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1.
Cell ; 146(6): 918-30, 2011 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-21925315

RESUMO

Inhibitors of DNA binding (IDs) antagonize basic-helix-loop-helix (bHLH) transcription factors to inhibit differentiation and maintain stem cell fate. ID ubiquitination and proteasomal degradation occur in differentiated tissues, but IDs in many neoplasms appear to escape degradation. We show that the deubiquitinating enzyme USP1 promotes ID protein stability and stem cell-like characteristics in osteosarcoma. USP1 bound, deubiquitinated, and thereby stabilized ID1, ID2, and ID3. A subset of primary human osteosarcomas coordinately overexpressed USP1 and ID proteins. USP1 knockdown in osteosarcoma cells precipitated ID protein destabilization, cell-cycle arrest, and osteogenic differentiation. Conversely, ectopic USP1 expression in mesenchymal stem cells stabilized ID proteins, inhibited osteoblastic differentiation, and enhanced proliferation. Consistent with USP1 functioning in normal mesenchymal stem cells, USP1-deficient mice were osteopenic. Our observations implicate USP1 in preservation of the stem cell state that characterizes osteosarcoma and identify USP1 as a target for differentiation therapy.


Assuntos
Endopeptidases/metabolismo , Proteínas Inibidoras de Diferenciação/metabolismo , Células-Tronco Mesenquimais/citologia , Células-Tronco Neoplásicas/citologia , Osteossarcoma/patologia , Animais , Proteínas de Arabidopsis , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Proteases Específicas de Ubiquitina , Ubiquitinação
2.
Immunity ; 44(3): 609-621, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-26944201

RESUMO

Targeted inhibition of mitogen-activated protein kinase (MAPK) kinase (MEK) can induce regression of tumors bearing activating mutations in the Ras pathway but rarely leads to tumor eradication. Although combining MEK inhibition with T-cell-directed immunotherapy might lead to more durable efficacy, T cell responses are themselves at least partially dependent on MEK activity. We show here that MEK inhibition did profoundly block naive CD8(+) T cell priming in tumor-bearing mice, but actually increased the number of effector-phenotype antigen-specific CD8(+) T cells within the tumor. MEK inhibition protected tumor-infiltrating CD8(+) T cells from death driven by chronic TCR stimulation while sparing cytotoxic activity. Combining MEK inhibition with anti-programmed death-ligand 1 (PD-L1) resulted in synergistic and durable tumor regression even where either agent alone was only modestly effective. Thus, despite the central importance of the MAP kinase pathway in some aspects of T cell function, MEK-targeted agents can be compatible with T-cell-dependent immunotherapy.


Assuntos
Antígeno B7-H1/imunologia , Linfócitos T CD8-Positivos/imunologia , Carcinoma/terapia , Neoplasias do Colo/terapia , Imunoterapia , Animais , Anticorpos Monoclonais/administração & dosagem , Apoptose , Azetidinas/administração & dosagem , Azetidinas/farmacologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Carcinoma/imunologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias do Colo/imunologia , Sinergismo Farmacológico , Tratamento Farmacológico , Quimioterapia Combinada , MAP Quinases Reguladas por Sinal Extracelular , Humanos , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Terapia de Alvo Molecular , Transplante de Neoplasias , Piperidinas/administração & dosagem , Piperidinas/farmacologia
3.
Nature ; 510(7505): 407-411, 2014 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-24919154

RESUMO

Inhibitors against the p110δ isoform of phosphoinositide-3-OH kinase (PI(3)K) have shown remarkable therapeutic efficacy in some human leukaemias. As p110δ is primarily expressed in leukocytes, drugs against p110δ have not been considered for the treatment of solid tumours. Here we report that p110δ inactivation in mice protects against a broad range of cancers, including non-haematological solid tumours. We demonstrate that p110δ inactivation in regulatory T cells unleashes CD8(+) cytotoxic T cells and induces tumour regression. Thus, p110δ inhibitors can break tumour-induced immune tolerance and should be considered for wider use in oncology.


Assuntos
Inibidores Enzimáticos/farmacologia , Tolerância Imunológica/efeitos dos fármacos , Neoplasias/enzimologia , Neoplasias/imunologia , Fosfatidilinositol 3-Quinases/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Ativação Enzimática/efeitos dos fármacos , Tolerância Imunológica/imunologia , Camundongos , Linfócitos T Reguladores/enzimologia , Linfócitos T Reguladores/imunologia
5.
Nature ; 471(7336): 110-4, 2011 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-21368834

RESUMO

Microtubules have pivotal roles in fundamental cellular processes and are targets of antitubulin chemotherapeutics. Microtubule-targeted agents such as Taxol and vincristine are prescribed widely for various malignancies, including ovarian and breast adenocarcinomas, non-small-cell lung cancer, leukaemias and lymphomas. These agents arrest cells in mitosis and subsequently induce cell death through poorly defined mechanisms. The strategies that resistant tumour cells use to evade death induced by antitubulin agents are also unclear. Here we show that the pro-survival protein MCL1 (ref. 3) is a crucial regulator of apoptosis triggered by antitubulin chemotherapeutics. During mitotic arrest, MCL1 protein levels decline markedly, through a post-translational mechanism, potentiating cell death. Phosphorylation of MCL1 directs its interaction with the tumour-suppressor protein FBW7, which is the substrate-binding component of a ubiquitin ligase complex. The polyubiquitylation of MCL1 then targets it for proteasomal degradation. The degradation of MCL1 was blocked in patient-derived tumour cells that lacked FBW7 or had loss-of-function mutations in FBW7, conferring resistance to antitubulin agents and promoting chemotherapeutic-induced polyploidy. Additionally, primary tumour samples were enriched for FBW7 inactivation and elevated MCL1 levels, underscoring the prominent roles of these proteins in oncogenesis. Our findings suggest that profiling the FBW7 and MCL1 status of tumours, in terms of protein levels, messenger RNA levels and genetic status, could be useful to predict the response of patients to antitubulin chemotherapeutics.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Proteínas F-Box/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Apoptose/efeitos dos fármacos , Proteínas de Ciclo Celular/genética , Linhagem Celular , Linhagem Celular Tumoral , Transformação Celular Neoplásica/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Proteínas F-Box/genética , Proteína 7 com Repetições F-Box-WD , Fibroblastos , Humanos , Camundongos , Mitose/efeitos dos fármacos , Proteína de Sequência 1 de Leucemia de Células Mieloides , Paclitaxel/farmacologia , Farmacogenética , Fosforilação/efeitos dos fármacos , Poliploidia , Complexo de Endopeptidases do Proteassoma/metabolismo , Ligação Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/deficiência , Proteínas Proto-Oncogênicas c-bcl-2/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ubiquitina-Proteína Ligases/deficiência , Ubiquitina-Proteína Ligases/genética , Vincristina/farmacologia
6.
Nature ; 463(7277): 103-7, 2010 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-20023629

RESUMO

MCL1 is essential for the survival of stem and progenitor cells of multiple lineages, and is unique among pro-survival BCL2 family members in that it is rapidly turned over through the action of ubiquitin ligases. B- and mantle-cell lymphomas, chronic myeloid leukaemia, and multiple myeloma, however, express abnormally high levels of MCL1, contributing to chemoresistance and disease relapse. The mechanism of MCL1 overexpression in cancer is not well understood. Here we show that the deubiquitinase USP9X stabilizes MCL1 and thereby promotes cell survival. USP9X binds MCL1 and removes the Lys 48-linked polyubiquitin chains that normally mark MCL1 for proteasomal degradation. Increased USP9X expression correlates with increased MCL1 protein in human follicular lymphomas and diffuse large B-cell lymphomas. Moreover, patients with multiple myeloma overexpressing USP9X have a poor prognosis. Knockdown of USP9X increases MCL1 polyubiquitination, which enhances MCL1 turnover and cell killing by the BH3 mimetic ABT-737. These results identify USP9X as a prognostic and therapeutic target, and they show that deubiquitinases may stabilize labile oncoproteins in human malignancies.


Assuntos
Neoplasias/metabolismo , Neoplasias/patologia , Poliubiquitina/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ubiquitina Tiolesterase/metabolismo , Animais , Apoptose/efeitos dos fármacos , Compostos de Bifenilo/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular , Dano ao DNA , Docetaxel , Etoposídeo/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Meia-Vida , Humanos , Lisina/metabolismo , Camundongos , Camundongos SCID , Proteína de Sequência 1 de Leucemia de Células Mieloides , Neoplasias/diagnóstico , Nitrofenóis/farmacologia , Fosforilação/efeitos da radiação , Piperazinas/farmacologia , Prognóstico , Ligação Proteica/efeitos da radiação , Estabilidade Proteica , Proteínas Proto-Oncogênicas c-bcl-2/genética , Interferência de RNA , Sulfonamidas/farmacologia , Taxoides/farmacologia , Ubiquitina Tiolesterase/deficiência , Ubiquitina Tiolesterase/genética , Ubiquitinação , Raios Ultravioleta , Ensaios Antitumorais Modelo de Xenoenxerto
7.
MAbs ; 15(1): 2229101, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37639687

RESUMO

The antibody-drug conjugate (ADC) field has undergone a renaissance, with substantial recent developmental investment and subsequent drug approvals over the past 6 y. In November 2022, ElahereTM became the latest ADC to be approved by the US Food and Drug Administration (FDA). To date, over 260 ADCs have been tested in the clinic against various oncology indications. Here, we review the clinical landscape of ADCs that are currently FDA approved (11), agents currently in clinical trials but not yet approved (164), and candidates discontinued following clinical testing (92). These clinically tested ADCs are further analyzed by their targeting tumor antigen(s), linker, payload choices, and highest clinical stage achieved, highlighting limitations associated with the discontinued drug candidates. Lastly, we discuss biologic engineering modifications preclinically demonstrated to improve the therapeutic index that if incorporated may increase the proportion of molecules that successfully transition to regulatory approval.


Assuntos
Antineoplásicos , Imunoconjugados , Estados Unidos , Imunoconjugados/uso terapêutico , Anticorpos Monoclonais , United States Food and Drug Administration
8.
Cancer Cell ; 2(2): 139-48, 2002 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12204534

RESUMO

Epigenetic regulation of gene expression significantly influences cell growth and differentiation. Here we show that epigenetic silencing of Fas determines tumor growth in vivo and apoptotic sensitivity in vitro. In established tumors with epigenetically repressed Fas, restoration of Fas activity either by transfection of fas or treatment with Trichostatin A (TSA), an inhibitor of histone deacetylase, suppresses tumor growth and restores chemosensitivity. The TSA-dependent chemosensitivity and tumor growth control require both tumor Fas and the host NK (natural killer) cell functions. This work demonstrates the importance of epigenetic modification of Fas in tumor progression and immune evasion, and emphasizes the essential interplay between Fas and innate immunity in the control of chemoresistant tumors.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Receptor fas/metabolismo , Animais , Apoptose , Diferenciação Celular , Divisão Celular/efeitos dos fármacos , Transformação Celular Neoplásica , Progressão da Doença , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Ácidos Hidroxâmicos/farmacologia , Imunidade Inata , Células Matadoras Naturais/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos SCID , Neoplasias/metabolismo , Neoplasias/patologia , Fatores de Tempo , Transfecção , Células Tumorais Cultivadas , Receptor fas/genética
9.
Dev Cell ; 2(3): 331-41, 2002 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11879638

RESUMO

Cellular differentiation involves transcriptional responses to environmental stimuli. Adipocyte differentiation is inhibited under hypoxic conditions, indicating that oxygen (O(2)) is an important physiological regulator of adipogenesis. Hypoxia inhibits PPAR gamma 2 nuclear hormone receptor transcription, and overexpression of PPAR gamma 2 or C/EBP beta stimulates adipogenesis under hypoxia. Mouse embryonic fibroblasts deficient in hypoxia-inducible transcription factor 1 alpha (HIF-1 alpha) are refractory to hypoxia-mediated inhibition of adipogenesis. The HIF-1-regulated gene DEC1/Stra13, a member of the Drosophila hairy/Enhancer of split transcription repressor family, represses PPAR gamma 2 promoter activation and functions as an effector of hypoxia-mediated inhibition of adipogenesis. These data indicate that an O(2)-sensitive signaling mechanism regulates adipogenesis. Thus, agents that regulate HIF-1 activity or O(2) sensing may be used to inhibit adipogenesis and control obesity.


Assuntos
Adipócitos/fisiologia , Proteínas de Ligação a DNA/genética , Proteínas de Homeodomínio/genética , Proteínas Nucleares/genética , Receptores Citoplasmáticos e Nucleares/genética , Fatores de Transcrição/genética , Células 3T3 , Adipócitos/citologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Diferenciação Celular/fisiologia , Hipóxia Celular/fisiologia , Proteínas de Ligação a DNA/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Fator 1 Induzível por Hipóxia , Subunidade alfa do Fator 1 Induzível por Hipóxia , Camundongos , Proteínas Nucleares/metabolismo , Oxigênio/farmacologia
10.
Nat Med ; 19(2): 202-8, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23291630

RESUMO

Proteins in the B cell CLL/lymphoma 2 (BCL-2) family are key regulators of the apoptotic process. This family comprises proapoptotic and prosurvival proteins, and shifting the balance toward the latter is an established mechanism whereby cancer cells evade apoptosis. The therapeutic potential of directly inhibiting prosurvival proteins was unveiled with the development of navitoclax, a selective inhibitor of both BCL-2 and BCL-2-like 1 (BCL-X(L)), which has shown clinical efficacy in some BCL-2-dependent hematological cancers. However, concomitant on-target thrombocytopenia caused by BCL-X(L) inhibition limits the efficacy achievable with this agent. Here we report the re-engineering of navitoclax to create a highly potent, orally bioavailable and BCL-2-selective inhibitor, ABT-199. This compound inhibits the growth of BCL-2-dependent tumors in vivo and spares human platelets. A single dose of ABT-199 in three patients with refractory chronic lymphocytic leukemia resulted in tumor lysis within 24 h. These data indicate that selective pharmacological inhibition of BCL-2 shows promise for the treatment of BCL-2-dependent hematological cancers.


Assuntos
Antineoplásicos/farmacologia , Plaquetas/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Neoplasias Hematológicas/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Sulfonamidas/farmacologia , Compostos de Anilina/farmacologia , Animais , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cães , Feminino , Células HeLa , Humanos , Camundongos , Camundongos SCID , Proteínas Proto-Oncogênicas c-bcl-2/química , Carga Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína bcl-X/antagonistas & inibidores
11.
Sci Signal ; 5(216): ra22, 2012 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-22434933

RESUMO

Tumor necrosis factor (TNF) family members are essential for the development and proper functioning of the immune system. TNF receptor (TNFR) signaling is mediated through the assembly of protein signaling complexes that activate the nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways in a ubiquitin-dependent manner. The cellular inhibitor of apoptosis (c-IAP) proteins c-IAP1 and c-IAP2 are E3 ubiquitin ligases that are recruited to TNFR signaling complexes through their constitutive association with the adaptor protein TNFR-associated factor 2 (TRAF2). We demonstrated that c-IAP1 and c-IAP2 were required for canonical activation of NF-κB and MAPK by members of the TNFR family. c-IAPs were required for the recruitment of inhibitor of κB kinase ß (IKKß), the IKK regulatory subunit NF-κB essential modulator (NEMO), and RBCK1/Hoil1-interacting protein (HOIP) to TNFR signaling complexes and the induction of gene expression by TNF family members. In contrast, TNFRs that stimulated the noncanonical NF-κB pathway triggered translocation of c-IAPs, TRAF2, and TRAF3 from the cytosol to membrane fractions, which led to their proteasomal and lysosomal degradation. Finally, we established that signaling by B cell-activating factor receptor 3 induced the cytosolic depletion of TRAF3, which enabled noncanonical NF-κB activation. These results define c-IAP proteins as critical regulators of the activation of NF-κB and MAPK signaling pathways by members of the TNFR superfamily.


Assuntos
Proteínas Inibidoras de Apoptose/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/imunologia , Fatores de Necrose Tumoral/metabolismo , Western Blotting , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Inativação Gênica , Humanos , Quinase I-kappa B/metabolismo , Proteínas Inibidoras de Apoptose/imunologia , Transporte Proteico , RNA Interferente Pequeno/genética , Receptores de Interleucina-4/metabolismo , Fator 2 Associado a Receptor de TNF/metabolismo , Fatores de Necrose Tumoral/imunologia , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases
12.
Mol Cancer Ther ; 10(12): 2340-9, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21914853

RESUMO

The ability of a cancer cell to avoid apoptosis is crucial to tumorigenesis and can also contribute to chemoresistance. The Bcl-2 family of prosurvival proteins (Bcl-2, Bcl-X(L), Bcl-w, Mcl-1, and A1) plays a key role in these processes. We previously reported the discovery of ABT-263 (navitoclax), a potent small-molecule inhibitor of Bcl-2, Bcl-X(L), and Bcl-w. While navitoclax exhibits single-agent activity in tumors dependent on Bcl-2 or Bcl-X(L) for survival, the expression of Mcl-1 has been shown to confer resistance to navitoclax, most notably in solid tumors. Thus, therapeutic agents that can downregulate or neutralize Mcl-1 are predicted to synergize potently with navitoclax. Here, we report the activity of navitoclax in combination with 19 clinically relevant agents across a panel of 46 human solid tumor cell lines. Navitoclax broadly enhanced the activity of multiple therapeutic agents in vitro and enhanced efficacy of both docetaxel and erlotinib in xenograft models. The ability of navitoclax to synergize with docetaxel or erlotinib corresponded to an altered sensitivity of the mitochondria toward navitoclax, which was associated with the downmodulation of Mcl-1 and/or upregulation of Bim. These data provide a rationale to interrogate these combinations clinically.


Assuntos
Compostos de Anilina/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Sulfonamidas/farmacologia , Compostos de Anilina/administração & dosagem , Animais , Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Sinergismo Farmacológico , Feminino , Células HCT116 , Células Hep G2 , Humanos , Células K562 , Masculino , Camundongos , Neoplasias/patologia , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Sulfonamidas/administração & dosagem , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína bcl-X/antagonistas & inibidores
13.
J Biol Chem ; 280(49): 40599-608, 2005 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-16227629

RESUMO

Apo2 ligand/tumor necrosis factor (TNF)-related apoptosis-inducing ligand (Apo2L/TRAIL) mainly activates programmed cell death through caspases. By contrast, TNF primarily induces gene transcription through the inhibitor of kappaB kinase (IKK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase pathways. Apo2L/TRAIL also can stimulate these kinases, albeit less strongly; however, the underlying mechanisms of this stimulation and its relation to apoptosis are not well understood. Here we show that Apo2L/TRAIL activates kinase pathways by promoting the association of a secondary signaling complex, subsequent to assembly of a primary, death-inducing signaling complex (DISC). The secondary complex retained the DISC components FADD and caspase-8, but recruited several factors involved in kinase activation by TNF, namely, RIP1, TRAF2, and NEMO/IKKgamma. Secondary complex formation required Fas-associated death domain (FADD), as well as caspase-8 activity. Apo2L/TRAIL stimulation of JNK and p38 further depended on RIP1 and TRAF2, whereas IKK activation required NEMO. Apo2L/TRAIL induced secretion of interleukin-8 and monocyte chemoattractant protein-1, augmenting macrophage migration. Thus, Apo2L/TRAIL and TNF organize common molecular determinants in distinct signaling complexes to stimulate similar kinase pathways. One function of kinase stimulation by Apo2L/TRAIL may be to promote phagocytic engulfment of apoptotic cells.


Assuntos
Proteínas Reguladoras de Apoptose/farmacologia , Glicoproteínas de Membrana/farmacologia , Proteínas Quinases/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Animais , Caspase 8 , Caspases/fisiologia , Linhagem Celular Tumoral , Quimiocina CCL2/metabolismo , Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte , Ativação Enzimática/efeitos dos fármacos , Proteína de Domínio de Morte Associada a Fas , Humanos , Quinase I-kappa B/metabolismo , Interleucina-8/metabolismo , Cinética , MAP Quinase Quinase 4/metabolismo , Camundongos , Camundongos Knockout , NF-kappa B/fisiologia , Fosforilação , RNA Interferente Pequeno , Transdução de Sinais/fisiologia , Fator 2 Associado a Receptor de TNF/fisiologia , Ligante Indutor de Apoptose Relacionado a TNF , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/fisiologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
14.
Cell ; 123(5): 931-44, 2005 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-16325585

RESUMO

Innate immunity is the first line of defense against infection, protecting the host during the development of adaptive immunity and critically affecting the nature of the adaptive response. We show that, in contrast to tumor necrosis factor alpha (TNF-alpha), the related protein TWEAK attenuates the transition from innate to adaptive mechanisms. TWEAK-/- mice had overabundant natural killer (NK) cells and displayed hypersensitivity to bacterial endotoxin, with their innate immune cells producing excess interferon (IFN)-gamma and interleukin (IL)-12. TWEAK inhibited stimulation of the transcriptional activator STAT-1 and induced p65 nuclear factor (NF)-kappaB association with histone deacetylase 1, repressing cytokine production. TWEAK-/- mice developed oversized spleens with expanded memory and T helper 1 (TH1) subtype cells upon aging and mounted stronger innate and adaptive TH1-based responses against tumor challenge. Thus, TWEAK suppresses production of IFN-gamma and IL-12, curtailing the innate response and its transition to adaptive TH1 immunity.


Assuntos
Imunidade Celular/fisiologia , Imunidade Inata/fisiologia , Fator de Necrose Tumoral alfa/imunologia , Fatores de Necrose Tumoral/imunologia , Animais , Células Cultivadas , Citocina TWEAK , Endotoxinas/imunologia , Histona Desacetilase 1 , Histona Desacetilases/metabolismo , Humanos , Hipersensibilidade/imunologia , Interferon gama/imunologia , Interleucina-12/imunologia , Células Matadoras Naturais/imunologia , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/imunologia , Camundongos , Camundongos Knockout , Receptores do Fator de Necrose Tumoral/genética , Receptores do Fator de Necrose Tumoral/metabolismo , Fator de Transcrição STAT1/metabolismo , Baço/anatomia & histologia , Baço/imunologia , Subpopulações de Linfócitos T/imunologia , Receptor de TWEAK , Fator de Transcrição RelA/metabolismo , Fatores de Necrose Tumoral/genética
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