese , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Oxirredutases atuantes sobre Doadores de Grupo Enxofre/biossíntese , Linfócitos T/efeitos dos fármacos , Fatores de Transcrição/genética , Fator de Crescimento Transformador beta/metabolismo , Células U937 , Regulação para Cima/efeitos dos fármacos
3.
Cell Death Differ ; 18(1): 183-90, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20671745

RESUMO

In this study, we evaluated the possible cross-talk between glucocorticoid (GC)-induced leucine zipper (Gilz) and caspase-8 in dexamethasone (Dex)-treated thymocytes. We determined that expression of Dex-induced Gilz protein was reduced when caspase-8 activity was inhibited, and this effect was not partially due to altered Gilz mRNA expression. Inhibition of the proteasome abrogated this reduction in Gilz expression, suggesting that Dex-induced caspase-8 activation protects Gilz from degradation. We hypothesized that the caspase-8-dependent protection of Gilz could be due to caspase-8-driven sumoylation. As a putative small ubiquitin-like modifier (SUMO)-binding site was identified in the Gilz sequence, we assessed whether SUMO-1 interacted with Gilz. We identified a 30-kDa protein that was compatible with the size of a Gilz-SUMO-1 complex and was recognized by the anti-SUMO-1 and anti-Gilz antibodies. In addition, Gilz bound to SUMO ubiquitin-conjugating (E2)-conjugating enzyme Ube21 (Ubc9), the specific SUMO-1 E2-conjugating enzyme, in vitro and coimmunoprecipitated with Ubc9 in vivo. Furthermore, Gilz coimmunoprecipitated with SUMO-1 both in vitro and in vivo, and this interaction depended on caspase-8 activation. This requirement for caspase-8 was further evaluated in caspase-8-deficient thymocytes and lymphocytes in which Gilz expression was reduced. In summary, our results suggest that caspase-8 activation protects Gilz from proteasomal degradation and induces its binding to SUMO-1 in GC-treated thymocytes.


Assuntos
Caspase 8/metabolismo , Dexametasona/farmacologia , Glucocorticoides/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteína SUMO-1/metabolismo , Glândula Tireoide/metabolismo , Fatores de Transcrição/metabolismo , Sequência de Aminoácidos , Animais , Anticorpos/imunologia , Sítios de Ligação , Caspase 8/genética , Caspase 8/fisiologia , Células Cultivadas , Camundongos , Dados de Sequência Molecular , Ligação Proteica , Sumoilação , Glândula Tireoide/citologia , Fatores de Transcrição/química , Fatores de Transcrição/genética , Enzimas de Conjugação de Ubiquitina/metabolismo
4.
J Chemother ; 19(5): 562-9, 2007 10.
Artigo em Inglês | MEDLINE | ID: mdl-18073156

RESUMO

We used transgenic mice to investigate the effect of IL-2 stimulation on T lymphocyte functions of GILZ-overexpressing splenic T cells. When compared to their controls, T cells from transgenic mice underwent normal activation after stimulation with anti-CD3 plus anti-CD28 monoclonal antibodies, as evaluated by CD25 expression, CD2 up-regulation and proliferation. IL-10, IL-13 and IFN-gamma increased more consistently in CD3/CD28-triggered TG compared to WT splenic CD4(+)cells. Analysis of the CD4(+)and CD8(+)T cells demonstrated a decreased CD4(+)/CD8(+)T-cell ratio (1:1 instead of 1:2) in response to IL-2 stimulation, possibly due to an unresponsiveness of IL-2 receptor beta and/or gamma chains. Finally, the total number of T cells was significantly increased in aged mice and this was due to the augmentation of CD4(+)T cells. These results support the hypothesis that GILZ regulates, at least in part, peripheral T-cell functions by influencing their responsiveness to IL-2.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Interleucina-2/metabolismo , Fatores de Transcrição/metabolismo , Envelhecimento/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Citocinas/biossíntese , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Interleucina-2/imunologia , Ativação Linfocitária/fisiologia , Camundongos , Camundongos Transgênicos , Baço/citologia , Baço/imunologia , Fatores de Transcrição/genética , Fatores de Transcrição/imunologia
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