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1.
Nucleic Acids Res ; 43(14): 6983-93, 2015 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-26101251

RESUMO

Melanoma is the most aggressive skin cancer; its prognosis, particularly in advanced stages, is disappointing largely due to the resistance to conventional anticancer treatments and high metastatic potential. NF-κB constitutive activation is a major factor for the apoptosis resistance of melanoma. Several studies suggest a role for the immunophilin FKBP51 in NF-κB activation, but the underlying mechanism is still unknown. In the present study, we demonstrate that FKBP51 physically interacts with IKK subunits, and facilitates IKK complex assembly. FKBP51-knockdown inhibits the binding of IKKγ to the IKK catalytic subunits, IKK-α and -ß, and attenuates the IKK catalytic activity. Using FK506, an inhibitor of the FKBP51 isomerase activity, we found that the IKK-regulatory role of FKBP51 involves both its scaffold function and its isomerase activity. Moreover, FKBP51 also interacts with TRAF2, an upstream mediator of IKK activation. Interestingly, both FKBP51 TPR and PPIase domains are required for its interaction with TRAF2 and IKKγ, whereas only the TPR domain is involved in interactions with IKKα and ß. Collectively, these results suggest that FKBP51 promotes NF-κB activation by serving as an IKK scaffold as well as an isomerase. Our findings have profound implications for designing novel melanoma therapies based on modulation of FKBP51.


Assuntos
Melanoma/metabolismo , NF-kappa B/metabolismo , Proteínas de Ligação a Tacrolimo/metabolismo , Linhagem Celular Tumoral , Humanos , Quinase I-kappa B/metabolismo , Melanoma/enzimologia , Domínios e Motivos de Interação entre Proteínas , Fator 2 Associado a Receptor de TNF/metabolismo , Proteínas de Ligação a Tacrolimo/química
2.
Nat Commun ; 6: 6074, 2015 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-25606824

RESUMO

Development of an immune or autoimmune response involves T-cell activation in lymphoid organs and subsequent migration to peripheral tissues. Here we show that T-cell-specific ablation of the kinase TBK1 promotes T-cell activation but causes retention of effector T cells in the draining lymph node in a neuroinflammatory autoimmunity model, experimental autoimmune encephalomyelitis (EAE). At older ages, the T-cell-conditional TBK1-knockout mice also spontaneously accumulate T cells with activated phenotype. TBK1 controls the activation of AKT and its downstream kinase mTORC1 by a mechanism involving TBK1-stimulated AKT ubiquitination and degradation. The deregulated AKT-mTORC1 signalling in turn contributes to enhanced T-cell activation and impaired effector T-cell egress from draining lymph nodes. Treatment of mice with a small-molecule inhibitor of TBK1 inhibits EAE induction. These results suggest a role for TBK1 in regulating T-cell migration and establish TBK1 as a regulator of the AKT-mTORC1 signalling axis.


Assuntos
Regulação da Expressão Gênica , Ativação Linfocitária/imunologia , Proteínas Serina-Treonina Quinases/metabolismo , Linfócitos T/citologia , Animais , Autoimunidade/imunologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD8-Positivos/citologia , Movimento Celular , Separação Celular , Sistema Nervoso Central/metabolismo , Encefalomielite Autoimune Experimental/genética , Feminino , Humanos , Células Jurkat , Macrófagos/metabolismo , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Complexos Multiproteicos/metabolismo , Orthomyxoviridae , Fenótipo , Fosforilação , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
3.
J Exp Med ; 211(8): 1689-702, 2014 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-24980047

RESUMO

Development of autoimmune diseases, such as multiple sclerosis and experimental autoimmune encephalomyelitis (EAE), involves the inflammatory action of Th1 and Th17 cells, but the underlying signaling mechanism is incompletely understood. We show that the kinase TPL2 is a crucial mediator of EAE and is required for the pathological action of Th17 cells. TPL2 serves as a master kinase mediating the activation of multiple downstream pathways stimulated by the Th17 signature cytokine IL-17. TPL2 acts by linking the IL-17 receptor signal to the activation of TAK1, which involves a dynamic mechanism of TPL2-TAK1 interaction and TPL2-mediated phosphorylation and catalytic activation of TAK1. These results suggest that TPL2 mediates TAK1 axis of IL-17 signaling, thereby promoting autoimmune neuroinflammation.


Assuntos
Autoimunidade/imunologia , Inflamação/imunologia , Inflamação/patologia , Interleucina-17/metabolismo , MAP Quinase Quinase Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais/imunologia , Animais , Diferenciação Celular/imunologia , Linhagem Celular , Sistema Nervoso Central/patologia , Encefalomielite Autoimune Experimental/etiologia , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Ativação Enzimática , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação da Expressão Gênica , Sistema Hematopoético/patologia , Humanos , Ativação Linfocitária/imunologia , MAP Quinase Quinase Quinases/deficiência , Camundongos Knockout , Fosforilação , Ligação Proteica , Proteínas Proto-Oncogênicas/deficiência , Tolerância a Radiação , Células Th17/imunologia
4.
J Immunol ; 193(1): 422-30, 2014 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-24899500

RESUMO

The noncanonical NF-κB pathway induces processing of the NF-κB2 precursor protein p100, and thereby mediates activation of p52-containing NF-κB complexes. This pathway is crucial for B cell maturation and humoral immunity, but its role in regulating T cell function is less clear. Using mutant mice that express a nonprocessible p100, NF-κB2(lym1), we show that the noncanonical NF-κB pathway has a T cell-intrinsic role in regulating the pathogenesis of a T cell-mediated autoimmunity, experimental autoimmune encephalomyelitis (EAE). Although the lym1 mutation does not interfere with naive T cell activation, it renders the Th17 cells defective in the production of inflammatory effector molecules, particularly the cytokine GM-CSF. We provide evidence that p52 binds to the promoter of the GM-CSF-encoding gene (Csf2) and cooperates with c-Rel in the transactivation of this target gene. Introduction of exogenous p52 or GM-CSF to the NF-κB2(lym1) mutant T cells partially restores their ability to induce EAE. These results suggest that the noncanonical NF-κB pathway mediates induction of EAE by regulating the effector function of inflammatory T cells.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Subunidade p52 de NF-kappa B/imunologia , Células Th17/imunologia , Ativação Transcricional/imunologia , Animais , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/patologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Camundongos , Camundongos Knockout , Mutação , Subunidade p52 de NF-kappa B/genética , Proteínas Proto-Oncogênicas c-rel/genética , Proteínas Proto-Oncogênicas c-rel/imunologia , Células Th17/patologia , Ativação Transcricional/genética
5.
Nat Commun ; 5: 3755, 2014 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-24806599

RESUMO

A variety of reactive organic compounds, called haptens, can cause allergic contact dermatitis. However, the innate immune mechanisms by which haptens stimulate dendritic cells (DCs) to sensitize T cells remain unclear. Here we show that the coupling of ITAM-Syk-CARD9 signalling to interleukin-1 (IL-1) secretion in DCs is crucial for allergic sensitization to haptens. Both MyD88 and Caspase recruitment domain-containing protein 9 (CARD9) signalling are required for contact hypersensitivity (CHS). Naïve T cells require signals received through IL-1R1-MyD88 for effector differentiation, whereas DCs require CARD9 and spleen tyrosine kinase (Syk) signalling for hapten-induced IL-1α/ß secretion and their ability to prime T cells. DC-specific deletion of CARD9, DAP12, Syk or NLRP3, but not MyD88, is sufficient to abolish CHS. All tested haptens, but not irritants, can induce Syk activation, leading to both the CARD9/BCL10-dependent pro-IL-1 synthesis (signal1) and reactive oxygen species-mediated NLRP3 inflammasome activation (signal2), required for IL-1 secretion. These data unveil an innate immune mechanism crucial for allergic contact sensitization to chemical compounds.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/imunologia , Dermatite de Contato/imunologia , Motivo de Ativação do Imunorreceptor Baseado em Tirosina/imunologia , Interleucina-1/biossíntese , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Proteínas Tirosina Quinases/imunologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Animais , Proteína 10 de Linfoma CCL de Células B , Proteínas Adaptadoras de Sinalização CARD/genética , Linfócitos T CD8-Positivos/imunologia , Proteínas de Transporte/genética , Caspase 1/metabolismo , Células Dendríticas/imunologia , Ativação Enzimática/imunologia , Inflamassomos/imunologia , Interleucina-1/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR , Proteínas Tirosina Quinases/genética , Espécies Reativas de Oxigênio/imunologia , Receptores Tipo I de Interleucina-1/antagonistas & inibidores , Receptores Tipo I de Interleucina-1/imunologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Quinase Syk
6.
Immunity ; 40(5): 692-705, 2014 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-24792914

RESUMO

Glutamine has been implicated as an immunomodulatory nutrient, but how glutamine uptake is mediated during T cell activation is poorly understood. We have shown that naive T cell activation is coupled with rapid glutamine uptake, which depended on the amino acid transporter ASCT2. ASCT2 deficiency impaired the induction of T helper 1 (Th1) and Th17 cells and attenuated inflammatory T cell responses in mouse models of immunity and autoimmunity. Mechanistically, ASCT2 was required for T cell receptor (TCR)-stimulated activation of the metabolic kinase mTORC1. We have further shown that TCR-stimulated glutamine uptake and mTORC1 activation also required a TCR signaling complex composed of the scaffold protein CARMA1, the adaptor molecule BCL10, and the paracaspase MALT1. This function was independent of IKK kinase, a major downstream target of the CARMA1 complex. These findings highlight a mechanism of T cell activation involving ASCT2-dependent integration of the TCR signal and a metabolic signaling pathway.


Assuntos
Sistema ASC de Transporte de Aminoácidos/imunologia , Glutamina/metabolismo , Complexos Multiproteicos/metabolismo , Receptores de Antígenos de Linfócitos T/imunologia , Serina-Treonina Quinases TOR/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Transferência Adotiva , Sistema ASC de Transporte de Aminoácidos/genética , Sistema ASC de Transporte de Aminoácidos/metabolismo , Animais , Proteína 10 de Linfoma CCL de Células B , Transporte Biológico , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Antígenos CD28/imunologia , Caspases/metabolismo , Diferenciação Celular/imunologia , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Ativação Enzimática/imunologia , Humanos , Inflamação/imunologia , Interleucina-2/biossíntese , Células Jurkat , Leucina/metabolismo , Ativação Linfocitária/imunologia , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Antígenos de Histocompatibilidade Menor , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa , Proteínas de Neoplasias/metabolismo , Transdução de Sinais/imunologia , Células Th1/imunologia
7.
Nat Immunol ; 15(6): 562-70, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24777531

RESUMO

Deubiquitinases (DUBs) are a new class of drug targets, although the physiological function of only few DUBs has been characterized. Here we identified the DUB USP15 as a crucial negative regulator of T cell activation. USP15 stabilized the E3 ubiquitin ligase MDM2, which in turn negatively regulated T cell activation by targeting the degradation of the transcription factor NFATc2. USP15 deficiency promoted T cell activation in vitro and enhanced T cell responses to bacterial infection and tumor challenge in vivo. USP15 also stabilized MDM2 in cancer cells and regulated p53 function and cancer-cell survival. Our results suggest that inhibition of USP15 may both induce tumor cell apoptosis and boost antitumor T cell responses.


Assuntos
Fatores de Transcrição NFATC/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/imunologia , Células Th1/imunologia , Proteases Específicas de Ubiquitina/imunologia , Transferência Adotiva , Animais , Apoptose/imunologia , Diferenciação Celular/imunologia , Linhagem Celular Tumoral , Sobrevivência Celular , Células HCT116 , Humanos , Leupeptinas/farmacologia , Listeria monocytogenes/imunologia , Listeriose/imunologia , Ativação Linfocitária/imunologia , Melanoma Experimental/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Proto-Oncogênicas c-mdm2/genética , Evasão Tumoral , Proteína Supressora de Tumor p53/imunologia , Proteases Específicas de Ubiquitina/genética , Ubiquitinação/genética , Ubiquitinação/imunologia
8.
Int Immunol ; 23(3): 195-202, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21393635

RESUMO

Suppressor of cytokine signaling (SOCS) 3 is a major negative feedback regulator of signal transducer and activator of transcription 3-activating cytokines. Studies using T-cell-specific SOCS3-deficient mice indicate that the absence of SOCS3 in T cells results in exacerbation of disease progression after infection by Leishmania major due to skewing of the T(h)3 cell phenotype accompanied by hyper-production of IL-10 and transforming growth factor ß (TGF-ß). Here we show that transgenic mice over-expressing the SOCS3 gene in T cells (Lck-SOCS3 Tg mice) are also susceptible to infection by L. major. Forced expression of SOCS3 in T cells did not affect the production of the anti-inflammatory cytokines IL-10 and TGF-ß or that of the protective T(h)1 type cytokine IFN-γ, which is required for parasite clearance. CD4(+) T cells isolated from infected-Lck-SOCS3 Tg mice produced much higher levels of IL-4 when they were re-stimulated with L. major antigen in vitro. Exacerbation of disease progression in Lck-SOCS3 Tg mice was completely reversed by administration of a neutralizing antibody against IL-4. These data suggest that tight regulation of SOCS3 expression in T(h) cells is crucial for disease control during infection by L. major.


Assuntos
Expressão Gênica , Interleucina-4/imunologia , Leishmaniose Cutânea/imunologia , Leishmaniose Cutânea/fisiopatologia , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Linfócitos T/imunologia , Animais , Citocinas/imunologia , Progressão da Doença , Leishmania major/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transdução de Sinais , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina/genética , Linfócitos T Reguladores/imunologia , Fatores de Tempo
9.
J Blood Med ; 1: 93-104, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-22282688

RESUMO

The nuclear factor-κB (NF-κB) plays a central role in the activation and survival of lymphocytes. NF-κB, therefore, is pivotal for acquired immunity, but the dysregulation of NF-κB signaling leads to inflammatory diseases and lymphomagenesis. Accumulating evidence has demonstrated that the mucosa-associated lymphoid tissue (MALT) lymphoma-related molecules, B-cell lymphoma 10 (BCL10) and MALT-lymphoma-translocation gene1 (MALT1), are essential signaling components for NF-κB and mitogen-activated protein kinase (MAPK) activation, mediated by the immunoreceptor tyrosine-based activation motif (ITAM)-coupled receptors involved in both innate and adaptive immunity. CARMA1 (also referred to as CARD11 and Bimp3) is a crucial regulator for ITAM-mediated signaling as it forms a complex with BCL10-MALT1 in lymphoid lineage cells such as T, B, natural killer (NK), and natural killer T (NKT) cells, known as the lymphoid CARMA1-BCL10-MALT1 (L-CBM) complex. In this review, recent understanding of the molecular and biological functions and the signal regulation mechanisms of the L-CBM complex are described and its role in disease development and potential as a therapeutic target is further discussed.

10.
J Immunol ; 183(11): 7047-53, 2009 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-19915050

RESUMO

Suppressor of cytokine signaling 3 (SOCS3), a negative-feedback molecule for cytokine signaling, has been implicated in protection against liver injury. Previous studies have shown that overexpression of SOCS3 in the liver by adenovirus or membrane permeable recombinant protein protected the liver from various injuries. However it remained uncertain in which type of cells SOCS3 suppresses liver injury. In this study, we demonstrated that forced expression of SOCS3 in T and NKT cells suppressed ConA-induced hepatitis using T and NKT cell-specific SOCS3 transgenic (Lck-SOCS3 Tg) mice. IFN-gamma and IL-4 production was reduced in Lck-SOCS3 Tg mice as well as splenocytes treated with ConA. IFN-gamma and IL-4 levels were also reduced in Lck-SOCS3 Tg mice administrated with alpha-galactosylceramide, suggesting that SOCS3 in NKT cells has suppressive function. Sustained expression of SOCS3 in an NKT cell line also resulted in reduced expression of various cytokines and transcription factors. In contrast, T and NKT cell-specific SOCS3 conditional knockout (Lck-SOCS3 cKO) mice were hypersensitive to ConA-mediated hepatitis. Isolated SOCS3-deficient NKT cells produced higher levels of IFN-gamma and IL-4. These data indicate that SOCS3 plays a negative regulatory role in NKT cell activation and that forced expression of SOCS3 in NKT cells is effective in preventing hepatitis.


Assuntos
Hepatite/imunologia , Ativação Linfocitária/imunologia , Células T Matadoras Naturais/imunologia , Proteínas Supressoras da Sinalização de Citocina/imunologia , Linfócitos T/imunologia , Animais , Western Blotting , Concanavalina A/toxicidade , Citocinas/biossíntese , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Hepatite/etiologia , Camundongos , Camundongos Transgênicos , Mitógenos/toxicidade , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína 3 Supressora da Sinalização de Citocinas
11.
J Leukoc Biol ; 86(6): 1295-303, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19801497

RESUMO

Cytokine-mediated immunity plays a crucial role in the pathogenesis of various diseases including infection and autoimmune diseases. IL-27, along with IL-12, -23, and -35, belongs to the IL-12 cytokine family. These family members play roles in regulation of Th cell differentiation. IL-27 is unique in that although it induces Th1 differentiation, the same cytokine suppresses immune responses. In the absence of IL-27-mediated immunosuppression, hyperproduction of various proinflammatory cytokines concomitant with severe inflammation is observed. The immunosuppressive effects of IL-27 depend on IL-2 suppression, inhibition of Th17 development, and induction of IL-10 production. Administration of IL-27 suppresses some diseases of autoimmune or allergic origin, demonstrating its potential in therapy of diseases mediated by inflammatory cytokines. In this review, we discuss recent studies about the role of IL-27 in immune regulation in view of its pro- and anti-inflammatory properties and possible therapeutic application.


Assuntos
Diferenciação Celular/imunologia , Tolerância Imunológica , Interleucinas/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Citocinas/imunologia , Humanos , Hipersensibilidade/tratamento farmacológico , Hipersensibilidade/imunologia , Inflamação/tratamento farmacológico , Inflamação/imunologia , Interleucinas/uso terapêutico
12.
J Immunol ; 182(10): 5929-37, 2009 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-19414744

RESUMO

The membrane microdomains known as lipid rafts have been shown to act as platforms for the initiation of various receptor signals. Through proteomic analysis, we have identified a novel protein termed Raftlin (raft-linking protein) as a major protein in lipid rafts. To determine the physiological and immunological functions of Raftlin in mammals, we generated Raftlin-deficient mice, as well as Raftlin-transgenic (Tg) mice. Although Raftlin was originally identified in B cells, we observe no severe abnormalities in the B cells of these mice, presumably due to a high expression of Raftlin-homologue (Raftlin-2). T cells, in contrast, expressed a substantial amount of Raftlin but no Raftlin-2. In Raftlin-deficient mice, T cell-dependent Ab production was reduced, and experimental autoimmune encephalomyelitis, a Th17-dependent autoimmune disease model, was ameliorated. In Raftlin-Tg mice, in contrast, Ab production was enhanced and experimental autoimmune encephalomyelitis was more severe. Cytokine production, especially that of IL-17, was reduced in Raftlin-deficient T cells, while it was enhanced in Raftlin-Tg T cells. We found that these changes were associated with the strength of the TCR-mediated signals. Importantly, localization of Lck protein in the lipid rafts was enhanced by Raftlin overexpression and reduced by Raftlin deficiency. These data indicate that Raftlin modulates TCR signals and is necessary for the fine-tuning of T cell-mediated immune responses.


Assuntos
Microdomínios da Membrana/imunologia , Proteínas de Membrana/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Asma/imunologia , Asma/metabolismo , Southern Blotting , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Interleucina-17/biossíntese , Interleucina-17/imunologia , Ativação Linfocitária/imunologia , Microdomínios da Membrana/genética , Microdomínios da Membrana/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Receptores de Antígenos de Linfócitos T/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Linfócitos T Auxiliares-Indutores/metabolismo
13.
Immunity ; 30(3): 372-83, 2009 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-19285436

RESUMO

Intracellular cyclic adenosine monophosphate (cAMP) suppresses innate immunity by inhibiting proinflammatory cytokine production from monocytic cells. Enhanced expression of interleukin-10 (IL-10) has been suggested to be the mechanism of suppression. However, cAMP is still capable of suppressing production of the cytokines TNF-alpha and IL-12 in IL-10-deficient dendritic cells (DCs). Here, we demonstrated that the transcription factor c-Fos was responsible for the cAMP-mediated suppression of inflammatory cytokine production. c-Fos accumulated at high amounts in response to cAMP and lipopolysaccharide (LPS). Overexpression of c-Fos suppressed LPS-induced cytokine production, whereas cAMP-mediated suppression of TNF-alpha and IL-12 was impaired in Fos(-/-) DCs or in RAW264.7 cells treated with c-Fos siRNA. c-Fos physically interacted with p65 protein and reduced the recruitment of p65 to the Tnf promoter. Multiple sites of c-Fos were phosphorylated by the IKKbeta protein. Thus, we propose that c-Fos is a substrate of IKKbeta and is responsible for the immunosuppressive effect of cAMP.


Assuntos
AMP Cíclico/imunologia , Citocinas/metabolismo , Regulação da Expressão Gênica , Proteínas Proto-Oncogênicas c-fos/imunologia , Animais , Células Cultivadas , Citocinas/antagonistas & inibidores , Células Dendríticas/imunologia , Ensaio de Imunoadsorção Enzimática , Quinase I-kappa B/metabolismo , Imunidade Inata , Camundongos , Camundongos Knockout , Fosforilação , Proteínas Proto-Oncogênicas c-fos/classificação , Proteínas Proto-Oncogênicas c-fos/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa
14.
J Biol Chem ; 283(25): 17003-8, 2008 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-18434325

RESUMO

The cytokine, transforming growth factor-beta1 (TGF-beta1), converts naive T cells into regulatory T cells that prevent autoimmunity. However, in the presence of interleukin (IL)-6, TGF-beta1 has also been found to promote differentiation into IL-17-producing helper T (Th17) cells that are deeply involved in autoimmunity and inflammation. However, it has not been clarified how TGF-beta1 and IL-6 determine such a distinct fate. Here we found that a master regulator for Th17, retinoic acid-related orphan receptor gammat (RORgammat), was rapidly induced by TGF-beta1 regardless of the presence of IL-6. IL-6 reduced Foxp3 expression, and overexpression of Foxp3 in a T cell line resulted in a strong reduction of IL-17A expression. We have characterized the IL-17A promoter and found that RORgammat binding is sufficient for activation of the minimum promoter in the HEK 293T cells. RORgammat-mediated IL-17A promoter activation was suppressed by forced expression of Foxp3. Foxp3 directly interacted with RORgammat through exon 2 region of Foxp3. The exon 2 region and forkhead (FKH) domain of Foxp3 were necessary for the suppression of RORgammat-mediated IL-17A promoter activation. We propose that induction of Foxp3 is the mechanism for the suppression of Th17 and polarization into inducible Treg.


Assuntos
Fatores de Transcrição Forkhead/metabolismo , Interleucina-17/química , Receptores do Ácido Retinoico/química , Receptores dos Hormônios Tireóideos/química , Transcrição Gênica , Animais , Sequência de Bases , Sítios de Ligação , Humanos , Camundongos , Modelos Biológicos , Dados de Sequência Molecular , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares , Regiões Promotoras Genéticas , Ligação Proteica , Homologia de Sequência do Ácido Nucleico , Linfócitos T/metabolismo
15.
Hepatology ; 47(5): 1644-54, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18393318

RESUMO

UNLABELLED: Acute liver failure is associated with significant mortality. However, the underlying pathophysiological mechanism is not yet fully understood. Suppressor of cytokine signaling-1 (SOCS1), which is a negative-feedback molecule for cytokine signaling, has been shown to be rapidly induced during liver injury. Here, using liver-specific SOCS1-conditional-knockout mice, we demonstrated that SOCS1 deletion in hepatocytes enhanced concanavalin A (ConA)-induced hepatitis, which has been shown to be dependent on activated T and natural killer T (NKT) cells. Although serum cytokine level and NKT cell activation were similar in wild-type (WT) and SOCS1-deficient mice after ConA treatment, proapoptotic signals, including signal transducers and activators of transcription 1 (STAT1) and Jun-terminal kinase (JNK) activation, were enhanced in SOCS1-deficient livers compared with those in WT livers. SOCS1-deficient hepatocytes had higher expression of Fas antigen and were more sensitive to anti-Fas antibody-induced apoptosis than were WT hepatocytes. Furthermore, SOCS1-deficient hepatocytes were more sensitive to tumor necrosis factor (TNF)-alpha-induced JNK activation and apoptosis. These data indicate that SOCS1 is important to the prevention of hepatocyte apoptosis induced by Fas and TNF-alpha. In contrast, SOCS1 overexpression in the liver by adenoviral gene transfer prevented ConA-induced liver injury. CONCLUSION: These findings indicate that SOCS1 plays important negative roles in fulminant hepatitis and that forced expression of SOCS1 is therapeutic in preventing hepatitis.


Assuntos
Apoptose/efeitos dos fármacos , Concanavalina A/toxicidade , Hepatite Animal/induzido quimicamente , Hepatite Animal/prevenção & controle , Fígado/patologia , Proteínas Supressoras da Sinalização de Citocina/genética , Doença Aguda , Animais , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Hepatite Animal/patologia , Fígado/efeitos dos fármacos , Falência Hepática/prevenção & controle , Linfócitos/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA/genética , RNA/isolamento & purificação , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína 1 Supressora da Sinalização de Citocina , Proteínas Supressoras da Sinalização de Citocina/deficiência
16.
Biochem Biophys Res Commun ; 359(4): 952-8, 2007 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-17562326

RESUMO

Type 1 diabetes results from the selective destruction of insulin-producing pancreatic beta-cells during islet inflammation, which involves inflammatory cytokines and free radicals. However, mechanisms for protecting beta-cells from destruction have not been clarified. In this study, we define the role of SOCS3 on beta-cell destruction using beta-cell-specific SOCS3-conditional knockout (cKO) mice. The beta-cell-specific SOCS3-deficient mice were resistant to the development of diabetes caused by streptozotocin (STZ), a genotoxic methylating agent, which has been used to trigger beta-cell destruction. The islets from cKO mice demonstrated hyperactivation of STAT3 and higher induction of Bcl-xL than did islets from WT mice, and SOCS3-deficient beta-cells were more resistant to apoptosis induced by STZ in vitro than were WT beta-cells. These results suggest that enhanced STAT3 signaling protects beta-cells from destruction induced by a genotoxic stress and that STAT3/SOCS3 can be a potential therapeutic target for the treatment of type 1 diabetes.


Assuntos
Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Resistência à Insulina , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Fator de Transcrição STAT3/metabolismo , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Animais , Células Cultivadas , Diabetes Mellitus Tipo 1/induzido quimicamente , Inativação Gênica , Imunidade Inata , Masculino , Camundongos , Camundongos Knockout , Estreptozocina , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina/genética
17.
Biosci Biotechnol Biochem ; 71(1): 253-5, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17213647

RESUMO

Royal jelly is known as a functional food containing many useful minerals. In this study, we found an anti-environmental estrogen activity of royal jelly. Bisphenol A (BPA) is an environmental estrogen that stimulates proliferation of human breast cancer MCF-7 cells. Royal jelly inhibited the growth-promoting effect of BPA on MCF-7 cells, even though it did not affect the proliferation of cells in the absence of BPA. In addition, this inhibiting effect of royal jelly was heat-stable.


Assuntos
Neoplasias da Mama/patologia , Ácidos Graxos/farmacologia , Fenóis/farmacologia , Compostos Benzidrílicos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Temperatura Alta , Humanos
18.
Biosci Biotechnol Biochem ; 70(1): 47-53, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16428820

RESUMO

We examined the effect of 17beta-estradiol (E2) on the cytokine production by mouse splenocytes. The production of interferon-gamma (IFN-gamma) was enhanced by E2 stimulation. E2 increased the number of cells expressing IFN-gamma and the IFN-gamma mRNA expression level in the cells. There were low- and high-level cells expressing IFN-gamma in the population. The natural killer (NK) cells and NKT cells were the low-level cells expressing IFN-gamma, and the number of these cells was increased by E2 stimulation. In addition, it was suggested that the enhancing effect of IFN-gamma production by E2 was mediated through estrogen receptor (ER) alpha, and ERbeta agonist stimulated IFN-gamma production. ERs are expressed on plasma membrane as well as in nucleus. The ligand specific to plasma membrane-associated ER (mER) enhanced the IFN-gamma production. In conclusion, our results indicated that E2 up-regulated the IFN-gamma production by mediating ERalpha, ERbeta and mERs.


Assuntos
Estradiol/farmacologia , Interferon gama/biossíntese , Baço/efeitos dos fármacos , Baço/metabolismo , Animais , Células Cultivadas , Receptor alfa de Estrogênio/agonistas , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/agonistas , Receptor beta de Estrogênio/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Interferon gama/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/genética
19.
Biochem Pharmacol ; 71(1-2): 108-14, 2005 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-16271352

RESUMO

Isoflavones, such as genistein and daidzein, are found in abundance in soybeans. These plant-derived substances have estrogenic activities and can bind to the estrogen receptors (ERs). In this study, we investigated that the effects of 17beta-estradiol (E2), genistein and daidzein on nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) activity in RAW264.7 cells. We found that these isoflavones significantly increased lipopolysaccharide-induced NO production and iNOS expression as much as E2 at physiological concentrations. Moreover, E2 and isoflavone enhanced the production of tumor necrosis factor-alpha that is one of the important cytokines regarding NO production. The enhancing effects of E2 and isoflavones on NO production were markedly inhibited by not only N(G)-nitro-L-arginine methyl ester (an inhibitor of NOS), but also ICI 182780 (ERs antagonist). Two types of ERs were identified as ERalpha and ERbeta. An ERalpha agonist could increase iNOS expression in RAW264.7 cells, while an ERbeta agonist could not. In conclusion, our results suggest E2, genistein and daidzein activate iNOS, and then up-regulate NO production. This enhancing effect is aroused through ERalpha pathway in RAW264.7 cells.


Assuntos
Genisteína/farmacologia , Isoflavonas/farmacologia , Lipopolissacarídeos/farmacologia , Óxido Nítrico Sintase Tipo II/metabolismo , Receptores de Estrogênio/metabolismo , Regulação para Cima/efeitos dos fármacos , Animais , Sequência de Bases , Western Blotting , Linhagem Celular , Primers do DNA , Ativação Enzimática , Estradiol/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/enzimologia , Macrófagos/metabolismo , Camundongos , Óxido Nítrico/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Necrose Tumoral alfa/biossíntese
20.
Immunol Lett ; 98(2): 225-31, 2005 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-15860222

RESUMO

Estrogens have diverse effects on cell growth, differentiation and homeostatic functions, and have been shown to play an important role in regulating immune system. In this study, we examined the effect of 17beta-estradiol (E2) on antibody production by splenocytes isolated from C57BL/6N mice. Our results suggest that the activation of immunoglobulin (Ig) M production by E2 requires direct cell-cell interaction between adherent and non-adherent cells in mouse splenocyte population, and the primary target of E2 is adherent cell population. In addition, we indicated that ER antagonist ICI 182780 suppressed this enhancing effect of E2. Both ERalpha agonist and ERalpha agonist enhanced IgM production of mouse splenocytes. ERs are expressed on plasma membrane as well as in nucleus. However, a plasma membrane-associated ER specific ligand has no stimulation effect on IgM production. In conclusion, our results indicate that adherent cells stimulated by E2 up-regulate IgM production of lymphocytes through the direct cell-cell interactions, and the enhancing effect of E2 is arouse through ERalpha and ERbeta on these cells.


Assuntos
Estrogênios/farmacologia , Imunoglobulina M/biossíntese , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Baço/citologia , Baço/efeitos dos fármacos , Animais , Adesão Celular , Células Cultivadas , Estradiol/farmacologia , Linfócitos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Estrogênio/metabolismo , Baço/imunologia
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