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1.
Immunohorizons ; 4(5): 282-291, 2020 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-32439753

RESUMO

Generation of allelic gene reporter mice has provided a powerful tool to study gene function in vivo. In conjunction with imaging technologies, reporter mouse models facilitate studies of cell lineage tracing, live cell imaging, and gene expression in the context of diseases. Although there are several advantages to using reporter mice, caution is important to ensure the fidelity of the reporter protein representing the gene of interest. In this study, we compared the efficiency of two Il9 reporter strains Il9citrine and Il9GFP in representing IL-9-producing CD4+ TH9 cells. Although both alleles show high specificity in IL-9-expressing populations, we observed that the Il9GFP allele visualized a much larger proportion of the IL-9-producing cells in culture than the Il9citrine reporter allele. In defining the mechanistic basis for these differences, chromatin immunoprecipitation and chromatin accessibility assay showed that the Il9citrine allele was transcriptionally less active in TH9 cells compared with the wild-type allele. The Il9citrine allele also only captured a fraction of IL-9-expressing bone marrow-derived mast cells. In contrast, the Il9 citrine reporter detected Il9 expression in type 2 innate lymphoid cells at a greater percentage than could be identified by IL-9 intracellular cytokine staining. Taken together, our findings demonstrate that the accuracy of IL-9 reporter mouse models may vary with the cell type being examined. These studies demonstrate the importance of choosing appropriate reporter mouse models that are optimal for detecting the cell type of interest as well as the accuracy of conclusions.

2.
J Clin Invest ; 130(7): 3820-3832, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32255767

RESUMO

Food allergies are a major clinical problem and are driven by IgE antibodies (Abs) specific for food antigens (Ags). T follicular regulatory (Tfr) cells are a specialized subset of FOXP3+ T cells that modulate Ab responses. Here, we analyzed the role of Tfr cells in regulating Ag-specific IgE using a peanut-based food allergy model in mice. Peanut-specific IgE titers and anaphylaxis responses were significantly blunted in Tfr cell-deficient Foxp3-Cre Bcl6fl/fl mice. Loss of Tfr cells led to greatly increased nonspecific IgE levels, showing that Tfr cells have both helper and suppressor functions in IgE production in the germinal center (GC) that work together to facilitate the production of Ag-specific IgE. Foxp3-Cre Ptenfl/fl mice with augmented Tfr cell responses had markedly higher levels of peanut-specific IgE, revealing an active helper function by Tfr cells on Ag-specific IgE. The helper function of Tfr cells for IgE production involves IL-10, and the loss of IL-10 signaling by B cells led to a severely curtailed peanut-specific IgE response, decreased GCB cell survival, and loss of GC dark zone B cells after peanut sensitization. We thus reveal that Tfr cells have an unexpected helper role in promoting food allergy and may represent a target for drug development.

3.
Artigo em Inglês | MEDLINE | ID: mdl-32179158

RESUMO

BACKGROUND: Bcl6 is required for the development of T follicular helper cells and T follicular regulatory (Tfr) cells that regulate germinal center responses. Bcl6 also affects the function of regulatory T (Treg) cells. OBJECTIVE: The goal of this study was to define the functions of Bcl6 in Treg cells, including Tfr cells, in the context of allergic airway inflammation. METHODS: We used a model of house dust mite sensitization to challenge wild-type, Bcl6fl/fl Foxp3-Cre, and Prdm1 (Blimp1)fl/fl Foxp3-Cre mice to study the reciprocal roles of Bcl6 and Blimp1 in allergic airway inflammation. RESULTS: In the house dust mite model, Tfr cells repress the production of IgE and Bcl6+ Treg cells suppress the generation of type 2 cytokine-producing cells in the lungs. In mice with Bcl6-deficient Treg cells, twice as many ST2+ (IL-33R+) Treg cells develop as are observed in wild-type mice. ST2+ Treg cells in the context of allergic airway inflammation are Blimp1 dependent, express type 2 cytokines, and share features of visceral adipose tissue Treg cells. Bcl6-deficient Treg cells are more susceptible, and Blimp1-deficient Treg cells are resistant, to acquiring the ST2+ Treg-cell phenotype in vitro and in vivo in response to IL-33. Bcl6-deficient ST2+ Treg cells, but not Bcl6-deficient ST2+ conventional T cells, strongly promote allergic airway inflammation when transferred into recipient mice. Lastly, ST2 is required for the exacerbated allergic airway inflammation in Bcl6fl/fl Foxp3-Cre mice. CONCLUSIONS: During allergic airway inflammation, Bcl6 and Blimp1 play dual roles in regulating Tfr-cell activity in the germinal center and in the development of ST2+ Treg cells that promote type 2 cytokine responses.

4.
Medicine (Baltimore) ; 98(44): e17764, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31689836

RESUMO

While stress is known to cause many diseases, there is no established method to determine individuals vulnerable to stress. Sasang typology categorizes humans into four Sasang types (So-Eum, Tae-Eum, So-Yang, and Tae-Yang), which have unique pathophysiologies because of their differential susceptibilities to specific stimuli, including stress. The purpose of this study was to determine if Sasang typology can be used identify individuals who are vulnerable to stress by evaluation of heart rate variability (HRV).This was a cross-sectional study. A total of 399 healthy men and women aged 30 to 49 years were recruited. Physical examinations for stress included HRV measurement and blood tests. The subjects also completed questionnaires about psychological stress, self-awareness, and lifestyle. HRV was analyzed using frequency-domain analysis. Subjects were divided into So-Eum (SE) and non-So-Eum (non-SE) groups according to their diagnosis.The weight and body mass index in the SE group were significantly lower than those in the non-SE group (both, P = .000). There were no significant between-group differences in any other demographic variables. In HRV analysis, the normalized high frequency (nHF) was higher (P = .008) while the normalized low frequency (nLF; P = .008) and LF:HF ratio (LF/HF; P = .002) were lower in the SE group than in the non-SE group.Although there was no difference in variables affecting HRV, HRV values were significantly different between groups. The LF/HF value for the SE group was at the lower limit of the normal range, although there were no associated clinical problems. These findings suggest that individuals with the SE type are more susceptible to stress than those with the other types. Thus, middle-aged individuals who are vulnerable to stress can be identified using Sasang typology.


Assuntos
Suscetibilidade a Doenças/diagnóstico , Frequência Cardíaca/fisiologia , Medicina Tradicional Coreana/métodos , Psicometria/métodos , Estresse Psicológico/diagnóstico , Adulto , Índice de Massa Corporal , Estudos Transversais , Suscetibilidade a Doenças/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Somatotipos/psicologia , Estresse Psicológico/psicologia , Inquéritos e Questionários
5.
J Immunol ; 203(7): 1989-1998, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31451674

RESUMO

The basic leucine zipper (bZIP) transcription factor BATF is expressed in multiple Th subsets and cooperates with other factors to regulate gene transcription. BATF activates lineage-specific cytokines in Th subsets, activating IL-9 in Th9 cells and IL-17 in Th17 cells, but not IL-9 or IL-17 in the reciprocal subset. The mechanism for this restricted activity is unclear. In this report, we define BATF binding partners that contribute to Th subset-specific functions. Although BATF and IRF4 are expressed in greater amounts in Th9 than Th17, increased expression of both factors is not sufficient to induce IL-9 in Th17 cells. BATF also requires heterodimer formation with Jun family members to bind DNA and induce gene expression. Using primary mouse T cell culture, we observed that JunB and c-Jun, but not JunD, promote IL-9 production in Th9 cells. Ectopic expression of BATF with either JunB or c-Jun generates modest, but significant, increases in IL-9 production in Th17 cells, suggesting that the low expression of Jun family members is one factor limiting the ability of BATF to induce IL-9 in Th17 cells. We further identified that Bach2 positively regulates IL-9 production by directly binding to the Il9 gene and by increasing transcription factor expression in Th9 cells. Strikingly, cotransduction of Bach2 and BATF significantly induces IL-9 production in both Th9 and Th17 cells. Taken together, our results reveal that JunB, c-Jun, and Bach2 cooperate with BATF to contribute to the specificity of BATF-dependent cytokine induction in Th subsets.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/imunologia , Regulação da Expressão Gênica/imunologia , Células Th17/imunologia , Animais , Fatores de Transcrição de Zíper de Leucina Básica/genética , Humanos , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/imunologia , Interleucina-9/genética , Interleucina-9/imunologia , Camundongos , Camundongos Transgênicos , Células Th17/citologia , Fatores de Transcrição/genética , Fatores de Transcrição/imunologia
6.
Immunohorizons ; 3(7): 306-316, 2019 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-31356160

RESUMO

Autoantibodies can result from excessive T follicular helper (Tfh) cell activity, whereas T follicular regulatory (Tfr) cells negatively regulate autoantibody production. IL-2 knockout (KO) mice on the BALB/c background have elevated Tfh responses, produce autoantibodies, and develop lethal autoimmunity. We analyzed Tfh and Tfr cells in IL-2 KO mice on the C57BL/6 (B6) genetic background. In B6 IL-2 KO mice, the spontaneous formation of Tfh cells and germinal center B cells was greatly enhanced, along with production of anti-DNA autoantibodies. IL-2 has been reported to repress Tfr cell differentiation; however, Tfr cells were not increased over wild-type levels in the B6 IL-2 KO mice. To assess Tfh and Tfr cell regulation of autoantibody production in IL-2 KO mice, we generated IL-2 KO mice with a T cell-specific deletion of the master Tfh cell transcription factor Bcl6. In IL-2 KO Bcl6 conditional KO (2KO-Bcl6TC) mice, Tfh cells, Tfr cells, and germinal center B cells were ablated. In contrast to expectations, autoantibody IgG titers in 2KO-Bcl6TC mice were significantly elevated over autoantibody IgG titers in IL-2 KO mice. Specific deletion of Tfr cells with Foxp3-cre Bcl6-flox alleles in IL-2 KO mice led to early lethality, before high levels of autoantibodies could develop. We found IL-2+/+ Tfr cell-deficient mice produce significant levels of autoantibodies. Our overall findings provide evidence that Tfh cells are dispensable for high-level production of autoantibodies and also reveal a complex interplay between Tfh and Tfr cells in autoantibody production and autoimmune disease.


Assuntos
Autoanticorpos/biossíntese , Autoimunidade/imunologia , Técnicas de Inativação de Genes , Interleucina-2/genética , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia , Animais , Diferenciação Celular , Interleucina-2/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Animais , Fator 88 de Diferenciação Mieloide/genética , Proteínas Proto-Oncogênicas c-bcl-6/genética , Linfócitos T Auxiliares-Indutores/metabolismo , Linfócitos T Reguladores/metabolismo
7.
J Immunol ; 203(5): 1111-1121, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31350354

RESUMO

IL-9 is an important mediator of allergic disease that is critical for mast cell-driven diseases. IL-9 is produced by many cell types, including T cells, basophils, and mast cells. Yet, how IL-9 is regulated in mast cells or basophils is not well characterized. In this report, we tested the effects of deficiency of a mouse Il9 gene regulatory element (Il9 CNS-25) in these cells in vivo and in vitro. In mast cells stimulated with IL-3 and IL-33, the Il9 CNS-25 enhancer is a potent regulator of mast cell Il9 gene transcription and epigenetic modification at the Il9 locus. Our data show preferential binding of STAT5 and GATA1 to CNS-25 over the Il9 promoter in mast cells and that T cells and mast cells have differing requirements for the induction of IL-9 production. Il9 CNS-25 is required for IL-9 production from T cells, basophils, and mast cells in a food allergy model, and deficiency in IL-9 expression results in decreased mast cell expansion. In a Nippostrongylus brasiliensis infection model, we observed a similar decrease in mast cell accumulation. Although decreased mast cells correlated with higher parasite egg burden and delayed clearance in vivo, T cell deficiency in IL-9 also likely contributes to the phenotype. Thus, our data demonstrate IL-9 production in mast cells and basophils in vivo requires Il9 CNS-25, and that Il9 CNS-25-dependent IL-9 production is required for mast cell expansion during allergic intestinal inflammation.


Assuntos
Basófilos/imunologia , Genes Reguladores , Interleucina-9/genética , Mastócitos/imunologia , Animais , Feminino , Hipersensibilidade Alimentar/imunologia , Helmintíase/imunologia , Interleucina-9/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL
8.
Medicine (Baltimore) ; 98(21): e15704, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31124947

RESUMO

INTRODUCTION: Mibyeongbogam (MBBG) is a mobile application developed for subhealth status self-management in the Republic of Korea. It aims to assess a user's subhealth status, and then to recommend relevant traditional Korean medicine (TKM)-based health-promoting strategies. The purpose of this study is to evaluate the feasibility and effectiveness of MBBG's employment for the subhealth management of general healthy adults. METHODS: This is a prospective, open-label, parallel group, randomized controlled trial that will seek to enroll 150 healthy adults, aged 30 to 49 years old, from 2 hospitals in the Republic of Korea. The eligible participants will then be randomly allocated to either the MBBG or control group, at a 1:1 allocation ratio. The MBBG group will use the application for 12 weeks, while the control group will undergo no intervention. The awareness of subhealth status will be primarily assessed. Health promoting behaviors, quality of life, TKM-based health questionnaires, and physical examination results will be assessed as secondary outcomes. DISCUSSION: The primary endpoint will be tested with a 2-sample t test, or a Wilcoxon rank sum test. Any other continuous variables will be tested via an analysis of covariance, while categorical variables will be tested by a Chi-squared or Fisher exact test. Repeated measure analysis of variance will be performed to explore any in-group differences. The results will be addressed with a 95% confidence interval. We expect that MBBG will be the 1st TKM-based mobile application to be feasible for primary care in subhealth management. TRIAL REGISTRATION: CRIS (Clinical Research Information Service), KCT0003488, February 11, 2019.


Assuntos
Promoção da Saúde/métodos , Nível de Saúde , Estilo de Vida Saudável , Aplicativos Móveis , Autocuidado/métodos , Adulto , Biomarcadores , Feminino , Comportamentos Relacionados com a Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Qualidade de Vida , República da Coreia , Projetos de Pesquisa
9.
J Immunol ; 203(1): 21-30, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31101666

RESUMO

Drug allergies occur when hapten-like drug metabolites conjugated to serum proteins, through their interactions with specific IgE, trigger allergic reactions that can be life threatening. A molecule termed covalent heterobivalent inhibitor (cHBI) was designed to specifically target drug hapten-specific IgE to prevent it from binding drug-haptenated serum proteins. cHBI binds the two independent sites on a drug hapten-specific Ab and covalently conjugates only to the specific IgE, permanently inhibiting it. The cHBI design was evaluated via ELISA to measure cHBI-IgE binding, degranulation assays of rat basophil leukemia cells for in vitro efficacy, and mouse models of ear swelling and systemic anaphylaxis responses for in vivo efficacy. The cHBI design was evaluated using two separate models: one specific to inhibit penicillin G-reactive IgE and another to inhibit IgE specific to a model compound, dansyl. We show that cHBI conjugated specifically to its target Ab and inhibited degranulation in cellular degranulation assays using rat basophil leukemia cells. Furthermore, cHBIs demonstrated in vivo inhibition of allergic responses in both murine models. We establish the cHBI design to be a versatile platform for inhibiting hapten/IgE interactions, which can potentially be applied to inhibit IgE-mediated allergic reactions to any drug/small-molecule allergy.


Assuntos
Anafilaxia/prevenção & controle , Basófilos/imunologia , Hipersensibilidade a Drogas/tratamento farmacológico , Naftalenos/metabolismo , Alérgenos/imunologia , Anafilaxia/etiologia , Animais , Complexo Antígeno-Anticorpo/imunologia , Degranulação Celular , Linhagem Celular , Modelos Animais de Doenças , Hipersensibilidade a Drogas/complicações , Ensaio de Imunoadsorção Enzimática , Epitopos/metabolismo , Feminino , Haptenos/imunologia , Humanos , Imunoglobulina E/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Naftalenos/síntese química , Penicilinas/imunologia , Ligação Proteica , Ratos
10.
Integr Med Res ; 8(1): 15-20, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30596014

RESUMO

Background: Complementary and alternative medicine treatment for insomnia has been sought due to the possible adverse effects of conventional pharmacotherapies. We performed a preliminary evaluation of the feasibility of using, and of the effect of a herbal tea (HT002), based on Traditional East Asian Medicine, in mild-to-moderate insomnia. Methods: Patients (n = 40) with mild-to-moderate insomnia were randomized to the HT002 (n = 20) or waitlist (n = 20) groups. The HT002 group consumed HT002 twice daily for 4 weeks. Outcomes were assessed using the Insomnia Severity Scale (ISI), Pittsburgh Sleep Quality Index (PSQI), and 12-item Short Form Health Survey (SF-12) at baseline and after 4 and 8 weeks. Results: The ISI score differences from baseline at weeks 4 and 8 were significantly greater in the HT002 than that in the waitlist group (week 4: -4.0 ± 0.8 vs. -0.4 ± 0.8, p < 0.05; week 8: -4.8 ± 0.7 vs. -0.9 ± 0.7, p < 0.05). Changes in PSQI and SF-12 physical component scores in the HT002 group were significantly greater at weeks 4 and 8 (p < 0.05), while SF-12 mental component scores were only significantly larger at 4 weeks (p < 0.05). HT002 was well-tolerated, with only one (5.0%) dropout, and no significant mean liver and renal function test changes post-treatment. Conclusion: Our preliminary results suggest that a 4-week treatment with HT002 may reduce the severity of insomnia symptoms and improve the quality of life. Further studies devoid of the limitations of our protocol may provide stronger conclusions. Trial registration: Clinical Research Information Service (CRIS), KCT0001900.

11.
Nat Commun ; 9(1): 4803, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30442929

RESUMO

Cytokine genes are regulated by multiple regulatory elements that confer tissue-specific and activation-dependent expression. The cis-regulatory elements of the gene encoding IL-9, a cytokine that promotes allergy, autoimmune inflammation and tumor immunity, have not been defined. Here we identify an enhancer (CNS-25) upstream of the Il9 gene that binds most transcription factors (TFs) that promote Il9 gene expression. Deletion of the enhancer in the mouse germline alters transcription factor binding to the remaining Il9 regulatory elements, and results in diminished IL-9 production in multiple cell types including Th9 cells, and attenuates IL-9-dependent immune responses. Moreover, deletion of the homologous enhancer (CNS-18) in primary human Th9 cultures results in significant decrease of IL-9 production. Thus, Il9 CNS-25/IL9 CNS-18 is a critical and conserved regulatory element for IL-9 production.


Assuntos
Linhagem da Célula/imunologia , Elementos Facilitadores Genéticos , Interleucina-9/genética , Linfócitos T Auxiliares-Indutores/imunologia , Fatores de Transcrição/genética , Animais , Sítios de Ligação , Sistemas CRISPR-Cas , Diferenciação Celular , Linhagem da Célula/genética , Sequência Conservada , Feminino , Edição de Genes , Regulação da Expressão Gênica , Humanos , Interleucina-9/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Cultura Primária de Células , Ligação Proteica , Linfócitos T Auxiliares-Indutores/citologia , Fatores de Transcrição/imunologia
12.
Eur J Immunol ; 47(7): 1136-1141, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28586108

RESUMO

The transcription factors Bcl6 and Blimp1 have opposing roles in the development of the follicular helper T (TFH ) cells: Bcl6 promotes and Blimp1 inhibits TFH -cell differentiation. Similarly, Bcl6 activates, while Blimp1 represses, expression of the TFH -cell marker PD-1. However, Bcl6 and Blimp1 repress each other's expression, complicating the interpretation of the regulatory network. Here we sought to clarify the extent to which Bcl6 and Blimp1 independently control TFH -cell differentiation by generating mice with T-cell specific deletion of both Bcl6 and Blimp1 (double conditional KO [dcKO] mice). Our data indicate that Blimp1 does not control TFH -cell differentiation independently of Bcl6. However, a population of T follicular regulatory (TFR ) cells developed independently of Bcl6 in dcKO mice. We have also analyzed regulation of IL-10 and PD-1, two genes controlled by both Bcl6 and Blimp1, and observed that Bcl6 regulates both genes independently of Blimp1. We found that Bcl6 positively regulates PD-1 expression by inhibiting the ability of T-bet/Tbx21 to repress Pdcd1 transcription. Our data provide a novel mechanism for positive control of gene expression by Bcl6, and illuminate how Bcl6 and Blimp1 control TFH -cell differentiation.


Assuntos
Diferenciação Celular , Receptor de Morte Celular Programada 1/genética , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Fatores de Transcrição/metabolismo , Animais , Expressão Gênica , Regulação da Expressão Gênica , Centro Germinativo/imunologia , Interleucina-10/genética , Interleucina-10/imunologia , Ativação Linfocitária , Camundongos , Camundongos Knockout , Fator 1 de Ligação ao Domínio I Regulador Positivo , Receptor de Morte Celular Programada 1/imunologia , Proteínas Proto-Oncogênicas c-bcl-6/deficiência , Proteínas Proto-Oncogênicas c-bcl-6/genética , Transdução de Sinais , Proteínas com Domínio T/genética , Proteínas com Domínio T/imunologia , Proteínas com Domínio T/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/fisiologia , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética
13.
J Immunol ; 198(5): 2165-2171, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28100679

RESUMO

IL-10 is an immunoregulatory cytokine that has broad effects across the immune system. In Th cell subsets, Th2 cells produce considerable amounts of IL-10. The transcription factors that regulate IL-10 production in Th2 cells are still incompletely described. In this study, we demonstrate that the ETS family transcription factor ETS variant (Etv)5 regulates IL-10 production in Th2 cells. T cell-specific Etv5-deficient and littermate control mice demonstrated that IL-10 production and gene expression were significantly decreased in the absence of Etv5. In an Aspergillus fumigatus extract-induced inflammation model, IL-10-producing CD4+ T cells in bronchoalveolar lavage and lung were significantly decreased in mice that lacked Etv5 in T cells, compared with control mice. We showed that Etv5 directly binds to the Il10 locus conserved noncoding sequence 3 site and that it activates gene expression in a luciferase reporter assay and following retroviral transduction. Etv5 deficiency did not affect the expression of other transcription factors known to be important for expression of IL-10, including Jun family members, GATA3, E4BP4, and IFN regulatory factor 4. However, in the absence of Etv5, binding of these transcription factors to the Il10 locus was dramatically reduced. Ectopic Etv5 expression in Th2 cells that lack Etv5 restored IL-10 production and the binding of IL-10-inducing transcription factors including E4BP4, IFN regulatory factor 4, and GATA3. Taken together, we conclude that Etv5 plays a crucial role in regulating IL-10 production in Th2 cells by facilitating the binding of IL-10-inducing transcription factors at the Il10 locus.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Hipersensibilidade/imunologia , Interleucina-10/metabolismo , Células Th2/imunologia , Células Th2/fisiologia , Fatores de Transcrição/metabolismo , Alérgenos/imunologia , Animais , Antígenos de Fungos/imunologia , Aspergillus fumigatus/imunologia , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Diferenciação Celular , Células Cultivadas , Proteínas de Ligação a DNA/genética , Interleucina-10/imunologia , Ativação Linfocitária , Camundongos , Camundongos Knockout , Ligação Proteica , Fatores de Transcrição/genética
14.
J Immunol ; 197(6): 2465-72, 2016 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-27496971

RESUMO

The IL-9-secreting Th9 subset of CD4 Th cells develop in response to an environment containing IL-4 and TGF-ß, promoting allergic disease, autoimmunity, and resistance to pathogens. We previously identified a requirement for the ETS family transcription factor PU.1 in Th9 development. In this report, we demonstrate that the ETS transcription factor ETS variant 5 (ETV5) promotes IL-9 production in Th9 cells by binding and recruiting histone acetyltransferases to the Il9 locus at sites distinct from PU.1. In cells that are deficient in both PU.1 and ETV5 there is lower IL-9 production than in cells lacking either factor alone. In vivo loss of PU.1 and ETV5 in T cells results in distinct effects on allergic inflammation in the lung, suggesting that these factors function in parallel. Together, these data define a role for ETV5 in Th9 development and extend the paradigm of related transcription factors having complementary functions during differentiation.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Interleucina-9/imunologia , Proteínas Proto-Oncogênicas/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Animais , Diferenciação Celular , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Expressão Gênica , Hipersensibilidade/imunologia , Hipersensibilidade/metabolismo , Inflamação/imunologia , Interleucina-9/biossíntese , Pulmão/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas/deficiência , Proteínas Proto-Oncogênicas/genética , Transdução de Sinais/imunologia , Linfócitos T Auxiliares-Indutores/fisiologia , Transativadores/deficiência , Transativadores/genética , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética
15.
Eur J Immunol ; 46(11): 2609-2613, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27510401

RESUMO

Atopic dermatitis (AD) is a chronic inflammatory skin disease induced by a complex interaction between susceptibility genes encoding skin barrier components and environmental allergen exposure that results in type 2 cytokine production. Although genetic lesions in either component can be risk factors for disease in patients, whether these pathways interact in the development of AD is not clear. To test this, we mated mice with T-cell specific expression of constitutively active Stat6 (Stat6VT) that spontaneously develop allergic skin inflammation with Flaky tail (Ft) mice that have mutations in Flg and Tmem79 genes that each affect skin barrier function. Our results demonstrate that over 90% of the Stat6VT transgenic mice carrying the Ft alleles (Stat6VTxFt-/- ) develop severe atopic dermatitis lesions by 3-5 months of age, compared with only 40% of Stat6VT mice that develop disease by 6-7 months of age. Further, histopathological analysis of skin tissues from Stat6VTxFt-/- mice revealed extensive thickening of the dermis with increased inflammatory infiltrates as compared with Stat6VT mice. Our study suggests that skin barrier defects and altered Th2 responses independently cooperate in the pathogenesis of allergic skin inflammation, similar to effects observed in patients with AD.


Assuntos
Dermatite Atópica/imunologia , Pele/imunologia , Pele/patologia , Células Th2/imunologia , Animais , Dermatite Atópica/patologia , Dermatite Atópica/fisiopatologia , Modelos Animais de Doenças , Humanos , Proteínas de Membrana/genética , Camundongos , Camundongos Transgênicos , Permeabilidade , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Fator de Transcrição STAT6/genética , Pele/fisiopatologia
16.
PLoS One ; 8(12): e83127, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24376650

RESUMO

PARP-14, a member of the poly ADP-ribose polymerase super family, promotes T helper cell 2 (Th2) differentiation by regulating interleukin-4 (IL-4) and STAT6-dependent transcription. Yet, whether PARP-14 globally impacts gene regulation has not been determined. In this report, using an RNA pol II ChIP-seq approach, we identify genes in Th2 cells that are regulated by PARP-14, and either dependent or independent of ADP-ribosyltransferase catalytic activity. Our data demonstrate that PARP-14 enhances the expression of Th2 genes as it represses the expression of Th1-associated genes. Among the relevant targets are Signal Transducer and Activator of Transcription genes required for polarizing Th1 and Th2 cells. To define a mechanism for PARP-14 function, we use an informatics approach to identify putative PARP-14 DNA binding sites. Two putative PARP-14 binding motifs are identified in multiple Th2 cytokine genes, and we demonstrate that PARP-14 interacts with each motif using in vitro binding assays. Taken together our results indicate that PARP-14 is an important factor for T helper cell differentiation and it binds to specific DNA sequences to mediate its function.


Assuntos
Citocinas/genética , DNA/metabolismo , Regulação da Expressão Gênica , Poli(ADP-Ribose) Polimerases/metabolismo , Células Th2/metabolismo , Animais , Diferenciação Celular , Citocinas/biossíntese , DNA/genética , Perfilação da Expressão Gênica , Interleucina-4/genética , Interleucina-4/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Dados de Sequência Molecular , Motivos de Nucleotídeos , Poli(ADP-Ribose) Polimerases/genética , Ligação Proteica , Fator de Transcrição STAT6/genética , Fator de Transcrição STAT6/metabolismo , Transdução de Sinais , Células Th1/citologia , Células Th1/metabolismo , Equilíbrio Th1-Th2 , Células Th2/citologia , Transcrição Genética
17.
Abdom Imaging ; 38(1): 52-5, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22527157

RESUMO

Bleeding jejunal varices are rare and could be life threatening. They are usually found in the presence of portal hypertension and prior history of gastrointestinal surgery. They can be effectively managed by radiological interventions such as transjugular intrahepatic portosystemic shunt or transhepatic embolization of varices. However, in patients with portal vein obstruction, an alternative access is necessary. We report a case of bleeding jejunal varices associated with postoperative adhesion in a patient with portal vein thrombosis which was successfully managed by percutaneous transsplenic embolization.


Assuntos
Embolização Terapêutica/métodos , Doenças do Jejuno/etiologia , Doenças do Jejuno/terapia , Cirrose Hepática/complicações , Trombose/complicações , Varizes/etiologia , Varizes/terapia , Idoso , Humanos , Doenças do Jejuno/diagnóstico por imagem , Cirrose Hepática/diagnóstico por imagem , Masculino , Veia Porta , Cintilografia , Trombose/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Varizes/diagnóstico por imagem
18.
BMC Complement Altern Med ; 12: 122, 2012 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-22889232

RESUMO

BACKGROUND: Appetite is intricately connected to eating behaviors and shows a high individual variability. In an attempt to approach the problem of gut hormone profiles, appetite, and eating behaviors at the individual level, we have adopted a constitutional typing system widely used in traditional East-Asian medicine, the Sasang constitutional typology, in order to determine the individual variations in appetite, eating behavior, and weight change. METHODS: This pilot study was designed to investigate the variability of appetite among individuals by tracking the gut hormone patterns across different constitutional types. Pre- and post-prandial concentrations of anorectic (peptide YY (PYY), glucagon-like peptide 1 (GLP-1)) and orexigenic (active ghrelin) gut hormones were measured in healthy, normal-weight (18.5 kg/m2 ≤BMI <23 kg/m2) male subjects aged 20-35 (Soyang (SY) (n = 9), Taeeum (TE) (n = 9), and Soeum (SE) (n = 10) constitutional types). RESULTS: Significant differences were found only in the PYY concentrations across the three groups (p = 0.031). The PYY concentration peaked at 30-min post-prandial in the SE group and was significantly higher compared to the other two groups (p = 0.004). The GLP-1 concentration peaked at 15-min post-prandial in the SE group (not significant). The ghrelin levels at 30-min pre-prandial were relatively lower in the TE group compared to the other groups (not significant). CONCLUSIONS: In conclusion, although with weak statistical power, meaningful gut hormone patterns specific to each constitutional type were discovered in this pilot study, which could offer a new method of approaching the problem of appetite and eating behavior from the angle of individual variability in appetite.


Assuntos
Apetite , Constituição Corporal , Comportamento Alimentar , Grelina/sangue , Peptídeo 1 Semelhante ao Glucagon/sangue , Peptídeo YY/sangue , Adulto , Humanos , Masculino , Projetos Piloto , Adulto Jovem
19.
Clin Exp Hypertens ; 33(8): 525-32, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21958429

RESUMO

It has been suggested that an approach to hypertension based on the constitutional make-up of an individual may be effective. We conducted a retrospective chart review to explore the association of Sasang constitution with hypertension. The results show that the prevalence of hypertension was highest in the Taeeum (TE) constitutional type, and that the TE constitutional type can act as an independent risk factor for hypertension (OR in TE group = 1.37 (CI 1.06-1.78) (vs. non-TE group)). This indicates that the Sasang constitutional type could explain the variability in individual susceptibilities to hypertension, suggesting a novel constitution-based approach to hypertension.


Assuntos
Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , Hipertensão/etnologia , Medicina Tradicional Coreana , Adulto , Idoso , Idoso de 80 Anos ou mais , Pressão Sanguínea , Diabetes Mellitus/etnologia , Dislipidemias/etnologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , República da Coreia/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Adulto Jovem
20.
Diabetes Res Clin Pract ; 91(3): e57-60, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21146241

RESUMO

The prevalence of insulin resistance (IR) was found to differ across different constitutional types defined by the Sasang constitutional medicine, a sub-division of the Korean traditional medicine, implying that the constitutional type of an individual is a trait that can act as an independent risk factor for IR.


Assuntos
Resistência à Insulina , Medicina Tradicional Coreana , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Coreia (Geográfico)/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Adulto Jovem
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