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1.
Eur J Immunol ; 51(5): 1039-1061, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33729549

RESUMO

Type I IFNs are so-named because they interfere with viral infection in vertebrate cells. The study of cellular responses to type I IFNs led to the discovery of the JAK-STAT signaling pathway, which also governs the response to other cytokine families. We review here the outcome of viral infections in mice and humans with engineered and inborn deficiencies, respectively, of (i) IFNAR1 or IFNAR2, selectively disrupting responses to type I IFNs, (ii) STAT1, STAT2, and IRF9, also impairing cellular responses to type II (for STAT1) and/or III (for STAT1, STAT2, IRF9) IFNs, and (iii) JAK1 and TYK2, also impairing cellular responses to cytokines other than IFNs. A picture is emerging of greater redundancy of human type I IFNs for protective immunity to viruses in natural conditions than was initially anticipated. Mouse type I IFNs are essential for protection against a broad range of viruses in experimental conditions. These findings suggest that various type I IFN-independent mechanisms of human cell-intrinsic immunity to viruses have yet to be discovered.


Assuntos
Predisposição Genética para Doença , Interferon Tipo I/metabolismo , Transdução de Sinais , Viroses/etiologia , Viroses/metabolismo , Alelos , Animais , Modelos Animais de Doenças , Genótipo , Humanos , Fator Gênico 3 Estimulado por Interferon, Subunidade gama/deficiência , Interferons/metabolismo , Janus Quinase 1/deficiência , Síndrome de Job/genética , Camundongos , Camundongos Knockout , Mutação , Fenótipo , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/metabolismo , Fator de Transcrição STAT1/deficiência , Fator de Transcrição STAT2/deficiência , TYK2 Quinase/deficiência , TYK2 Quinase/genética
2.
Sci Rep ; 10(1): 12378, 2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32704046

RESUMO

Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne pathogen causing a febrile illness in humans, which can progress to hemorrhagic manifestations, multi-organ failure, and death. Current mouse models of CCHFV infection reliably succumb to virus challenge but vary in their ability to reflect signs of disease similar to humans. In this study, we established a signal transducer and activator of transcription 2 (STAT2) knockout hamster model to expand the repertoire of animal models of CCHFV pathogenesis that can be used for therapeutic development. These hamsters demonstrated a systemic and lethal disease in response to infection. Hallmarks of human disease were observed including petechial rash, blood coagulation dysfunction, and various biochemistry and blood cell count abnormalities. Furthermore, we also demonstrated the utility of this model for anti-CCHFV therapeutic evaluation. The STAT2 knock-out hamster model of CCHFV infection may provide some further insights into clinical disease, viral pathogenesis, and pave the way for testing of potential drug and vaccine candidates.


Assuntos
Animais Geneticamente Modificados , Modelos Animais de Doenças , Vírus da Febre Hemorrágica da Crimeia-Congo/metabolismo , Febre Hemorrágica da Crimeia , Fator de Transcrição STAT2/deficiência , Animais , Animais Geneticamente Modificados/genética , Animais Geneticamente Modificados/metabolismo , Animais Geneticamente Modificados/virologia , Linhagem Celular , Cricetinae , Feminino , Técnicas de Inativação de Genes , Vírus da Febre Hemorrágica da Crimeia-Congo/genética , Febre Hemorrágica da Crimeia/genética , Febre Hemorrágica da Crimeia/metabolismo , Febre Hemorrágica da Crimeia/patologia , Masculino , Fator de Transcrição STAT2/metabolismo
3.
FEBS Open Bio ; 10(4): 515-524, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31981447

RESUMO

Prostate cancer is the fifth leading cause of cancer-related deaths in males globally. Tripartite Motif Containing 66 (TRIM66) functions as transcriptional repressor and exerts its effect at least partially through promotion of deacetylase. TRIM66 has been previously reported to play an oncogenic role in a number of human cancers. Here, we investigated the potential oncogenic properties of TRIM66 in prostate cancer. We report that shRNA-mediated knockdown of TRIM66 significantly suppressed viability and proliferation of both PC-3 and DU145 prostate cancer cell lines. Furthermore, TRIM66 deficiency inhibited migration and invasion of prostate cancer cells. Mechanistically, TRIM66 positively regulated signal transducer and activator of transcription 2 (STAT2) and interleukin-2 (IL-2) expression. The predominance of STAT2-IL-2 in mediating the oncogenic properties of TRIM66 was determined using a rescue assay, wherein overexpression of either STAT2 or IL-2 almost completely abolished the inhibitory effects on cell proliferation, migration and invasion elicited by TRIM66 deficiency in prostate cancer cells. Our study highlights the importance of the TRIM66-STAT2-IL-2 signaling axis in the tumor biology of prostate cancer.


Assuntos
Carcinogênese/genética , Progressão da Doença , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Janus Quinases/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Fator de Transcrição STAT2/deficiência , Transdução de Sinais/genética , Animais , Movimento Celular/genética , Proliferação de Células/genética , Sobrevivência Celular/genética , Técnicas de Silenciamento de Genes , Inativação Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Camundongos , Invasividade Neoplásica/genética , Oncogenes , Células PC-3 , Fator de Transcrição STAT2/genética , Transfecção , Carga Tumoral/genética , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Front Immunol ; 11: 624415, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33679716

RESUMO

STAT2 is a transcription factor that plays an essential role in antiviral immunity by mediating the activity of type I and III interferons (IFN-I and IFN-III). It also has a recently established function in the negative regulation of IFN-I signaling. Homozygous STAT2 deficiency is an ultra-rare inborn error of immunity which provides unique insight into the pathologic consequence of STAT2 dysfunction. We report here a novel genetic cause of homozygous STAT2 deficiency with several notable clinical features. The proband presented aged 12 months with hemophagocytic lymphohistiocytosis (HLH) closely followed by clinical varicella, both occurring within three weeks of measles, mumps, and rubella (MMR) and varicella vaccinations. There was a history of life-threatening influenza A virus (IAV) disease 2 months previously. Genetic investigation uncovered homozygosity for a novel nonsense variant in STAT2 (c. 1999C>T, p. Arg667Ter) that abrogated STAT2 protein expression. Compatible with STAT2 deficiency, dermal fibroblasts from the child demonstrated a defect of interferon-stimulated gene expression and a failure to mount an antiviral state in response to treatment with IFN-I, a phenotype that was rescued by lentiviral complementation by wild type STAT2. This case significantly expands the phenotypic spectrum of STAT2 deficiency. The occurrence of life-threatening influenza, which has not previously been reported in this condition, adds STAT2 to the list of monogenetic causes of this phenotype and underscores the critical importance of IFN-I and IFN-III to influenza immunity. The development of probable vaccine-strain varicella is also a novel occurrence in STAT2 deficiency, implying a role for IFN-I/III immunity in control of attenuated varicella zoster virus in vivo and reinforcing the susceptibility to pathologic effects of live-attenuated viral vaccines in disorders of IFN-I immunity. Finally, the occurrence of HLH in this case reinforces emerging links to hyperinflammation in patients with STAT2 deficiency and other related defects of IFN-I signaling-highlighting an important avenue for further scientific enquiry.


Assuntos
Vacina contra Varicela/efeitos adversos , Códon sem Sentido , Homozigoto , Influenza Humana , Fator de Transcrição STAT2/deficiência , Vacina contra Varicela/imunologia , Criança , Humanos , Influenza Humana/genética , Influenza Humana/imunologia , Influenza Humana/patologia , Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/imunologia , Linfo-Histiocitose Hemofagocítica/patologia , Masculino , Fator de Transcrição STAT2/imunologia
5.
Viruses ; 10(11)2018 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-30463176

RESUMO

Rift Valley fever virus (RVFV) is an emerging pathogen capable of causing severe disease in livestock and humans and can be transmitted by multiple routes including aerosol exposure. Several animal models have been developed to gain insight into the pathogenesis associated with aerosolized RVFV infection, but work with these models is restricted to high containment biosafety level (BSL) laboratories limiting their use for antiviral and vaccine development studies. Here, we report on a new RVFV inhalation infection model in STAT2 KO hamsters exposed to aerosolized MP-12 vaccine virus by nose-only inhalation that enables a more accurate delivery and measurement of exposure dose. RVFV was detected in hepatic and other tissues 4⁻5 days after challenge, consistent with virus-induced lesions in the liver, spleen and lung. Furthermore, assessment of blood chemistry and hematological parameters revealed alterations in several liver disease markers and white blood cell parameters. Our results indicate that STAT2 KO hamsters develop a disease course that shares features of disease observed in human cases and in other animal models of RVFV aerosol exposure, supporting the use of this BSL-2 infection model for countermeasure development efforts.


Assuntos
Aerossóis , Modelos Animais de Doenças , Febre do Vale de Rift/patologia , Fator de Transcrição STAT2/deficiência , Administração por Inalação , Estruturas Animais/patologia , Estruturas Animais/virologia , Animais , Análise Química do Sangue , Cricetinae , Técnicas de Inativação de Genes , Leucócitos/imunologia , Fatores de Tempo
6.
Virology ; 511: 175-183, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28865344

RESUMO

Heartland virus (HRTV) is an emerging tick-borne virus (Bunyaviridae, Phlebovirus) that has caused sporadic cases of human disease in several central and mid-eastern states of America. Animal models of HRTV disease are needed to gain insights into viral pathogenesis and advancing antiviral drug development. Presence of clinical disease following HRTV challenge in hamsters deficient in STAT2 function underscores the important role played by type I interferon-induced antiviral responses. However, the recovery of most of the infected animals suggests that other mechanisms to control infection and limit disease offer substantial protection. The most prominent disease sign with HRTV infection in STAT2 knockout hamsters was dramatic weight loss with clinical laboratory and histopathology demonstrating acute inflammation in the spleen, lymph node, liver and lung. Finally, we show that HRTV disease in hamsters can be prevented by the use of favipiravir, a promising broad-spectrum antiviral in clinical development for the treatment of influenza.


Assuntos
Amidas/uso terapêutico , Antivirais/uso terapêutico , Infecções por Bunyaviridae/patologia , Infecções por Bunyaviridae/prevenção & controle , Pirazinas/uso terapêutico , Fator de Transcrição STAT2/deficiência , Estruturas Animais/patologia , Animais , Quimioprevenção , Cricetinae , Modelos Animais de Doenças , Inflamação/patologia , Interferon Tipo I/imunologia , Resultado do Tratamento
7.
Virology ; 507: 89-95, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28431283

RESUMO

Zika virus (ZIKV) infection was investigated in adult and fetal STAT2 knock-out (KO) hamsters. Subcutaneous injection of ZIKV of adults resulted in morbidity, mortality, and infection of the uterus, placenta, brain, spinal cord, and testicles, thus providing an opportunity to evaluate congenital ZIKV infection in a second rodent species besides mice. ZIKV-infected cells with morphologies of Sertoli cells and spermatogonia were observed in the testes, which may have implications for sexual transmission and male sterility. Neonates exposed as fetuses to ZIKV at 8 days post-coitus were not smaller than controls. Nevertheless, infectious virus and ZIKV RNA was detected in some, but not all, placentas and fetal brains of KO hamsters. STAT2 KO hamsters may be useful for addressing sexual transmission, pathogenesis, routes of fetal infection, and neurological disease outcomes, and may also be used in antiviral or vaccine studies to identify intervention strategies.


Assuntos
Fator de Transcrição STAT2/deficiência , Infecção por Zika virus/embriologia , Zika virus/fisiologia , Animais , Encéfalo/patologia , Encéfalo/virologia , Cricetinae , Modelos Animais de Doenças , Feminino , Feto/patologia , Feto/virologia , Humanos , Transmissão Vertical de Doenças Infecciosas , Masculino , Mesocricetus , Camundongos Knockout , Placenta/patologia , Placenta/virologia , Gravidez , Complicações Infecciosas na Gravidez/patologia , Complicações Infecciosas na Gravidez/virologia , Fator de Transcrição STAT2/genética , Zika virus/genética , Infecção por Zika virus/genética , Infecção por Zika virus/metabolismo , Infecção por Zika virus/virologia
10.
PLoS Pathog ; 11(8): e1005084, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26291525

RESUMO

Human adenoviruses have been studied extensively in cell culture and have been a model for studies in molecular, cellular, and medical biology. However, much less is known about adenovirus replication and pathogenesis in vivo in a permissive host because of the lack of an adequate animal model. Presently, the most frequently used permissive immunocompetent animal model for human adenovirus infection is the Syrian hamster. Species C human adenoviruses replicate in these animals and cause pathology that is similar to that seen with humans. Here, we report findings with a new Syrian hamster strain in which the STAT2 gene was functionally knocked out by site-specific gene targeting. Adenovirus-infected STAT2 knockout hamsters demonstrated an accentuated pathology compared to the wild-type control animals, and the virus load in the organs of STAT2 knockout animals was 100- to 1000-fold higher than that in wild-type hamsters. Notably, the adaptive immune response to adenovirus is not adversely affected in STAT2 knockout hamsters, and surviving hamsters cleared the infection by 7 to 10 days post challenge. We show that the Type I interferon pathway is disrupted in these hamsters, revealing the critical role of interferon-stimulated genes in controlling adenovirus infection. This is the first study to report findings with a genetically modified Syrian hamster infected with a virus. Further, this is the first study to show that the Type I interferon pathway plays a role in inhibiting human adenovirus replication in a permissive animal model. Besides providing an insight into adenovirus infection in humans, our results are also interesting from the perspective of the animal model: STAT2 knockout Syrian hamster may also be an important animal model for studying other viral infections, including Ebola-, hanta-, and dengue viruses, where Type I interferon-mediated innate immunity prevents wild type hamsters from being effectively infected to be used as animal models.


Assuntos
Infecções por Adenoviridae/imunologia , Adenovírus Humanos/patogenicidade , Modelos Animais de Doenças , Interferon Tipo I/imunologia , Fator de Transcrição STAT2/deficiência , Infecções por Adenoviridae/patologia , Adenovírus Humanos/imunologia , Animais , Animais Geneticamente Modificados , Linhagem Celular Tumoral , Cricetinae , Citometria de Fluxo , Técnicas de Inativação de Genes , Humanos , Mesocricetus , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição STAT2/imunologia
11.
Brain ; 138(Pt 10): 2834-46, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26122121

RESUMO

Defects of mitochondrial dynamics are emerging causes of neurological disease. In two children presenting with severe neurological deterioration following viral infection we identified a novel homozygous STAT2 mutation, c.1836 C>A (p.Cys612Ter), using whole exome sequencing. In muscle and fibroblasts from these patients, and a third unrelated STAT2-deficient patient, we observed extremely elongated mitochondria. Western blot analysis revealed absence of the STAT2 protein and that the mitochondrial fission protein DRP1 (encoded by DNM1L) is inactive, as shown by its phosphorylation state. All three patients harboured decreased levels of DRP1 phosphorylated at serine residue 616 (P-DRP1(S616)), a post-translational modification known to activate DRP1, and increased levels of DRP1 phosphorylated at serine 637 (P-DRP1(S637)), associated with the inactive state of the DRP1 GTPase. Knockdown of STAT2 in SHSY5Y cells recapitulated the fission defect, with elongated mitochondria and decreased P-DRP1(S616) levels. Furthermore the mitochondrial fission defect in patient fibroblasts was rescued following lentiviral transduction with wild-type STAT2 in all three patients, with normalization of mitochondrial length and increased P-DRP1(S616) levels. Taken together, these findings implicate STAT2 as a novel regulator of DRP1 phosphorylation at serine 616, and thus of mitochondrial fission, and suggest that there are interactions between immunity and mitochondria. This is the first study to link the innate immune system to mitochondrial dynamics and morphology. We hypothesize that variability in JAK-STAT signalling may contribute to the phenotypic heterogeneity of mitochondrial disease, and may explain why some patients with underlying mitochondrial disease decompensate after seemingly trivial viral infections. Modulating JAK-STAT activity may represent a novel therapeutic avenue for mitochondrial diseases, which remain largely untreatable. This may also be relevant for more common neurodegenerative diseases, including Alzheimer's, Huntington's and Parkinson's diseases, in which abnormalities of mitochondrial morphology have been implicated in disease pathogenesis.


Assuntos
Doenças Mitocondriais/genética , Doenças Mitocondriais/metabolismo , Dinâmica Mitocondrial/fisiologia , Fator de Transcrição STAT2/deficiência , Transdução de Sinais/genética , Apoptose/genética , Pré-Escolar , Dinaminas , Eletroencefalografia , Saúde da Família , Feminino , Citometria de Fluxo , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Células HEK293 , Humanos , Lactente , Masculino , Microscopia Eletrônica , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Músculo Esquelético/patologia , Músculo Esquelético/ultraestrutura , Neuroblastoma/patologia , Fosforilação , Processamento de Proteína Pós-Traducional , RNA Nuclear Pequeno/farmacologia , Fator de Transcrição STAT2/genética , Transfecção
12.
J Immunol ; 195(1): 210-216, 2015 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-26019270

RESUMO

IFNs, which transduce pivotal signals through Stat1 and Stat2, effectively suppress the replication of Legionella pneumophila in primary murine macrophages. Although the ability of IFN-γ to impede L. pneumophila growth is fully dependent on Stat1, IFN-αß unexpectedly suppresses L. pneumophila growth in both Stat1- and Stat2-deficient macrophages. New studies demonstrating that the robust response to IFN-αß is lost in Stat1-Stat2 double-knockout macrophages suggest that Stat1 and Stat2 are functionally redundant in their ability to direct an innate response toward L. pneumophila. Because the ability of IFN-αß to signal through Stat1-dependent complexes (i.e., Stat1-Stat1 and Stat1-Stat2 dimers) has been well characterized, the current studies focus on how Stat2 is able to direct a potent response to IFN-αß in the absence of Stat1. These studies reveal that IFN-αß is able to drive the formation of a Stat2 and IFN regulatory factor 9 complex that drives the expression of a subset of IFN-stimulated genes, but with substantially delayed kinetics. These observations raise the possibility that this pathway evolved in response to microbes that have devised strategies to subvert Stat1-dependent responses.


Assuntos
Fator Gênico 3 Estimulado por Interferon, Subunidade gama/imunologia , Legionelose/imunologia , Macrófagos/imunologia , Receptor de Interferon alfa e beta/imunologia , Fator de Transcrição STAT1/imunologia , Fator de Transcrição STAT2/imunologia , Animais , Células da Medula Óssea/imunologia , Células da Medula Óssea/microbiologia , Células da Medula Óssea/patologia , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno , Fator Gênico 3 Estimulado por Interferon, Subunidade gama/genética , Interferon gama/genética , Interferon gama/imunologia , Legionella pneumophila/imunologia , Legionelose/genética , Legionelose/microbiologia , Legionelose/patologia , Macrófagos/microbiologia , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Cultura Primária de Células , Multimerização Proteica , Receptor de Interferon alfa e beta/genética , Fator de Transcrição STAT1/deficiência , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT2/deficiência , Fator de Transcrição STAT2/genética , Transdução de Sinais , Fatores de Tempo
13.
J Virol ; 86(12): 6932-46, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22496215

RESUMO

Interferon (IFN) signaling is crucial for antiviral immunity. While type I IFN signaling is mediated by STAT1, STAT2, and IRF9, type II IFN signaling requires only STAT1. Here, we studied the roles of these signaling factors in the host response to systemic infection with lymphocytic choriomeningitis virus (LCMV). In wild-type (WT) mice and mice lacking either STAT2 or IRF9, LCMV infection was nonlethal, and the virus either was cleared (WT) or established persistence (STAT2 knockout [KO] and IRF9 KO). However, in the case of STAT1 KO mice, LCMV infection was lethal and accompanied by severe multiorgan immune pathology, elevated expression of various cytokine genes in tissues, and cytokines in the serum. This lethal phenotype was unaltered by the coabsence of the gamma interferon (IFN-γ) receptor and hence was not dependent on IFN-γ. Equally, the disease was not due to a combined defect in type I and type II IFN signaling, as IRF9 KO mice lacking the IFN-γ receptor survived infection with LCMV. Clearance of LCMV is mediated normally by CD8(+) T cells. However, the depletion of these cells in LCMV-infected STAT1 KO mice was delayed, but did not prevent, lethality. In contrast, depletion of CD4(+) T cells prevented lethality in LCMV-infected STAT1 KO mice and was associated with a reduction in tissue immune pathology. These studies highlight a fundamental difference in the role of STAT1 versus STAT2 and IRF9. While all three factors are required to limit viral replication and spread, only STAT1 has the unique function of preventing the emergence of a lethal antiviral CD4(+) T-cell response.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Fator Gênico 3 Estimulado por Interferon, Subunidade gama/imunologia , Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/fisiologia , Fator de Transcrição STAT1/imunologia , Fator de Transcrição STAT2/imunologia , Animais , Linfócitos T CD4-Positivos/virologia , Feminino , Humanos , Fator Gênico 3 Estimulado por Interferon, Subunidade gama/deficiência , Fator Gênico 3 Estimulado por Interferon, Subunidade gama/genética , Interferons/genética , Interferons/imunologia , Coriomeningite Linfocítica/genética , Coriomeningite Linfocítica/virologia , Vírus da Coriomeningite Linfocítica/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator de Transcrição STAT1/deficiência , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT2/deficiência , Fator de Transcrição STAT2/genética
14.
Virology ; 380(2): 338-43, 2008 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-18774582

RESUMO

The p150 form of the RNA-specific adenosine deaminase ADAR1 is interferon-inducible and catalyzes A-to-I editing of viral and cellular RNAs. We have characterized mouse genomic clones containing the promoter regions required for Adar1 gene transcription and analyzed interferon induction of the p150 protein using mutant mouse cell lines. Transient transfection analyses using reporter constructs led to the identification of three promoters, one interferon-inducible (P(A)) and two constitutively active (P(B) and P(C)). The TATA-less P(A) promoter, characterized by the presence of a consensus ISRE element and a PKR kinase KCS-like element, directed interferon-inducible reporter expression in rodent and human cells. Interferon induction of p150 was impaired in mouse cells deficient in IFNAR receptor, JAK1 kinase or STAT2 but not STAT1. Whereas Adar1 gene organization involving multiple promoters and alternative exon 1 structures was highly preserved, sequences of the promoters and exon 1 structures were not well conserved between human and mouse.


Assuntos
Adenosina Desaminase/biossíntese , Adenosina Desaminase/genética , Interferons/metabolismo , Regiões Promotoras Genéticas , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT2/metabolismo , Transcrição Gênica , Animais , Fusão Gênica Artificial , Sequência de Bases , Sítios de Ligação , Linhagem Celular , Sequência Conservada , Genes Reporter , Humanos , Janus Quinase 1/deficiência , Luciferases/biossíntese , Luciferases/genética , Camundongos , Dados de Sequência Molecular , Proteínas de Ligação a RNA , Receptor de Interferon alfa e beta/deficiência , Fator de Transcrição STAT1/deficiência , Fator de Transcrição STAT2/deficiência , Análise de Sequência de DNA
15.
J Exp Med ; 204(10): 2383-96, 2007 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-17846149

RESUMO

The best-characterized type 1 interferon (IFN) signaling pathway depends on signal transducer and activator of transcription 1 (STAT1) and STAT2. The cytokines can, however, conditionally activate all STATs. Regulation of their access to particular signaling pathways is poorly understood. STAT4 is important for IFN-gamma induction, and NK cells are major producers of this cytokine. We report that NK cells have high basal STAT4 levels and sensitivity to type 1 IFN-mediated STAT4 activation for IFN-gamma production. Increases in STAT1, driven during viral infection by either type 1 IFN or IFN-gamma, are associated with decreased STAT4 access. Both STAT1 and STAT2 are important for antiviral defense, but STAT1 has a unique role in protecting against sustained NK cell IFN-gamma production and resulting disease. The regulation occurs with an NK cell type 1 IFN receptor switch from a STAT4 to a STAT1 association. Thus, a fundamental characteristic of NK cells is high STAT4 bound to the type 1 IFN receptor. The conditions of infection result in STAT1 induction with displacement of STAT4. These studies elucidate the critical role of STAT4 levels in predisposing selection of specific signaling pathways, define the biological importance of regulation within particular cell lineages, and provide mechanistic insights for how this is accomplished in vivo.


Assuntos
Interferon Tipo I/metabolismo , Células Matadoras Naturais/metabolismo , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT4/metabolismo , Animais , Regulação da Expressão Gênica , Interferon Tipo I/genética , Interferon gama/metabolismo , Células Matadoras Naturais/imunologia , Ativação Linfocitária , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/metabolismo , Vírus da Coriomeningite Linfocítica/imunologia , Camundongos , Camundongos Transgênicos , Receptor de Interferon alfa e beta/metabolismo , Fator de Transcrição STAT1/deficiência , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT2/deficiência , Fator de Transcrição STAT2/genética , Fator de Transcrição STAT2/metabolismo , Fator de Transcrição STAT4/deficiência , Fator de Transcrição STAT4/genética
16.
J Immunol ; 179(1): 463-71, 2007 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-17579067

RESUMO

MHC type II (MHC II) expression is tightly regulated in macrophages and potently induced by IFN-gamma (type II IFN). In contrast, type I IFNs (IFN-Is), which are far more widely expressed, fail to induce MHC II expression, even though both classes of IFNs direct target gene expression through Stat1. The unexpected finding that IFN-Is effectively induce MHC II expression in Stat2(-/-) macrophages provided an opportunity to explore this conundrum. The ensuing studies revealed that deletion of Stat2, which uniquely transduces signals for IFN-Is, leads to a loss in the IFN-I-dependent induction of suppressor of cytokine signaling-1. Impairment in the expression of this important negative regulator led to a striking prolongation in IFN-I-dependent Stat1 activation, as well as enhanced expression of the target gene, IFN-regulatory factor-1. The prolonged activity of these two transcription factors synergized to drive the transcription of CIITA, the master regulator of MHC II expression, analogous to the pattern observed in IFN-gamma-treated macrophages. Thus, IFN-I-dependent suppressor of cytokine signaling-1 expression plays an important role in distinguishing the biological response between type I and II IFNs in macrophages.


Assuntos
Regulação da Expressão Gênica/imunologia , Antígenos de Histocompatibilidade Classe II/biossíntese , Antígenos de Histocompatibilidade Classe II/genética , Fator de Transcrição STAT2/fisiologia , Animais , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Linhagem Celular , Células Cultivadas , Humanos , Interferon-alfa/fisiologia , Células L , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/metabolismo , Camundongos , Camundongos Knockout , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/biossíntese , Proteínas Nucleares/genética , Regiões Promotoras Genéticas/imunologia , Fator de Transcrição STAT2/deficiência , Fator de Transcrição STAT2/genética , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Proteína 1 Supressora da Sinalização de Citocina , Proteínas Supressoras da Sinalização de Citocina/biossíntese , Proteínas Supressoras da Sinalização de Citocina/genética , Proteínas Supressoras da Sinalização de Citocina/fisiologia , Transativadores/antagonistas & inibidores , Transativadores/biossíntese , Transativadores/genética , Transcrição Gênica/imunologia
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