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1.
World J Surg ; 40(6): 1336-43, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26822156

RESUMO

BACKGROUND: The relationship between economic status and pediatric surgical capacity in low- and middle-income countries (LMICs) is poorly understood. In sub-Saharan Africa (SSA), Nigeria accounts for 20 % of the population and has the highest Gross Domestic Product (GDP), but whether this economic advantage translates to increased pediatric surgical capacity is unknown. This study compares the pediatric surgical capacity between Nigeria and other countries within the region. METHODS: The Pediatric Personnel, Infrastructure, Procedures, Equipment and Supplies (PediPIPES) survey, a recent tool that is useful in assessing and comparing the capacity of health facilities to deliver essential and emergency surgical care (EESC) to children in LMICs, was used for this evaluation. RESULTS: Data from hospitals in Nigeria (n = 24) and hospitals in 17 other sub-Saharan African countries (n = 25) were compared. The GDP of Nigeria was approximately twenty-five times the average GDP of the 17 other countries represented in our survey. Running water was unavailable in 58 % of the hospitals in Nigeria compared to 20 % of the hospitals in the other countries. Most hospitals in Nigeria and in the other countries did not have a CT scan (67 and 60 %, respectively). Endoscopes were unavailable in 58 % of the hospitals in Nigeria and 44 % of the hospitals in the other countries. CONCLUSIONS: Despite better economic indicators in Nigeria, there were no distinct advantages over the other countries in the ability to deliver EESC to children. Our findings highlighted the urgent need for specific allocation of more resources to pediatric surgical capacity building efforts across the entire region.


Assuntos
Países em Desenvolvimento/economia , Recursos em Saúde/provisão & distribuição , Hospitais/estatística & dados numéricos , Pediatria/estatística & dados numéricos , Procedimentos Cirúrgicos Operatórios/estatística & dados numéricos , África Subsaariana , Países em Desenvolvimento/estatística & dados numéricos , Serviços Médicos de Emergência/provisão & distribuição , Endoscópios/provisão & distribuição , Produto Interno Bruto , Humanos , Nigéria , Tomógrafos Computadorizados/provisão & distribuição , Abastecimento de Água/estatística & dados numéricos , Recursos Humanos
2.
J Allergy Clin Immunol ; 136(2): 433-40.e1, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25746972

RESUMO

BACKGROUND: IL-9 is important for the growth and survival of mast cells. IL-9 is produced by T cells, natural killer T cells, mast cells, eosinophils, and innate lymphoid cells, although the cells required for mast cell accumulation during allergic inflammation remain undefined. OBJECTIVE: We sought to elucidate the role of TH9 cells in promoting mast cell accumulation in models of allergic lung inflammation. METHODS: Adoptive transfer of ovalbumin-specific TH2 and TH9 cells was used to assess the ability of each subset to mediate mast cell accumulation in tissues. Mast cell accumulation was assessed in wild-type mice and mice with PU.1-deficient T cells subjected to acute and chronic models of allergic inflammation. RESULTS: Adoptive transfer experiments demonstrated that recipients of TH9 cells had significantly higher mast cell accumulation and expression of mast cell proteases compared with control or TH2 recipients. Mast cell accumulation was dependent on IL-9, but not IL-13, a cytokine required for many aspects of allergic inflammation. In models of acute and chronic allergic inflammation, decreased IL-9 levels in mice with PU.1-deficient T cells corresponded to diminished tissue mast cell numbers and expression of mast cell proteases. Mice with PU.1-deficient T cells have defects in IL-9 production from CD4(+) T cells, but not natural killer T cells or innate lymphoid cells, suggesting a TH cell-dependent phenotype. Rag1(-/-) mice subjected to a chronic model of allergic inflammation displayed reduced mast cell infiltration comparable with accumulation in mice with PU.1-deficient T cells, emphasizing the importance of IL-9 produced by T cells in mast cell recruitment. CONCLUSION: TH9 cells are a major source of IL-9 in models of allergic inflammation and play an important role in mast cell accumulation and activation.


Assuntos
Hipersensibilidade a Ovo/imunologia , Interleucina-9/imunologia , Mastócitos/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Células Th2/imunologia , Transferência Adotiva , Animais , Linhagem da Célula/imunologia , Movimento Celular , Hipersensibilidade a Ovo/genética , Hipersensibilidade a Ovo/patologia , Feminino , Deleção de Genes , Regulação da Expressão Gênica , Genótipo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/imunologia , Interleucina-13/genética , Interleucina-13/imunologia , Interleucina-9/genética , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Mastócitos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ovalbumina , Fenótipo , Proteínas Proto-Oncogênicas/deficiência , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/imunologia , Transdução de Sinais , Linfócitos T Auxiliares-Indutores/patologia , Linfócitos T Auxiliares-Indutores/transplante , Células Th2/patologia , Células Th2/transplante , Transativadores/deficiência , Transativadores/genética , Transativadores/imunologia
3.
J Clin Invest ; 123(11): 4641-53, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24216482

RESUMO

T helper 9 (Th9) cells are specialized for the production of IL-9, promote allergic inflammation in mice, and are associated with allergic disease in humans. It has not been determined whether Th9 cells express a characteristic transcriptional signature. In this study, we performed microarray analysis to identify genes enriched in Th9 cells compared with other Th subsets. This analysis defined a transcriptional regulatory network required for the expression of a subset of Th9-enriched genes. The activator protein 1 (AP1) family transcription factor BATF (B cell, activating transcription factor­like) was among the genes enriched in Th9 cells and was required for the expression of IL-9 and other Th9-associated genes in both human and mouse T cells. The expression of BATF was increased in Th9 cultures derived from atopic infants compared with Th9 cultures from control infants. T cells deficient in BATF expression had a diminished capacity to promote allergic inflammation compared with wild-type controls. Moreover, mouse Th9 cells ectopically expressing BATF were more efficient at promoting allergic inflammation than control transduced cells. These data indicate that BATF is a central regulator of the Th9 phenotype and contributes to the development of allergic inflammation.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Interleucina-9/biossíntese , Subpopulações de Linfócitos T/classificação , Subpopulações de Linfócitos T/imunologia , Linfócitos T Auxiliares-Indutores/classificação , Linfócitos T Auxiliares-Indutores/imunologia , Transferência Adotiva , Animais , Fatores de Transcrição de Zíper de Leucina Básica/deficiência , Fatores de Transcrição de Zíper de Leucina Básica/genética , Linhagem da Célula/genética , Linhagem da Célula/imunologia , Humanos , Hipersensibilidade/etiologia , Hipersensibilidade/imunologia , Hipersensibilidade/metabolismo , Hipersensibilidade Imediata/genética , Hipersensibilidade Imediata/imunologia , Hipersensibilidade Imediata/metabolismo , Lactente , Inflamação/etiologia , Inflamação/imunologia , Inflamação/metabolismo , Fatores Reguladores de Interferon/deficiência , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , Interleucina-9/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Análise de Sequência com Séries de Oligonucleotídeos , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Auxiliares-Indutores/metabolismo , Transcrição Gênica
4.
Immunity ; 38(2): 360-72, 2013 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-23376058

RESUMO

Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine important for the initiation and development of T helper (Th2) cell-mediated allergic inflammation. In this study, we identified a positive association between interleukin-9 (IL-9) and TSLP concentration in the serum of infants with atopic dermatitis. In primary cell cultures, the addition of TSLP led to an increase in IL-9 production from human and mouse Th9 cells, and induced an increase in signal transducer and activator of transcription 5 (STAT5) activation and binding to the Il9 promoter. In vivo, use of an adoptive transfer model demonstrated that TSLP promoted IL-9-dependent, Th9 cell-induced allergic inflammation by acting directly on T cells. Moreover, transgenic expression of TSLP in the lung stimulated IL-9 production in vivo, and anti-IL-9 treatment attenuated TSLP-induced airway inflammation. Together, our results demonstrate that TSLP promotes Th9 cell differentiation and function and define a requirement for IL-9 in TSLP-induced allergic inflammation.


Assuntos
Citocinas/imunologia , Dermatite Atópica/imunologia , Inflamação/imunologia , Interleucina-9/imunologia , Fator de Transcrição STAT5/imunologia , Células Th2/imunologia , Transferência Adotiva , Animais , Anticorpos Neutralizantes/farmacologia , Diferenciação Celular/efeitos dos fármacos , Citocinas/genética , Citocinas/farmacologia , Dermatite Atópica/genética , Dermatite Atópica/patologia , Expressão Gênica/efeitos dos fármacos , Humanos , Lactente , Inflamação/genética , Inflamação/patologia , Interleucina-9/antagonistas & inibidores , Interleucina-9/genética , Linfonodos/efeitos dos fármacos , Linfonodos/imunologia , Linfonodos/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Cultura Primária de Células , Regiões Promotoras Genéticas , Ligação Proteica , Sistema Respiratório/efeitos dos fármacos , Sistema Respiratório/imunologia , Sistema Respiratório/patologia , Fator de Transcrição STAT5/agonistas , Fator de Transcrição STAT5/genética , Transdução de Sinais/efeitos dos fármacos , Células Th2/efeitos dos fármacos , Células Th2/patologia , Linfopoietina do Estroma do Timo
5.
J Immunol ; 189(10): 4759-69, 2012 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-23053511

RESUMO

The transcriptional repressor Bcl6 is a critical arbiter of Th cell fate, promoting the follicular Th lineage while repressing other Th cell lineages. Bcl6-deficient (Bcl6(-/-)) mice develop a spontaneous and severe Th2-type inflammatory disease, thus warranting assessment of Bcl6 in regulatory T cell (Treg) function. Bcl6(-/-) Tregs were competent at suppressing T cell proliferation in vitro and Th1-type colitogenic T cell responses in vivo. In contrast, Bcl6(-/-) Tregs strongly exacerbated lung inflammation in a model of allergic airway disease and promoted higher Th2 responses, including systemic upregulation of microRNA-21. Further, Bcl6(-/-) Tregs were selectively impaired at controlling Th2 responses, but not Th1 and Th17 responses, in mixed chimeras of Bcl6(-/-) bone marrow with Foxp3(-/-) bone marrow. Bcl6(-/-) Tregs displayed increased levels of the Th2 transcription factor Gata3 and other Th2 and Treg genes. Bcl6 potently repressed Gata3 transcriptional transactivation, providing a mechanism for the increased expression of Th2 genes by Bcl6(-/-) Tregs. Gata3 has a critical role in regulating Foxp3 expression and functional fitness of Tregs; however, the signal that regulates Gata3 and restricts its transactivation of Th2 cytokines in Tregs has remained unexplored. Our results identify Bcl6 as an essential transcription factor regulating Gata3 activity in Tregs. Thus, Bcl6 represents a crucial regulatory layer in the Treg functional program that is required for specific suppression of Gata3 and Th2 effector responses by Tregs.


Assuntos
Proteínas de Ligação a DNA/imunologia , Fator de Transcrição GATA3/imunologia , Linfócitos T Reguladores/imunologia , Células Th2/imunologia , Transcrição Gênica/imunologia , Ativação Transcricional/imunologia , Animais , Citocinas/genética , Citocinas/imunologia , Citocinas/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Fator de Transcrição GATA3/genética , Fator de Transcrição GATA3/metabolismo , Camundongos , Camundongos Knockout , MicroRNAs/genética , MicroRNAs/imunologia , MicroRNAs/metabolismo , Pneumonia/genética , Pneumonia/imunologia , Pneumonia/metabolismo , Proteínas Proto-Oncogênicas c-bcl-6 , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/metabolismo , Células Th1/citologia , Células Th1/imunologia , Células Th1/metabolismo , Células Th17/citologia , Células Th17/imunologia , Células Th17/metabolismo , Células Th2/citologia , Células Th2/metabolismo , Transcrição Gênica/genética , Ativação Transcricional/genética
6.
Proc Natl Acad Sci U S A ; 109(2): 541-6, 2012 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-22190484

RESUMO

The inverse correlation between DNA methylation and lineage-specific gene expression during T helper cell development is well documented. However, the specific functions of the de novo methyltransferases Dnmt3a and Dnmt3b in cytokine gene regulation have not been defined. We demonstrate that the expression of Dnmt3a and Dnmt3b are induced to a greater extent in T helper 2 (Th2) cells than in T helper 1 cells during polarization. Using conditional mutant mice, we determined that Dnmt3a, but not Dnmt3b, regulated expression of T helper cell cytokine genes, with the Il13 gene most prominently affected. Dnmt3a deficiency was accompanied by decreases in DNA methylation and changes in the H3K27 acetylation/methylation status at the Il13 locus. Dnmt3a-dependent regulation of Il13 also occurred in vivo because Dnmt3a(fl/fl)Cd4cre mice exhibited increased lung inflammation in a murine asthma model, compared with littermate controls. Based on these observations, we conclude that Dnmt3a is required for controlling normal Il13 gene expression and functions as a rate-limiting factor to restrict T helper 2-mediated inflammation.


Assuntos
DNA (Citosina-5-)-Metiltransferases/metabolismo , Metilação de DNA/imunologia , Regulação da Expressão Gênica/imunologia , Interleucina-13/metabolismo , Hipersensibilidade Respiratória/imunologia , Células Th2/metabolismo , Animais , DNA Metiltransferase 3A , Primers do DNA/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células Th2/imunologia
7.
J Immunol ; 186(8): 4959-66, 2011 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-21402898

RESUMO

Periostin is a 90-kDa member of the fasciclin-containing family and functions as part of the extracellular matrix. Periostin is expressed in a variety of tissues and expression is increased in airway epithelial cells from asthmatic patients. Recent studies have implicated a role for periostin in allergic eosinophilic esophagitis. To further define a role for periostin in Th2-mediated inflammatory diseases such as asthma, we studied the development of allergic pulmonary inflammation in periostin-deficient mice. Sensitization and challenge of periostin-deficient mice with OVA resulted in increased peripheral Th2 responses compared with control mice. In the lungs, periostin deficiency resulted in increased airway resistance and significantly enhanced mucus production by goblet cells concomitant with increased expression of Gob5 and Muc5ac compared with wild type littermates. Periostin also inhibited the expression of Gob5, a putative calcium-activated chloride channel involved in the regulation of mucus production, in primary murine airway epithelial cells. Our studies suggest that periostin may be part of a negative-feedback loop regulating allergic inflammation that could be therapeutic in the treatment of atopic disease.


Assuntos
Moléculas de Adesão Celular/imunologia , Células Caliciformes/imunologia , Hipersensibilidade/imunologia , Pneumonia/imunologia , Animais , Antígenos CD/imunologia , Antígenos CD/metabolismo , Western Blotting , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Células Cultivadas , Citocinas/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Citometria de Fluxo , Células Caliciformes/metabolismo , Células Caliciformes/patologia , Humanos , Hipersensibilidade/genética , Hipersensibilidade/metabolismo , Imuno-Histoquímica , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Metaplasia , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Muco/imunologia , Muco/metabolismo , Pneumonia/genética , Pneumonia/metabolismo , Baço/citologia , Baço/imunologia , Baço/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Células Th2/imunologia , Células Th2/metabolismo
8.
Immunity ; 34(1): 39-49, 2011 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-21215659

RESUMO

Signal transducer and activator of transcription (STAT) family members direct the differentiation of T helper cells, with specific STAT proteins promoting distinct effector subsets. STAT6 is required for the development of T helper 2 (Th2) cells, whereas STAT3 promotes differentiation of Th17 and follicular helper T cell subsets. We demonstrated that STAT3 was also activated during Th2 cell development and was required for the expression of Th2 cell-associated cytokines and transcription factors. STAT3 bound directly to Th2 cell-associated gene loci and was required for the ability of STAT6 to bind target genes. In vivo, STAT3 deficiency in T cells eliminated the allergic inflammation in mice sensitized and challenged with ovalbumin or transgenic for constitutively active STAT6. Thus, STAT3 cooperates with STAT6 in promoting Th2 cell development. These results demonstrate that differentiating T helper cells integrate multiple STAT protein signals during Th2 cell development.


Assuntos
Hipersensibilidade/imunologia , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT6/metabolismo , Células Th17/metabolismo , Células Th2/metabolismo , Animais , Diferenciação Celular/imunologia , Células Cultivadas , Citocinas/genética , Citocinas/imunologia , Citocinas/metabolismo , Hipersensibilidade/genética , Hipersensibilidade/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Ligação Proteica/imunologia , Receptor Cross-Talk/imunologia , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT6/genética , Transdução de Sinais/imunologia , Células Th17/imunologia , Células Th17/patologia , Células Th2/imunologia , Células Th2/patologia , Ativação Transcricional
9.
J Allergy Clin Immunol ; 126(3): 483-8.e1, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20816184

RESUMO

BACKGROUND: Childhood asthma is most often characterized by recurrent wheezing, airway hyperreactivity, and atopy; however, our understanding of these relationships from early in life remains unclear. Respiratory tract illnesses and atopic sensitization early in life might produce an interaction between innate and acquired immune responses, leading to airway inflammation and heightened airway reactivity. OBJECTIVE: We hypothesized that premorbid airway reactivity and immunologic characteristics of infants without prior episodes of wheezing would be associated with subsequent wheezing during a 1-year follow-up. METHODS: One hundred sixteen infants with chronic dermatitis were enrolled before episodes of wheezing. Airway reactivity, allergen-specific IgE levels, cytokine production by stimulated PBMCs, and percentages of dendritic cells were measured on entry, and airway reactivity was reassessed at the 1-year follow-up. Linear regression models were used to evaluate a predictor's effect on continuous outcomes. RESULTS: Milk sensitization, egg sensitization, or both were associated with heightened airway reactivity before wheezing and after the onset of wheezing; however, these factors were not associated with an increased risk of wheezing. There was an interaction between initial airway reactivity and wheezing as a determinant of airway reactivity at follow-up. In addition, cytokine production by stimulated PBMCs was a risk factor for wheezing, whereas increased percentages of conventional dendritic cells were protective against wheezing. CONCLUSION: Our data in a selected cohort of infants support a model with multiple risk factors for subsequent wheezing that are independent of initial airway reactivity; however, the causative factors that produce wheezing very early in life might contribute to heightened airway reactivity.


Assuntos
Asma/imunologia , Sons Respiratórios/imunologia , Idade de Início , Asma/epidemiologia , Asma/fisiopatologia , Citocinas/imunologia , Células Dendríticas/citologia , Células Dendríticas/imunologia , Feminino , Seguimentos , Hipersensibilidade Alimentar/imunologia , Humanos , Imunoglobulina E/sangue , Lactente , Leucócitos Mononucleares/imunologia , Masculino , Testes de Função Respiratória , Fatores de Risco
10.
Nat Immunol ; 11(6): 527-34, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20431622

RESUMO

CD4(+) helper T cells acquire effector phenotypes that promote specialized inflammatory responses. We show that the ETS-family transcription factor PU.1 was required for the development of an interleukin 9 (IL-9)-secreting subset of helper T cells. Decreasing PU.1 expression either by conditional deletion in mouse T cells or the use of small interfering RNA in human T cells impaired IL-9 production, whereas ectopic PU.1 expression promoted IL-9 production. Mice with PU.1-deficient T cells developed normal T helper type 2 (T(H)2) responses in vivo but showed attenuated allergic pulmonary inflammation that corresponded to lower expression of Il9 and chemokines in peripheral T cells and in lungs than that of wild-type mice. Together our data suggest a critical role for PU.1 in generating the IL-9-producing (T(H)9) phenotype and in the development of allergic inflammation.


Assuntos
Diferenciação Celular , Hipersensibilidade , Interleucina-9/metabolismo , Proteínas Proto-Oncogênicas/imunologia , Linfócitos T/imunologia , Transativadores/imunologia , Animais , Feminino , Humanos , Inflamação , Interleucina-9/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Reação em Cadeia da Polimerase Via Transcriptase Reversa
11.
J Immunol ; 184(6): 3186-90, 2010 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-20147633

RESUMO

IL-4 promotes the development of Th2 cells and allergic inflammation. In atopic dermatitis lesions, IL-4 decreases the expression of multiple genes associated with innate defense, including genes in the epidermal differentiation complex (EDC) that regulate epidermal barrier function. However, it is not clear whether IL-4 also contributes to homeostatic control of EDC genes. In this report, we demonstrate that expression of EDC genes and barrier function is increased in the absence of endogenous IL-4. Mice that express a constitutively active Stat6 (Stat6VT) are prone to the development of allergic skin inflammation and have decreased expression of EDC genes. IL-4 deficiency protects Stat6VT transgenic mice from the development of allergic skin inflammation and decreased recovery time in barrier function following skin irritation, with a concomitant increase in EDC gene expression. These data suggest that IL-4 plays an important role in regulating epidermal homeostasis and innate barrier function.


Assuntos
Dermatite Atópica/genética , Dermatite Atópica/imunologia , Predisposição Genética para Doença , Homeostase/genética , Homeostase/imunologia , Mediadores da Inflamação/fisiologia , Interleucina-4/fisiologia , Fator de Transcrição STAT6/genética , Animais , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Dermatite Atópica/patologia , Epiderme/imunologia , Epiderme/patologia , Feminino , Regulação da Expressão Gênica/imunologia , Humanos , Imunidade Inata/genética , Interleucina-4/deficiência , Interleucina-4/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Permeabilidade , Fator de Transcrição STAT6/biossíntese , Fator de Transcrição STAT6/fisiologia , Regulação para Cima/genética , Regulação para Cima/imunologia
12.
Immunology ; 127(4): 587-95, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19604309

RESUMO

T-cell responses to a cytokine milieu instruct the development of multiple effector phenotypes. While transforming growth factor-beta(1) (TGF-beta(1)) inhibits the development of T helper type 1 (Th1) and Th2 cells, we demonstrate that like interleukin-6 (IL-6) and IL-4, IL-12 can inhibit the development of TGF-beta(1)-induced Foxp3-expressing adaptive T regulatory (aTreg) cells. Signal transducer and activator of transcription 4 (STAT4) is critical for the response to IL-12, although there is a parallel pathway involving T box expressed in T cells (T-bet), and cells from mice double-deficient in STAT4 and T-bet are refractory to the inhibition of aTreg-cell development by IL-12. While the ability of these cytokines to promote Th differentiation may contribute to this effect, we observe that culture with IL-12, or other instructive cytokines, results in an increase in repressive chromatin modifications at the Foxp3 locus that limit STAT5 binding to Foxp3, without observed effects on IL-2 signalling pathways. In a model of allergic lung inflammation there are increased percentages of Treg cells in the lungs of Stat4(-/-) mice, compared with wild-type mice, and increases in Treg cells correlate with decreased allergic inflammation. Overall, these results suggest an important role for STAT4 in regulating Treg-cell development.


Assuntos
Fator de Transcrição STAT4/imunologia , Linfócitos T Reguladores/imunologia , Animais , Diferenciação Celular/imunologia , Células Cultivadas , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/metabolismo , Interleucina-12/imunologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Hipersensibilidade Respiratória/imunologia , Fator de Crescimento Transformador beta1/imunologia
13.
Blood ; 113(23): 5887-90, 2009 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-19359411

RESUMO

IL-12 activates STAT4, which is a critical regulator of inflammation and T helper type I (Th1) lineage development in murine systems. The requirement for STAT4 in the generation of human Th1 cells has not been examined thoroughly. Compared with control Th1 cultures, expression of the Th1 genes IFNgamma, IL-12Rbeta2, and TNFalpha is greatly reduced in Th1 cultures of CD4 T cells isolated from lymphoma patients after autologous stem cell transplantation who have acquired STAT4 deficiency. Moreover, IL-4 and IL-5 production is increased in patient Th1 cultures though there are no defects in the development of Th2 cells. Reconstitution of STAT4 in patient T cells allowed recovery of IFNgamma and IL-12Rbeta2 expression, whereas ectopic expression of IL-12Rbeta2 did not rescue STAT4 expression, and increased IFNgamma production only to levels intermediate between control and patient samples. These results demonstrate that, as in murine systems, STAT4 is required for optimal human Th1 lineage development.


Assuntos
Diferenciação Celular/imunologia , Fator de Transcrição STAT4/deficiência , Fator de Transcrição STAT4/metabolismo , Células Th1/citologia , Células Th1/metabolismo , Células Cultivadas , Humanos , Linfoma/genética , Linfoma/imunologia , Linfoma/metabolismo , Receptores de Interleucina-12/metabolismo , Fator de Transcrição STAT4/genética , Células Th1/imunologia
14.
Immunity ; 29(5): 679-90, 2008 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-18993086

RESUMO

Transcriptional regulatory networks direct the development of specialized cell types. The transcription factors signal tranducer and activator of transcription 4 (Stat4) and T-bet are required for the interleukin-12 (IL-12)-stimulated development of T helper 1 (Th1) cells, although the hierarchy of activity by these factors has not been clearly defined. In this report, we show that these factors did not function in a linear pathway and that each factor played a unique role in programming chromatin architecture for Th1 gene expression, with subsets of genes depending on Stat4, T-bet, or both for expression in Th1 cells. T-bet was not able to transactivate expression of Stat4-dependent genes in the absence of endogenous Stat4 expression. Thus, T-bet requires Stat4 to achieve complete IL-12-dependent Th1 cell-fate determination. These data provide a basis for understanding how transiently activated and lineage-specific transcription factors cooperate in promoting cellular differentiation.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Regulação da Expressão Gênica , Fator de Transcrição STAT4/metabolismo , Proteínas com Domínio T/metabolismo , Células Th1/imunologia , Animais , Linfócitos T CD4-Positivos/metabolismo , Cromatina/genética , Cromatina/isolamento & purificação , Técnicas de Inativação de Genes , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-12/imunologia , Interleucina-12/metabolismo , Interleucina-4/imunologia , Interleucina-4/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Células Th1/metabolismo , Transcrição Gênica , Transdução Genética
15.
J Immunol ; 180(5): 3551-9, 2008 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-18292582

RESUMO

IL-4 is required for the pathogenesis of atopic diseases and immune regulation. Stat6 is critical for IL-4-induced gene expression and Th cell differentiation. Recently, we have generated mice expressing a mutant Stat6 (Stat6VT) under control of the CD2 locus control region that is transcriptionally active independent of IL-4 stimulation. To determine whether active Stat6 in T cells is sufficient to alter immune regulation in vivo, we mated Stat6VT transgenic mice to IL-4-deficient mice. Stat6VT expression in IL-4-deficient lymphocytes was sufficient to alter lymphocyte homeostasis and promote Th2 differentiation in vitro. HyperTh2 levels in Stat6 transgenic mice correlated with an atopic phenotype that manifested as blepharitis and pulmonary inflammation with a high level of eosinophilic infiltration. In the absence of endogenous IL-4, Stat6VT transgenic mice were protected from allergic inflammation. Thus, in mice with hyperTh2 immune responses in vivo, IL-4 is a critical effector cytokine.


Assuntos
Receptor gp130 de Citocina/genética , Hipersensibilidade/imunologia , Hipersensibilidade/patologia , Mediadores da Inflamação/fisiologia , Interleucina-4/fisiologia , Fator de Transcrição STAT6/genética , Substituição de Aminoácidos/genética , Animais , Linfócitos B/citologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Blefarite/genética , Blefarite/imunologia , Blefarite/patologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Receptor gp130 de Citocina/biossíntese , Receptor gp130 de Citocina/fisiologia , Homeostase/genética , Homeostase/imunologia , Hipersensibilidade/genética , Mediadores da Inflamação/metabolismo , Interleucina-4/deficiência , Interleucina-4/genética , Pulmão/imunologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Fator de Transcrição STAT6/biossíntese , Fator de Transcrição STAT6/fisiologia , Células Th2/imunologia , Células Th2/metabolismo , Células Th2/patologia
16.
J Leukoc Biol ; 82(2): 370-9, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17513694

RESUMO

IL-4 is a critical cytokine in the regulation of immune responses. In B lymphocytes, IL-4 signaling promotes the Stat6-dependent cell surface expression of several proteins including MHC Class II and CD86. However, the requirement for other transcription factors in IL-4-induced B cell gene expression has not been studied extensively. Here, we show that IL-4 induces NF-kappaB p100 processing to NF-kappaB p52 in B cells but not in T cells or macrophages. IL-4 induced NF-kappaB p52 production requires PI-3K activity and correlates with IkappaB kinase phosphorylation and TNF receptor-associated factor 3 degradation. Blocking NF-kappaB activity eliminates IL-4-stimulated gene expression in B cells by reducing IL-4-induced DNA binding but not phosphorylation or nuclear localization of Stat6. These results describe a novel role for NF-kappaB in IL-4-induced signaling and gene expression.


Assuntos
DNA/metabolismo , Interleucina-4/farmacologia , NF-kappa B/metabolismo , Fator de Transcrição STAT6/metabolismo , Animais , Linfócitos B/metabolismo , Células Cultivadas , Genes Reporter , Luciferases/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/fisiologia
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