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1.
Eur J Immunol ; 49(1): 66-78, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30365177

RESUMEN

The interferon-inducible transmembrane (Ifitm/Fragilis) genes encode homologous proteins that are induced by IFNs. Here, we show that IFITM proteins regulate murine CD4+ Th cell differentiation. Ifitm2 and Ifitm3 are expressed in wild-type (WT) CD4+ T cells. On activation, Ifitm3 was downregulated and Ifitm2 was upregulated. Resting Ifitm-family-deficient CD4+ T cells had higher expression of Th1-associated genes than WT and purified naive Ifitm-family-deficient CD4+ T cells differentiated more efficiently to Th1, whereas Th2 differentiation was inhibited. Ifitm-family-deficient mice, but not Ifitm3-deficient mice, were less susceptible than WT to induction of allergic airways disease, with a weaker Th2 response and less severe disease and lower Il4 but higher Ifng expression and IL-27 secretion. Thus, the Ifitm family is important in adaptive immunity, influencing Th1/Th2 polarization, and Th2 immunopathology.


Asunto(s)
Hipersensibilidad/inmunología , Inflamación/inmunología , Proteínas de la Membrana/metabolismo , Sistema Respiratorio/inmunología , Células TH1/inmunología , Células Th2/inmunología , Animales , Diferenciación Celular/genética , Células Cultivadas , Interferón gamma/metabolismo , Interleucina-27/metabolismo , Interleucina-4/metabolismo , Activación de Linfocitos/genética , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Balance Th1 - Th2/genética
2.
PLoS One ; 13(7): e0198624, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29969445

RESUMEN

The clinical profile of human rhinovirus (HRV) with regard to lower respiratory infections remains unclear. We analyzed the clinical features and cytokine responses of HRV isolates in children with respiratory infections. Quantitative analysis and genotyping of the HRV-positive samples from 601 nasopharyngeal aspirates (NPAs) were performed using VP4/VP2 sequencing. To compare T-helper1 (Th1) type (IFN-γ, TNF-α) and Th2 type (IL-4, IL-10) cytokine responses between HRV-A, B and C, the levels of the four cytokines were measured. The HRV-positive children had shorter fever duration (P = 0.018), and higher frequencies of chest retraction (P = 0.002) and wheezing (P = 0.022) than did the HRV-negative group. HRV-A was identified in 55 cases (58.5%), HRV-B in 8 (8.5%), and HRV-C in 31 (33.0%). There were no significant differences in the clinical data or NPA cytokines levels between patients with HRV-A and HRV-C infections. HRV is an important pathogen of the lower respiratory tract in young children. HRV-A and HRV-C are the dominant species that cause respiratory difficulty in young children.


Asunto(s)
Fiebre/diagnóstico , Infecciones por Picornaviridae/diagnóstico , Ruidos Respiratorios/diagnóstico , Infecciones del Sistema Respiratorio/diagnóstico , Rhinovirus/genética , Balance Th1 - Th2/genética , Enfermedad Aguda , Preescolar , Femenino , Fiebre/inmunología , Fiebre/fisiopatología , Fiebre/virología , Expresión Génica , Genotipo , Humanos , Lactante , Recién Nacido , Interferón gamma/genética , Interferón gamma/inmunología , Interleucina-10/genética , Interleucina-10/inmunología , Interleucina-4/genética , Interleucina-4/inmunología , Masculino , Infecciones por Picornaviridae/inmunología , Infecciones por Picornaviridae/fisiopatología , Ruidos Respiratorios/inmunología , Ruidos Respiratorios/fisiopatología , Infecciones del Sistema Respiratorio/inmunología , Infecciones del Sistema Respiratorio/fisiopatología , Infecciones del Sistema Respiratorio/virología , Estudios Retrospectivos , Rhinovirus/clasificación , Rhinovirus/aislamiento & purificación , Células TH1/inmunología , Células TH1/virología , Células Th2/inmunología , Células Th2/virología , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunología
3.
EBioMedicine ; 32: 43-49, 2018 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-29885866

RESUMEN

The prevalence of allergic rhinitis (AR) and obesity in children increased concurrently during recent decades. However, the molecular pathway involved in the interaction between obesity and AR is still unclear. We aimed to investigate the interaction between leptin and osteopontin (OPN) and their effect on T helper (TH) response in the development of AR in children. Thirty AR and 30 healthy children with or without obesity were enrolled. Serum leptin and OPN levels were measured and their relationship with TH1/2 cytokines was analyzed. TH cell differentiation and cytokine production in peripheral blood mononuclear cells (PBMCs) stimulated by leptin and/or OPN were analyzed by enzyme linked immunosorbent assay (ELISA). Obese AR mice models were established to verify the effect of obesity on leptin and OPN as well TH regulation. Immunoprecipitation was performed to confirm the interaction between OPN and leptin in CD4+ T cells. Our results showed elevated serum leptin and OPN in AR children correlated with TH2 cytokines expression. Leptin and OPN enhanced TH2 inflammation in house dust mite stimulated PBMCs from AR children synergistically. Obese AR mice showed as more severe inflammatory reaction, symptoms and expression of nasal leptin and OPN compared with other groups. Immunoprecipitation suggested that OPN and leptin may interact with each other and this process may be mediated by α4 integrin and PI3K/AKT pathway in CD4+ T cells. Our data provide evidence that leptin-mediated OPN upregulation promote TH2 inflammation in AR and this process is achieved through the α4 integrin and PI3K/AKT signaling pathways.


Asunto(s)
Leptina/genética , Obesidad/genética , Osteopontina/genética , Rinitis Alérgica/genética , Animales , Linfocitos T CD4-Positivos/metabolismo , Niño , Femenino , Humanos , Integrina alfa4/genética , Integrina alfa4/metabolismo , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/patología , Masculino , Ratones , Ratones Obesos , Obesidad/complicaciones , Obesidad/metabolismo , Obesidad/patología , Fosfatidilinositol 3-Quinasas/genética , Proteínas Proto-Oncogénicas c-akt/genética , Rinitis Alérgica/complicaciones , Rinitis Alérgica/metabolismo , Rinitis Alérgica/patología , Transducción de Señal/genética , Células TH1/metabolismo , Balance Th1 - Th2/genética
4.
Med Sci Monit ; 24: 3591-3603, 2018 May 29.
Artículo en Inglés | MEDLINE | ID: mdl-29813046

RESUMEN

BACKGROUND A wide range of microRNAs (miRNAs) have been shown to play a significant role in disease regulation. The objective of this study was to explore the role of miR-155 and miR-19a in the regulation of oral lichen planus (OLP). MATERIAL AND METHODS Microarray assay, real-time PCR, Western blot assay, computational analysis, luciferase assay, ELISA, and immunohistochemistry analysis were carried out to investigate the role of miR-155 and miR-19a in OLP. RESULTS According to microarray assay and real-time PCR results, the expression of miR-155 was most significantly decreased among the 16 candidate miRNAs in the OLP group, whereas the expression of miR-19a was most significantly increased. MiR-155 and miR-19a directly targeted endothelial nitric oxide synthase (eNOS) and TLR2, respectively, since only the cells co-transfected with miR-155/wild-type eNOS 3'UTR or cells co-transfected with miR-19a/wild-type TLR2 3'UTR exhibited decreased luciferase activity. In addition, the expression of TLR2 was highly upregulated in OLP, whereas the expression of eNOS was significantly downregulated. A negative correlation was found between miR-19a and TLR2 mRNA, with a coefficient value of -0.40. Similarly, a negative correlation was found between miR-155 and eNOS mRNA, with a coefficient value of -0.54. A lower level of NO, IL-4, IL-5, and IL-10 was observed in OLP, which was also accompanied by a higher level of TNF-α and IFN-γ. Finally, the upregulation in miR-155 directly decreased the expression of eNOS and further inhibited the production of NO. Downregulation of miR-19a directly increased the expression of TLR2. The inhibition of NO production and the enhancement in TLR2 expression synergistically increased the production of TNF-α and IFN-γ, while decreasing the levels of IL-4, IL-5, and IL-10. CONCLUSIONS In this study, the peripheral blood mononuclear cells (PBMCs) from subjects with or without OLP were collected and their gene expression profiles were compared. It was found that OLP changed the expression profile of miR-155 and miR-19a, which in turn directly affected the production of eNOS and TLR2, respectively. In addition, by synergistically inducing an imbalance between Th1 and Th2, the simultaneous deregulation of miR-155/eNOS and miR-19a/TLR2 was responsible for an elevated risk of OLP.


Asunto(s)
Liquen Plano Oral/genética , MicroARNs/genética , Óxido Nítrico Sintasa de Tipo III/genética , Balance Th1 - Th2/genética , Receptor Toll-Like 2/genética , Adolescente , Adulto , Anciano , Estudios de Casos y Controles , Regulación hacia Abajo , Femenino , Humanos , Leucocitos Mononucleares/metabolismo , Liquen Plano Oral/sangre , Liquen Plano Oral/metabolismo , Masculino , MicroARNs/biosíntesis , Persona de Mediana Edad , Óxido Nítrico Sintasa de Tipo III/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN Mensajero/genética , Receptor Toll-Like 2/metabolismo , Transcriptoma , Regulación hacia Arriba , Adulto Joven
6.
Phytother Res ; 32(6): 1135-1143, 2018 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-29484729

RESUMEN

Korean red pine (Pinus densiflora) bark has been traditionally used in Korea and other parts of East Asia to relieve inflammatory diseases. Although many studies using P. densiflora bark have been reported, its effect on atopic dermatitis (AD) has not been elucidated. Thus, we investigated whether the P. densiflora bark extract (PBE) has potential to attenuate AD symptoms and elucidated the molecular mechanism. Oral administration of PBE to mice with 2,4-dinitrochlorobenzene (DNCB)-induced AD lessened dermatitis scores and scratching behavior and significantly reduced measures of epidermal thickness, infiltration of mast cells and eosinophils, levels of immunoglobulin E (IgE), and IgG1 /IgG2a ratio in serum. PBE not only inhibited IL-4, IL-5, and IL-13 but also increased IFN-γ in splenic production. Furthermore, PBE significantly suppressed mRNA expression of thymic stromal lymphopoietin and further downregulated the mRNA expression of Th2 and Th17 cytokines such as IL-4, IL-13, IL-17, IL-31, and TNF-α. In addition, the protein expressions of filaggrin, involucrin, and loricrin in lesional skin were recovered by PBE. These results suggest that PBE attenuates DNCB-induced AD via regulating Th1/Th2 balance and skin barrier function.


Asunto(s)
Dermatitis Atópica/inducido químicamente , Dinitroclorobenceno/efectos adversos , Piel/efectos de los fármacos , Balance Th1 - Th2/genética , Animales , Masculino , Ratones
7.
Int Immunopharmacol ; 54: 68-77, 2018 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-29107863

RESUMEN

Airborne fine particulate matter (PM2.5) is detrimental to human health, and frequently leads to a variety of lung diseases. Recently, IARC conclude that particulate matter is carcinogenic to humans (level one). However, the pulmonary toxicological mechanism induced by PM2.5 remains obscure. Our previous studies confirmed that PM2.5 hurt the human immune system by means of causing the imbalance of Th1/Th2 lymphocytes. MicroRNAs (miRNAs) are post-transcriptional gene suppressors and potential mediators of environmental effects, which play an important role in the regulation of CD4+T lymphocyte differentiation. In order to further understand the roles of microRNAs in regulating the imbalance of Th1/Th2 differentiation triggered by PM2.5, mice were subjected to intratracheal instillation of 2.5, 10, or 20mg/kg PM2.5 in this study. Mice were euthanized on the 1st, 7th and 14th day to screen out differential miRNAs in lung tissue by employing the miRNA microarray. The expression levels of IL-4 and IFN-γ in bronchoalveolar lavage fluid (BALF) were quantified by ELISA and their mRNA expressions in lung tissue were detected by qRT-PCR. The experiment demonstrated that 10 differential miRNAs (miR-146a, -146b, -139, -129, -340, -691, -181a, -155, -21-3p, and -21-5p) were up-regulated. IL-4 levels were found decreased, nevertheless, IFN-γ levels were increased, and the IL-4/IFN-γ ratio was inclined to Th1 shifting. Besides that, we also found that miRNA-691, -181a, -146a, -146b, -21a-3p, -21a-5p, and -340 had a positive linear correlation with BALF IFN-γ, while a negative linear correlation between microRNAs (miR-146, -139, -340, -21, and -181a) and the IL-4/IFN-γ level of BALF was observed. In conclusion, elevated microRNAs profiles correlated with T lymphocyte immune imbalance, driving a Th1-biased immune response after acute PM2.5 exposure. These findings improve our understanding of the toxicological pathways of PM2.5 exposure.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Enfermedades Pulmonares/genética , MicroARNs/genética , Balance Th1 - Th2/genética , Animales , Carcinógenos Ambientales/efectos adversos , Exposición a Riesgos Ambientales/efectos adversos , Interferón gamma/genética , Interferón gamma/metabolismo , Interleucina-4/genética , Interleucina-4/metabolismo , Enfermedades Pulmonares/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Material Particulado/efectos adversos
8.
J Biol Regul Homeost Agents ; 31(4): 1109-1113, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29254322

RESUMEN

Cardiac surgery is accompanied by an important immune response that is poorly understood. This inflammatory response is caused by several stimuli: surgical trauma, cardiopulmonary bypass apparatus, aortic-cross clamping, reperfusion injury and hypothermia. The aim of the present study is to investigate the cytokine level profile involved in the inflammatory pathway of patients undergoing cardiac surgery. One hundred and two patients undergoing elective cardiac surgery utilizing cardiopulmonary bypass (CPB) apparatus were enrolled in the study. In the hematological and biochemical profiles investigated, we observed a significant increase of WBC and blood glucose concentration and a strong decrease of RBC, HB, HCT and PLT 24 h post-surgery compared to baseline and immediately after surgery groups. Furthermore, we found a modulation of cytokine levels mostly for IL-10 and an increase of IL-6, detected at 6 h post-surgery, IL-8 at 6 and 24 h, and TNFα only at 24 h post-surgery. In conclusion, these findings evidence a time course profile on cytokine levels and a balance between pro- and anti-inflammatory cytokine activation during and after cardiac surgery. In fact, IL-6 and IL-10, a pro- and an anti-inflammatory cytokine, respectively, increased immediately after surgery. The plasma level of TNF-α could be inhibited by the high concentration of IL-10 up to 6 h post-surgery. An IL-10 reduction at baseline level, after 24 h post-surgery, could explain a rise of TNF-α plasma concentration. On the other hand, considering the dual role of IL-6 on inflammation acting both as an activator of inflammatory cascade or an anti-inflammatory agent, the increased IL-6 levels 24 h after surgery could be related to the negative feedback action on TNFα activity.


Asunto(s)
Angina Estable/inmunología , Angina Inestable/inmunología , Arritmias Cardíacas/inmunología , Puente Cardiopulmonar , Infarto del Miocardio/inmunología , Balance Th1 - Th2/genética , Anciano , Angina Estable/sangre , Angina Estable/genética , Angina Estable/cirugía , Angina Inestable/sangre , Angina Inestable/genética , Angina Inestable/cirugía , Arritmias Cardíacas/sangre , Arritmias Cardíacas/genética , Arritmias Cardíacas/cirugía , Recuento de Células Sanguíneas , Glucemia/metabolismo , Procedimientos Quirúrgicos Electivos/métodos , Femenino , Expresión Génica , Perfilación de la Expresión Génica , Humanos , Inmunidad Innata , Interleucina-10/sangre , Interleucina-10/inmunología , Interleucina-6/sangre , Interleucina-6/inmunología , Interleucina-8/sangre , Interleucina-8/inmunología , Masculino , Persona de Mediana Edad , Infarto del Miocardio/sangre , Infarto del Miocardio/genética , Infarto del Miocardio/cirugía , Factor de Necrosis Tumoral alfa/sangre , Factor de Necrosis Tumoral alfa/inmunología
9.
Cell Death Dis ; 8(6): e2840, 2017 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-28569792

RESUMEN

AP1 transcription factors are important controllers of epidermal differentiation. Multiple family members are expressed in the epidermis in a differentiation-dependent manner, where they function to regulate gene expression. To study the role of AP1 factor signaling, TAM67 (dominant-negative c-jun) was inducibly expressed in the suprabasal epidermis. The TAM67-positive epidermis displays keratinocyte hyperproliferation, hyperkeratosis and parakeratosis, delayed differentiation, extensive subdermal vasodilation, nuclear loricrin localization, tail and digit pseudoainhum and reduced filaggrin level. These changes are associated with increased levels of IFNγ, CCL3, CCL5, CXCL9, CXCL10, and CXCL11 (Th1-associated chemokines), and CCL1, CCL2, CCL5 and CCL11 (Th2-associated chemokines) in the epidermis and serum. S100A8 and S100A9 protein levels are also markedly elevated. These changes in epidermal chemokine level are associated with increased levels of the corresponding chemokine mRNA. The largest increases were observed for CXCL9, CXCL10, CXCL11, and S100A8 and S100A9. To assess the role of CXCL9, CXCL10, CXCL11, which bind to CXCR3, on phenotype development, we expressed TAM67 in CXCR3 knockout mice. Using a similar strategy, we examine the role of S100A8 and S100A9. Surprisingly, loss of CXCR3 or S100A8/A9 did not attenuate phenotype development. These studies suggest that interfering with epidermal AP1 factor signaling initiates a loss of barrier function leading to enhanced epidermal chemokine production, but that CXCR3 and S100A8/A9 do not mediate the phenotypic response.


Asunto(s)
Ictiosis/genética , Proteínas de Filamentos Intermediarios/genética , Fragmentos de Péptidos/genética , Proteínas Proto-Oncogénicas c-jun/genética , Balance Th1 - Th2/genética , Factor de Transcripción AP-1/genética , Animales , Calgranulina A/genética , Calgranulina A/metabolismo , Calgranulina B/genética , Calgranulina B/metabolismo , Diferenciación Celular , Quimiocinas CC/genética , Quimiocinas CC/metabolismo , Quimiocinas CXC/genética , Quimiocinas CXC/metabolismo , Modelos Animales de Enfermedad , Epidermis/metabolismo , Epidermis/patología , Femenino , Regulación de la Expresión Génica , Humanos , Ictiosis/metabolismo , Ictiosis/patología , Interferón gamma/genética , Interferón gamma/metabolismo , Proteínas de Filamentos Intermediarios/metabolismo , Queratinocitos/metabolismo , Queratinocitos/patología , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Ratones Transgénicos , Fragmentos de Péptidos/metabolismo , Fenotipo , Proteínas Proto-Oncogénicas c-jun/metabolismo , Transducción de Señal , Factor de Transcripción AP-1/deficiencia
10.
BMC Immunol ; 18(1): 26, 2017 05 16.
Artículo en Inglés | MEDLINE | ID: mdl-28511637

RESUMEN

BACKGROUND: T-helper cell type 1 (Th1) polarization in chronic immune thrombocytopenia (cITP) has been reported at the protein and mRNA levels. We evaluated the impact of Th1/Th2 cytokine and cytokine receptor functional polymorphisms on both susceptibility to, and severity of, cITP. We analysed IFN-γ + 874 T/A, IFN-γR -611G/A, IL-4 -590C/T, and IL-4Rα Q576R polymorphisms in 126 cITP patients (male/female: 34/92; median age: 47.7 years) and 202 healthy control donors. Genotyping was determined by PCR and direct sequencing. The Th1/Th2 ratio was detected in peripheral blood mononuclear cells via flow cytometry. RESULTS: cITP patients had a higher frequency of the IL-4Rα 576 non-QQ genotype compared to healthy subjects (P = 0.04). cITP patients with the IFN-γ +874 non-AA genotype (high expression type) showed more severe thrombocytopenia than those with the AA genotype (P < 0.05). cITP patients had a significantly higher Th1/Th2 ratio than control patients (P < 0.01); this ratio was inversely correlated with platelet counts. Furthermore, patients with both IFN-γ +874 non-AA genotype (high expression type) and IFN-γR -611 non-AA genotype (high-function type) had a significantly higher Th1/Th2 ratio (P < 0.05). CONCLUSIONS: The cytokine polymorphisms affecting Th1/Th2 increase the susceptibility to, and severity of, chronic ITP.


Asunto(s)
Interferón gamma/genética , Subunidad alfa del Receptor de Interleucina-4/genética , Interleucina-4/genética , Púrpura Trombocitopénica Idiopática/genética , Receptores de Interferón/genética , Células TH1/inmunología , Células Th2/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Células Cultivadas , Niño , Preescolar , Enfermedad Crónica , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Interferón gamma/metabolismo , Interleucina-4/metabolismo , Subunidad alfa del Receptor de Interleucina-4/metabolismo , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Púrpura Trombocitopénica Idiopática/inmunología , Receptores de Interferón/metabolismo , Balance Th1 - Th2/genética , Adulto Joven
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