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1.
Phytomedicine ; 80: 153392, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33113503

RESUMO

BACKGROUND: Acacetin 7-O-ß-D-glucoside (tilianin) is a major constituent of Agastache rugosa, a traditional medicine that has long been used for the treatment of gastrointestinal disorders. Tilianin has a wide variety of pharmacological properties such as cardioprotective, neuroprotective, and anti-atherogenic activities. We recently discovered that tilianin has the ability to suppress MUC5AC expression in vitro. In addition, we have established an in vivo model of allergic asthma using house dust mite (HDM) that can be applied to tilianin. PURPOSE: We investigated the effects of tilianin on airway inflammation in a HDM-induced asthma mouse model and associated mechanisms. METHODS: Tilianin was treated in splenocytes cultured in Th0 condition and HDM-stimulated bone marrow-derived dendritic cells (BMDCs), and their mRNA expression and cytokines production were determined by quantitative real-time PCR and ELISA. To evaluate the effects of tilianin in an allergic asthma model, mice were sensitized and challenged with HDM. Tilianin was administered prior to challenge by oral gavage and airway hyper-reactivity (AHR) to methacholine, inflammatory cell infiltration, cytokine levels, and airway remodeling were assessed. RESULTS: Tilianin inhibited the production of Th2-related cytokines in splenocytes, which play pivotal roles in allergic airway inflammation. When treated in HDM-stimulated BMDCs, tilianin decreased Th2-skewing cytokine IL-33 and transcription factor IRF4. On the contrary, tilianin increased Th1-skewing regulators, IL-12 and IRF1. In an HDM-induced asthmatic mouse model, tilianin attenuated AHR and airway inflammation. Tilianin suppressed the expression of Th2-related cytokines, IL-13 and IL-33 in lung tissues. As seen in HDM-stimulated BMDCs, tilianin also downregulated the expression of the transcription factor IRF4 but not IRF1. CONCLUSION: Taken together, these results suggest that tilianin attenuates HDM-induced allergic airway inflammation by inhibiting Th2-mediated inflammation through the selective inhibition of the IRF4-IL-33 axis in dendritic cells.


Assuntos
Antiasmáticos/farmacologia , Asma/tratamento farmacológico , Flavonoides/farmacologia , Glicosídeos/farmacologia , Fatores Reguladores de Interferon/metabolismo , Células Th2/efeitos dos fármacos , Remodelação das Vias Aéreas , Animais , Asma/imunologia , Asma/metabolismo , Citocinas/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Feminino , Hipersensibilidade/tratamento farmacológico , Hipersensibilidade/etiologia , Fatores Reguladores de Interferon/imunologia , Interleucina-33/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/metabolismo , Camundongos Endogâmicos BALB C , Pyroglyphidae/patogenicidade , Células Th2/imunologia , Células Th2/metabolismo
2.
Nat Commun ; 11(1): 4368, 2020 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-32868758

RESUMO

Increased extracellular sodium activates Th17 cells, which provide protection from bacterial and fungal infections. Whilst high salt diets have been shown to worsen autoimmune disease, the immunological consequences of clinical salt depletion are unknown. Here, we investigate immunity in patients with inherited salt-losing tubulopathies (SLT). Forty-seven genotyped SLT patients (with Bartter, Gitelman or EAST Syndromes) are recruited. Clinical features of dysregulated immunity are recorded with a standardised questionnaire and immunological investigations of IL-17 responsiveness undertaken. The effects of altering extracellular ionic concentrations on immune responses are then assessed. Patients are hypokalaemic and hypomagnesaemic, with reduced interstitial sodium stores determined by 23Na-magnetic resonance imaging. SLT patients report increased mucosal infections and allergic disease compared to age-matched controls. Aligned with their clinical phenotype, SLT patients have an increased ratio of Th2:Th17 cells. SLT Th17 and Tc17 polarisation is reduced in vitro, yet STAT1 and STAT3 phosphorylation and calcium flux following T cell activation are unaffected. In control cells, the addition of extracellular sodium (+40 mM), potassium (+2 mM), or magnesium (+1 mM) reduces Th2:Th17 ratio and augments Th17 polarisation. Our results thus show that the ionic environment typical in SLT impairs IL-17 immunity, but the intracellular pathways that mediate salt-driven Th17 polarisation are intact and in vitro IL-17 responses can be reinvigorated by increasing extracellular sodium concentration. Whether better correction of extracellular ions can rescue the immunophenotype in vivo in SLT patients remains unknown.


Assuntos
Síndromes de Imunodeficiência/etiologia , Interleucina-17/metabolismo , Túbulos Renais Distais/patologia , Adolescente , Adulto , Idoso de 80 Anos ou mais , Animais , Pré-Escolar , Doença Crônica , Estudos de Coortes , Feminino , Doenças Genéticas Inatas , Humanos , Magnésio/metabolismo , Masculino , Pessoa de Meia-Idade , Potássio/metabolismo , Sais/metabolismo , Sais/uso terapêutico , Sódio/metabolismo , Cloreto de Sódio/metabolismo , Cloreto de Sódio na Dieta/uso terapêutico , Células Th17/metabolismo , Células Th2/metabolismo , Adulto Jovem
3.
Nat Commun ; 11(1): 3998, 2020 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-32778730

RESUMO

Allergic asthma is a leading chronic disease associated with airway hyperreactivity (AHR). Type-2 innate lymphoid cells (ILC2s) are a potent source of T-helper 2 (Th2) cytokines that promote AHR and lung inflammation. As the programmed cell death protein-1 (PD-1) inhibitory axis regulates a variety of immune responses, here we investigate PD-1 function in pulmonary ILC2s during IL-33-induced airway inflammation. PD-1 limits the viability of ILC2s and downregulates their effector functions. Additionally, PD-1 deficiency shifts ILC2 metabolism toward glycolysis, glutaminolysis and methionine catabolism. PD-1 thus acts as a metabolic checkpoint in ILC2s, affecting cellular activation and proliferation. As the blockade of PD-1 exacerbates AHR, we also develop a human PD-1 agonist and show that it can ameliorate AHR and suppresses lung inflammation in a humanized mouse model. Together, these results highlight the importance of PD-1 agonistic treatment in allergic asthma and underscore its therapeutic potential.


Assuntos
Asma/imunologia , Asma/metabolismo , Imunidade Inata/imunologia , Linfócitos/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Animais , Citocinas/metabolismo , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Humanos , Inflamação/imunologia , Subunidade gama Comum de Receptores de Interleucina/genética , Interleucina-33/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Receptor de Morte Celular Programada 1/genética , Células Th2/metabolismo , Transcriptoma
4.
PLoS One ; 15(7): e0236744, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32730309

RESUMO

Repeated exposures to environmental allergens in susceptible individuals drive the development of type 2 inflammatory conditions such as asthma, which have been traditionally considered to be mainly mediated by Th2 cells. However, emerging evidence suggest that a new innate cell type, group 2 innate lymphoid cells (ILC2), plays a central role in initiating and amplifying a type 2 response, even in the absence of adaptive immunity. At present, the regulatory mechanisms for controlling ILC2 activation remain poorly understood. Here we report that respiratory delivery of immunogenic extracellular RNA (exRNAs) derived from RNA- and DNA-virus infected cells, was able to activate a protective response against acute type 2 lung immunopathology and airway hyperresponsiveness (AHR) induced by IL-33 and a fungal allergen, A. flavus, in mice. Mechanistically, we found that the innate immune responses triggered by exRNAs had a potent suppressive effect in vivo on the proliferation and function of ILC2 without the involvement of adaptive immunity. We further provided the loss-of-function genetic evidence that the TLR3- and MAVS-mediated signaling axis is essential for the inhibitory effects of exRNAs in mouse lungs. Thus, our results indicate that the host detection of extracellular immunostimulatory RNAs generated during respiratory viral infections have an important function in the regulation of ILC2-driven acute lung inflammation.


Assuntos
Armadilhas Extracelulares/imunologia , Imunidade Inata/imunologia , Linfócitos/imunologia , Pneumonia/imunologia , RNA/imunologia , Hipersensibilidade Respiratória/imunologia , Imunidade Adaptativa , Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Proteínas Adaptadoras de Transporte Vesicular/fisiologia , Alérgenos/imunologia , Alérgenos/metabolismo , Animais , Citocinas/metabolismo , Armadilhas Extracelulares/metabolismo , Interleucina-33/imunologia , Interleucina-33/metabolismo , Linfócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pneumonia/metabolismo , Pneumonia/patologia , RNA/metabolismo , Hipersensibilidade Respiratória/metabolismo , Hipersensibilidade Respiratória/patologia , Transdução de Sinais , Células Th2/imunologia , Células Th2/metabolismo , Receptor 3 Toll-Like/fisiologia
5.
BMC Womens Health ; 20(1): 126, 2020 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-32552719

RESUMO

BACKGROUND: Nearly all uterine cervical cancer (UCC) cases result from human papillomavirus (HPV) infection. After high-risk HPV infection, most HPV infections are naturally cleared by humoral and cell-mediated immune responses. Thus, cervical lesions of only few patients progress into cervical cancer via cervical intraepithelial neoplasia (CIN) and lead to persistent oncogenic HPV infection. This suggests that immunoregulation plays an instrumental role in the carcinogenesis. However, there was a few studies on the relation between the immunologic dissonance and clinical characteristics of UCC patients. METHOD: We examined the related immune cells (Th1, Th2, Th17, and Treg cells) by flow cytometric analysis and analyzed their relations with UCC stages, tumor size, differentiation, histology type, lymph node metastases, and vasoinvasion. Next, we quantified the Th1, Th2, Th17, and Treg cells before and after the operation both in UCC and CIN patients. RESULTS: When compared with stage I patients, decreased levels of circulating Th1 cells and elevated levels of Th2, Th17, and Treg cells were detected in stage II patients. In addition, the imbalance of Th1/Th2 and Th17/Treg cells was related to the tumor size, lymph node metastases, and vasoinvasion. We found that immunological cell levels normalized after the operations. In general, immunological cell levels in CIN patients normalized sooner than in UCC patients. CONCLUSIONS: Our findings suggested that peripheral immunological cell levels reflect the patient's condition.


Assuntos
Neoplasia Intraepitelial Cervical/imunologia , Linfócitos T Reguladores/metabolismo , Células Th1/metabolismo , Células Th17/metabolismo , Células Th2/metabolismo , Neoplasias do Colo do Útero/imunologia , Adulto , Neoplasia Intraepitelial Cervical/sangue , Citocinas/metabolismo , Feminino , Citometria de Fluxo , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th17/imunologia , Células Th2/imunologia , Carga Tumoral , Neoplasias do Colo do Útero/sangue , Neoplasias do Colo do Útero/metabolismo
6.
Nat Immunol ; 21(6): 671-683, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32424366

RESUMO

Urinary tract infections (UTIs) typically evoke prompt and vigorous innate bladder immune responses, including extensive exfoliation of the epithelium. To explain the basis for the extraordinarily high recurrence rates of UTIs, we examined adaptive immune responses in mouse bladders. We found that, following each bladder infection, a highly T helper type 2 (TH2)-skewed immune response directed at bladder re-epithelialization is observed, with limited capacity to clear infection. This response is initiated by a distinct subset of CD301b+OX40L+ dendritic cells, which migrate into the bladder epithelium after infection before trafficking to lymph nodes to preferentially activate TH2 cells. The bladder epithelial repair response is cumulative and aberrant as, after multiple infections, the epithelium was markedly thickened and bladder capacity was reduced relative to controls. Thus, recurrence of UTIs and associated bladder dysfunction are the outcome of the preferential focus of the adaptive immune response on epithelial repair at the expense of bacterial clearance.


Assuntos
Cistite/etiologia , Cistite/metabolismo , Ativação Linfocitária/imunologia , Membrana Mucosa/imunologia , Membrana Mucosa/metabolismo , Células Th2/imunologia , Células Th2/metabolismo , Animais , Carga Bacteriana , Biomarcadores , Linhagem Celular , Cistite/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Knockout , Membrana Mucosa/patologia , Células Th1/imunologia , Células Th1/metabolismo , Células Th1/patologia , Infecções Urinárias/etiologia , Infecções Urinárias/metabolismo , Infecções Urinárias/microbiologia , Cicatrização/genética , Cicatrização/imunologia
7.
Proc Natl Acad Sci U S A ; 117(23): 12980-12990, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32461368

RESUMO

The aryl hydrocarbon receptor (AhR) represents an environmental sensor regulating immune responses. In the skin, AhR is expressed in several cell types, including keratinocytes, epidermal Langerhans cells (LC), and dermal dendritic cells (DC). The mechanisms how AhR activates or inhibits cutaneous immune responses remain controversial, owing to differences in the cell-specific functions of AhR and the different activating ligands. Therefore, we sought to investigate the role of AhR in LC and langerin+ and negative DC in the skin. To this aim, we generated Langerin-specific and CD11c-specific knockout (-/-) mice lacking AhR, respectively, in LC and Langerin+ dermal DC and in all CD11c+ cells. These were then tested in an epicutaneous protein (ovalbumin, Ova) sensitization model. Immunofluorescence microscopy and flow cytometry revealed that Langerin-AhR-/- but not CD11c-AhR-/- mice harbored a decreased number of LC with fewer and stunted dendrites in the epidermis as well as a decreased number of LC in skin-draining lymph nodes (LN). Moreover, in the absence of AhR, we detected an enhanced T helper type-2 (Th2) [increased interleukin 5 (IL-5) and interleukin 13 (IL-13)] and T regulatory type-1 (Tr1) (IL-10) response when LN cells were challenged with Ova in vitro, though the number of regulatory T cells (Treg) in the LN remained comparable. Langerin-AhR-/- mice also exhibited increased blood levels of Ova-specific immunoglobulin E (IgE). In conclusion, deletion of AhR in langerin-expressing cells diminishes the number and activation of LC, while enhancing Th2 and Tr1 responses upon epicutaneous protein sensitization.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Células de Langerhans/imunologia , Receptores de Hidrocarboneto Arílico/metabolismo , Linfócitos T Reguladores/imunologia , Células Th2/imunologia , Administração Cutânea , Animais , Antígenos de Superfície/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Epiderme/imunologia , Epiderme/metabolismo , Técnicas de Inativação de Genes , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Células de Langerhans/metabolismo , Lectinas Tipo C/metabolismo , Lectinas de Ligação a Manose/metabolismo , Camundongos , Camundongos Transgênicos , Ovalbumina/administração & dosagem , Ovalbumina/imunologia , Receptores de Hidrocarboneto Arílico/genética , Linfócitos T Reguladores/metabolismo , Células Th2/metabolismo
8.
Arch Immunol Ther Exp (Warsz) ; 68(2): 12, 2020 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-32248339

RESUMO

The effect of TNF-blockers on T-lymphocyte subsets is largely unknown in inflammatory bowel diseases (IBDs). The aim of the present study was to analyze the prevalence of T-cell subtypes and their correlation to therapeutic response. Sixty-eight patients with Crohn's disease (CD), 46 with ulcerative colitis (UC) were enrolled. (1) The clinical course was followed after the initiation of TNF-blockers (prospective study). (2) The immunophenotype was also compared between long-term anti-TNF treated-responders and non-responders (cross-sectional study). The results were compared with those of therapy-naïve patients with active disease and those in remission with non-biological immunosuppressive therapy, and with healthy controls. Fourteen subtypes of peripheral blood T cells were measured with flow cytometry. The prevalence of Th2 and Th17 cells, of HLA-DR- and CD69-positive CD4 and CD8 cells, was higher, whereas the percentage of CD45RA-positive CD4 and CD8 cells was lower in both IBDs than in controls. CD8CD69 cell frequency was lower in remission, and decreased during anti-TNF therapy in CD responders. CD8CD45RO memory cells had higher prevalence in UC non-responders than in those starting anti-TNF. CD4CD45RO percentage < 49.05 at the initiation of TNF-blockers was predictive of a subsequent therapeutic response in CD, and Th2 and Th17 prevalence correlated with the duration of remission on TNF-blockers in UC. This study provided a detailed description of the T-cell composition in IBDs. CD8CD69 prevalence may be an activity marker in CD, and CD4CD45RO, Th2 and Th17 levels could be predictive for a therapeutic response to anti-TNF.


Assuntos
Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/imunologia , Subpopulações de Linfócitos T/citologia , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Adulto , Idoso , Biomarcadores/metabolismo , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/imunologia , Doença de Crohn/tratamento farmacológico , Doença de Crohn/imunologia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Subpopulações de Linfócitos T/metabolismo , Células Th17/citologia , Células Th17/metabolismo , Células Th2/citologia , Células Th2/metabolismo , Resultado do Tratamento , Adulto Jovem
9.
PLoS One ; 15(4): e0231865, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32315360

RESUMO

Gut microbiome plays an essential role in asthma development, and probiotic-based manipulation of the gut microbiome has been proposed to prevent asthma. Although the preventive effect of Lactobacillus supplementation against allergies has been reported, the precise Lactobacillus species beneficial for effective prevention of asthma remain unidentified and the underlying mechanisms remain unclear. Therefore, we aimed to investigate the efficacy of oral administration of six Lactobacillus species and the mechanism underlying asthma prevention via gut microbiome modulation. We investigated the effects of oral administration of L. rhamnosus, L. fermentum, L. casei, L. gasseri, L. salivarius, and L. reuteri (five strains of each species) on asthma and gut microbiome of house dust mite (HDM)-treated murine models of asthma. Of these, L. reuteri administration was the most effective: it alleviated airway inflammation, decreased total IgE and HDM-IgG1, and reduced Th2-associated pro-inflammatory cytokines. Moreover, modulation of specific microbial genera by L. reuteri was more effective in asthma prevention than the modulation of the overall microbiota composition. Lactobacillus and Enterococcus were enriched after L. reuteri supplementation and were closely associated with total IgE and IL-13 production. Furthermore, L. reuteri specifically altered the gut microbial function toward butyrate generation. Thus, L. reuteri may reduce the risk of asthma development by modulating specific gut microbiota to improve the lung immune environment. Our study suggests a novel option for gut microbiome manipulation via L. reuteri supplementation for suppression of asthma and other allergic diseases.


Assuntos
Asma/patologia , Microbioma Gastrointestinal , Lactobacillus reuteri/fisiologia , Pyroglyphidae/imunologia , Administração Oral , Animais , Asma/imunologia , Butiratos/metabolismo , Ceco/metabolismo , Modelos Animais de Doenças , Imunoglobulina E/sangue , Interleucina-13/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Células Th2/citologia , Células Th2/imunologia , Células Th2/metabolismo
10.
Horm Metab Res ; 52(4): 228-235, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32268424

RESUMO

Prolactin is known to have immune modulatory effects acting through the prolactin receptor, which is present on a variety of immune cells. Certain chemokines contribute to form the type of T helper (Th) preponderance in the immune response. The objective of this work was to assess if hyperprolactinemia not related to pregnancy is associated with changes in circulating levels of chemokines and other immunological markers. In this cross sectional study, 35 patients with hyperprolactinemia (5 men), and 102 healthy blood donors (19 men) were included. Serum levels of Th1- Th2- and Th17-associated chemokines, C-reactive protein, immunoglobulins, and the B cell attracting chemokine CXCL13 were assessed. The hyperprolactinemic group had significantly higher levels of Th2 associated CCL22 (p=0.022), Th17 associated CXCL1 (p=0.001), B cell attracting CXCL13 (p=0.003), and C-reactive protein (p<0.001) compared to controls, and these proteins were also positively correlated with prolactin levels. While differences in CCL22, CXCL1, CXCL13, and C-reactive protein were present in patients with low or moderate hyperprolactinemia, no differences were observed at high (>3600 mU/l) prolactin levels. To evaluate a possible dose-associated response to prolactin, an in vitro model was used, showing prolactin-induced increase in T-helper cell activation at moderate levels, while activation decreased at higher levels. Hyperprolactinemia seems to have several immunomodulatory effects and was associated with increased levels of chemokines associated with Th2 and Th17 responses and B cell attraction. However, patients with greatly increased prolactin had normal levels of chemokines, and in vitro, high levels of prolactin decreased T-helper cell activation.


Assuntos
Quimiocinas/metabolismo , Hiperprolactinemia/sangue , Hiperprolactinemia/imunologia , Imunomodulação/fisiologia , Prolactina/sangue , Adulto , Biomarcadores/sangue , Proteína C-Reativa/análise , Proteína C-Reativa/metabolismo , Estudos de Casos e Controles , Quimiocina CXCL13/metabolismo , Feminino , Humanos , Imunoglobulinas/análise , Imunoglobulinas/sangue , Ativação Linfocitária/fisiologia , Masculino , Pessoa de Meia-Idade , Células Th1/metabolismo , Células Th17/metabolismo , Células Th2/metabolismo
11.
Scand J Immunol ; 91(5): e12865, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32185817

RESUMO

Plasmacytoid dendritic cells (pDCs) regulate immunity and promote tolerance in asthma. Notch signalling is a highly conserved pathway that regulates the immune response; however, its role in pDC-mediated asthmatic airway inflammation is unclear. This study clarified the effects of Notch signalling on pDC-mediated airway inflammation using murine models of ovalbumin-sensitized allergic asthma. RBP-J-deficient pDCs (RBP-J-/- pDCs) were co-cultured with naïve CD4+ T cells and supernatants and T cell subtypes were analysed. RBP-J-/- pDCs were intranasally transferred to the airways of ovalbumin-sensitized recipient mice. Lung samples of all mice were subjected to tests for histopathology, cytokine profile of bronchoalveolar lavage fluid, airway hyperactivity and expression of T helper type 1 (Th1)/Th2 cells, regulatory T cells and type 2 innate lymphoid cells (ILC2s). The results showed that pDCs with and without RBP-J deficiency significantly differed in expression levels of cluster of differentiation 83 (CD83), but not CD80, CD86 and major histocompatibility complex class II. Co-culturing pDCs with naïve T cells revealed a poorer immunosuppressive effect of RBP-J-/- pDCs. This may be attributed to the lower expression levels of inducible co-stimulator ligand and lower production of interleukin 10 in RBP-J-/- pDCs than in control pDCs, which impeded T cell activation and Treg suppression. RBP-J-/- pDCs were associated with high ILC2 expression and severe Th2 immune responses and airway inflammation. Therefore, Notch signalling is critical for pDC-dependent immunoregulation, and RBP-J deficiency reduces pDC-based immunosuppression via T cell activation and Th cell differentiation. Thus, this pathway may be a therapeutic target for pDC-based anti-asthma immunotherapy.


Assuntos
Diferenciação Celular , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Imunomodulação , Receptores Notch/metabolismo , Transdução de Sinais , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Animais , Asma/etiologia , Asma/metabolismo , Asma/patologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças , Feminino , Expressão Gênica , Humanos , Ligante Coestimulador de Linfócitos T Induzíveis/genética , Ligante Coestimulador de Linfócitos T Induzíveis/metabolismo , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Camundongos , Células Th2/imunologia , Células Th2/metabolismo
12.
Clin Immunol ; 214: 108383, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32169441

RESUMO

The relationship between microRNA (miR) and immune activity in allergic rhinitis (AR) remains unclear. 37 children with AR and 30 healthy children were enrolled to study the correlation of miR-223 and IL-35. There was a significant inverse correlation between plasma levels of IL-35 and serum eosinophil cationic protein (ECP) levels and eosinophils counts, while there was a positive correlation between serum miR-223 level and ECP levels and eosinophils counts. Besides, the serum levels of IL-35 or miR-223 were found to be negatively or positively correlated with TNSS respectively. The serum level of miR-223 was increased, while IL-35 level was decreased. Moreover, the expression of miRNA-223 was inversely correlated with expression of IL-35. Finally, the levels of miR-223 and IL-35 were related to Th1/Th2 cytokines, eosinophils count as well as the clinical severity. Our study suggests the potential of miR-223 and IL-35 as a molecular target for the treatment of AR.


Assuntos
Citocinas/biossíntese , Interleucinas/sangue , MicroRNAs/sangue , Rinite Alérgica/sangue , Células Th1/metabolismo , Células Th2/metabolismo , Estudos de Casos e Controles , Criança , Pré-Escolar , Citocinas/sangue , Citocinas/genética , Proteína Catiônica de Eosinófilo/sangue , Eosinófilos , Feminino , Humanos , Lactente , Interferon gama/sangue , Contagem de Leucócitos , Masculino , Reação em Cadeia da Polimerase em Tempo Real , Rinite Alérgica/genética , Rinite Alérgica/fisiopatologia
13.
BMC Cancer ; 20(1): 206, 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32164594

RESUMO

BACKGROUND: The clinical success demonstrates the enormous potential of immunotherapy in cancer treatment. METHODS: This article presented research linking gastric cancer to immune cells, based on RNA-seq data of Stomach adenocarcinoma (STAD) and gene expression profile of GSE84437, 24 kinds of tumor-infiltrating immune cells were quantified by single-sample gene set enrichment analysis. RESULTS: Th2 cells, T helper cells, and Mast cells were identified as prognostic immune cells in both TCGA and GEO groups. Then SUPV3L1 and SLC22A17 were identified as hub genes which may affect immune cell infiltration by correlation analysis. Survival analysis further proved that hub genes and prognostic immune cells are associated with the prognosis of gastric cancer. In gastrointestinal tumors, hub genes and prognostic immune cells also found differences in non-tumor and tumor tissues. CONCLUSIONS: We found that three immune cells infiltration are associated with the prognosis of gastric cancer and further identify two hub genes. These two key genes may affect immune cell infiltration, result in the different prognosis of patients.


Assuntos
RNA Helicases DEAD-box/genética , Perfilação da Expressão Gênica/métodos , Mastócitos/metabolismo , Proteínas de Transporte de Cátions Orgânicos/genética , Neoplasias Gástricas/mortalidade , Células Th2/metabolismo , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Prognóstico , RNA Mensageiro/genética , Análise de Sequência de RNA , Neoplasias Gástricas/genética , Neoplasias Gástricas/imunologia , Análise de Sobrevida
14.
J Immunol Res ; 2020: 2714257, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32149156

RESUMO

Pseudorabies is an important infectious disease of swine, and immunization using attenuated pseudorabies virus (aPrV) vaccine is a routine practice to control this disease in swine herds. This study was to evaluate a saline solution containing ginseng stem-leaf saponins (GSLS) and sodium selenite (Se) as a vaccine adjuvant for its enhancement of immune response to aPrV vaccine. The results showed that aPrV vaccine diluted with saline containing GSLS-Se (aP-GSe) induced significantly higher immune responses than that of the vaccine diluted with saline alone (aP-S). The aP-GSe promoted higher production of gB-specific IgG, IgG1, and IgG2a, neutralizing antibody titers, secretion of Th1-type (IFN-γ, IL-2, IL-12), and Th2-type (IL-4, IL-6, IL-10) cytokines, and upregulated the T-bet/GATA-3 mRNA expression when compared to aP-S. In addition, cytolytic activity of NK cells, lymphocyte proliferation, and CD4+/CD8+ ratio was also significantly increased by aP-GSe. More importantly, aP-GSe conferred a much higher resistance of mice to a field virulent pseudorabies virus (fPrV) challenge. As the present study was conducted in mice, further study is required to evaluate the aP-GSe to improve the vaccination against PrV in swine.


Assuntos
Adjuvantes Imunológicos , Panax/química , Saponinas/farmacologia , Selênio/farmacologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Vacinas/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Biomarcadores , Relação CD4-CD8 , Citocinas/metabolismo , Feminino , Expressão Gênica , Imunoglobulina G/imunologia , Camundongos , Vacinas contra Pseudorraiva/imunologia , Saponinas/química , Selênio/química , Soluções , Baço/efeitos dos fármacos , Baço/imunologia , Baço/metabolismo , Suínos , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Células Th1/metabolismo , Células Th2/metabolismo
15.
PLoS One ; 15(2): e0228381, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32027660

RESUMO

Tuberculosis (TB) is a major health problem of global concern. The control of this disease requires appropriate preventive measures, including vaccines. In TB, T helper (Th)1 cytokines provide protection whereas Th2 and T regulatory (Treg) cytokines contribute to the pathogenesis and Th17 cytokines play a role in both protection and pathogenesis. Previous studies with Mycobacterium tuberculosis-specific proteins have identified seven low molecular weight proteins, PE35, ESXA, ESXB, Rv2346c, Rv2347c, Rv3619c, and Rv3620c, as immunodominant antigens inducing Th1-cell responses in humans following natural infection with M. tuberculosis. The aim of this study was to characterize the cytokine responses induced in mice immunized with these proteins, using various adjuvants and delivery systems, i.e. chemical adjuvants (Alum and IFA), non-pathogenic mycobacteria (M. smegmatis and M. vaccae) and a DNA vaccine plasmid (pUMVC6). The immune responses were monitored by quantifying the marker cytokines secreted by Th1 (IFN-É£), Th2 (IL-5), Treg (IL-10), and Th17 (IL-17A) cells. DNA corresponding to pe35, esxa, esxb, rv2346c, rv2347c, rv3619c, and rv3620c genes were cloned into the expression vectors pGES-TH-1, pDE22 and pUMVC6 for expression in Escherichia coli, mycobacteria and eukaryotic cells, respectively. Mice were immunized with the recombinants using different adjuvants and delivery systems, and spleen cells were stimulated in vitro with peptides of immunizing proteins to investigate antigen-specific secretion of Th1 (IFN-É£), Th2 (IL-5), Treg (IL-10), and Th17 (IL-17A) cytokines. The results showed that spleen cells, from mice immunized with all antigens, secreted the protective Th1 cytokine IFN-É£, except ESXB, with one or more adjuvants and delivery systems. However, only Rv3619c consistently induced Th1-biased responses, without the secretion of significant concentrations of Th2, Th17 and Treg cytokines, with all adjuvants and delivery systems. Rv3619c also induced antigen-specific IgG antibodies in immunized mice.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Proteínas de Bactérias/imunologia , Citocinas/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Mycobacterium tuberculosis/imunologia , Tuberculose/prevenção & controle , Adjuvantes Farmacêuticos/administração & dosagem , Animais , Proteínas de Bactérias/genética , Células Cultivadas , Feminino , Imunização/métodos , Camundongos , Camundongos Endogâmicos BALB C , Mycobacterium tuberculosis/genética , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Células Th1/imunologia , Células Th1/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Células Th2/imunologia , Células Th2/metabolismo , Tuberculose/imunologia , Tuberculose/metabolismo
16.
Artigo em Inglês | MEDLINE | ID: mdl-32004685

RESUMO

Lysophosphatidic acid (LPA) species are present in almost all organ systems and play diverse roles through its receptors. Asthma is an airway disease characterized by chronic allergic inflammation where various innate and adaptive immune cells participate in establishing Th2 immune response. Here, we will review the contribution of LPA and its receptors to the functions of immune cells that play a key role in establishing allergic airway inflammation and aggravation of allergic asthma.


Assuntos
Asma/imunologia , Lisofosfolipídeos/metabolismo , Diester Fosfórico Hidrolases/metabolismo , Receptores de Ácidos Lisofosfatídicos/metabolismo , Transdução de Sinais/imunologia , Animais , Asma/sangue , Asma/genética , Asma/patologia , Movimento Celular/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Células Endoteliais/imunologia , Células Endoteliais/metabolismo , Endotélio Vascular/citologia , Endotélio Vascular/imunologia , Endotélio Vascular/metabolismo , Técnicas de Introdução de Genes , Humanos , Pulmão/irrigação sanguínea , Pulmão/citologia , Pulmão/imunologia , Pulmão/patologia , Linfonodos/irrigação sanguínea , Linfonodos/imunologia , Linfonodos/metabolismo , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/metabolismo , Camundongos , Camundongos Knockout , Diester Fosfórico Hidrolases/genética , Receptores de Ácidos Lisofosfatídicos/genética , Células Th2/imunologia , Células Th2/metabolismo
17.
Int J Mol Sci ; 21(4)2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32069819

RESUMO

The study of the immunoskeletal interface has led to the discovery of numerous cytokines involved in the regulation of bone remodeling, providing valuable information on the pathogenesis of osteoporosis. The role of inflammatory cytokines of the Th1 and Th17 profile in osteoporosis is well known. Here we focus on two newly discovered Th2 cytokines, IL-31 and IL-33, whose implications in osteoporosis are recently emerging. Clinical and experimental observations suggest an important role of the IL-33/IL-31 axis in osteoporosis. IL-33 induces IL-31 secretion by Th2 cells and inhibits RANKL-dependent osteoclastogenesis, thus counteracting bone loss. IL-31 influences Th1/Th17 osteoclastogenetic inflammation and limits Th2 osteoprotective processes, thus favoring osteoporosis. Better knowledge of the role of IL-31 and IL-33 and their receptor complexes in osteoporosis could provide an interesting perspective for the development of new and more effective therapies, possibly with less side effects.


Assuntos
Interleucina-33/genética , Interleucinas/genética , Osteoporose/genética , Ligante RANK/genética , Remodelação Óssea/genética , Humanos , Osteogênese/genética , Osteoporose/patologia , Transdução de Sinais/genética , Células Th1/metabolismo , Células Th17/metabolismo , Células Th2/metabolismo , Células Th2/patologia
18.
J Immunol ; 204(6): 1650-1660, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-32060135

RESUMO

Cystic fibrosis is characterized by dehydration of the airway surface liquid layer with persistent mucus obstruction. Th2 immune responses are often manifested as increased mucous cell density (mucous cell metaplasia) associated with mucus obstruction. IL-33 is a known inducer of Th2 immune responses, but its roles in mucus obstruction and related phenotypes in a cystic fibrosis-like lung disease model (i.e., Scnn1b-Tg-positive [Tg+]) mouse, remain unclear. Accordingly, IL-33 knockout (IL-33KO) Tg+ mice were examined and compared with IL-33 heterozygous (IL-33HET) Tg+ mice. As compared with IL-33HET/Tg+ mice, IL-33KO/Tg+ mice had complete absence of bronchoalveolar lavage fluid eosinophilia, accompanied with significant reduction in bronchoalveolar lavage fluid concentration of IL-5, a cytokine associated with eosinophil differentiation and recruitment, and IL-4, a major Th2 cytokine. As compared with IL-33HET/Tg+ mice, IL-33KO/Tg+ mice had significantly reduced levels of Th2-associated gene signatures (Slc26a4, Clca1, Retnla, and Chi3l4), along with complete loss of intracellular mucopolysaccharide staining in the airway epithelium. As compared with IL-33HET/Tg+ mice, although the IL-33KO/Tg+ mice had significantly reduced levels of MUC5AC protein expression, they showed no reduction in the degree of mucus obstruction, MUC5B protein expression, bacterial burden, and neonatal mortality. Interestingly, the histological features, including subepithelial airway inflammation and alveolar space enlargement, were somewhat exaggerated in IL-33KO/Tg+ mice compared with IL-33HET/Tg+ mice. Taken together, our data indicate that although IL-33 modulates Th2 inflammatory responses and MUC5AC protein production, mucus obstruction is not dependent on IL-33.


Assuntos
Fibrose Cística/imunologia , Interleucina-33/metabolismo , Pulmão/patologia , Mucina-5AC/metabolismo , Células Th2/imunologia , Animais , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Fibrose Cística/diagnóstico , Fibrose Cística/genética , Fibrose Cística/patologia , Modelos Animais de Doenças , Eosinófilos/imunologia , Eosinófilos/metabolismo , Canais Epiteliais de Sódio/genética , Humanos , Interleucina-33/genética , Pulmão/citologia , Pulmão/imunologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Muco/imunologia , Muco/metabolismo , Mucosa Respiratória/citologia , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo , Células Th2/metabolismo
19.
Sci Rep ; 10(1): 323, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31941986

RESUMO

CD93 has been shown critical roles in inflammatory and immune diseases. However, in allergic asthma, the potential roles of soluble CD93 (sCD93) have not been well studied. We conducted house dust mite (HDM) stimulation with Der p 1 in BEAS-2B and U937 cells, followed by treatment with dexamethasone or small interfering RNA against CD93. A HDM-induced murine allergic asthma model was also established. We estimated the power of sCD93 to predict allergic asthma in a retrospective post-hoc analysis containing 96 human samples. HDM-stimulated BEAS-2B cells showed increased mRNA expression levels of IL-6, IL-8, IL-33, TSLP, and CD93. The CD93 level in culture supernatants steadily increased for 24 h after allergen stimulation, which was significantly suppressed by both dexamethasone and CD93 silencing. CD93 silencing increased IL-6 and TSLP, but not IL-33 levels in culture supernatants. HDM-induced asthma mice showed significant airway hyperresponsiveness and inflammation with Th2 cytokine activation, along with decreased CD93 expression in bronchial epithelial cells and lung homogenates but increased serum CD93 levels. The sCD93 level in asthma patients was significantly higher than that in healthy controls and could predict asthma diagnosis with moderate sensitivity (71.4%) and specificity (82.4%) (AUC = 0.787, P < 0.001). The level of sCD93 which has potential role to predict asthma significantly increased after HDM stimulation via IL-6 and TSLP in vitro and in vivo.


Assuntos
Asma/diagnóstico , Glicoproteínas de Membrana/metabolismo , Receptores de Complemento/metabolismo , Animais , Asma/metabolismo , Asma/patologia , Biomarcadores/sangue , Brônquios/citologia , Linhagem Celular , Modelos Animais de Doenças , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Humanos , Interleucina-33/genética , Interleucina-33/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/sangue , Glicoproteínas de Membrana/genética , Camundongos , Pyroglyphidae/imunologia , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptores de Complemento/antagonistas & inibidores , Receptores de Complemento/sangue , Receptores de Complemento/genética , Estudos Retrospectivos , Sensibilidade e Especificidade , Células Th2/citologia , Células Th2/imunologia , Células Th2/metabolismo
20.
Andrologia ; 52(3): e13516, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31989657

RESUMO

Benign prostatic hyperplasia (BPH) is a pathology characterised by an increase in prostate size associated with low urinary tract symptoms. Finasteride (F), a 5a-reductase inhibitor, is the standard treatment for BPH reducing prostate weight but also sexual desire. The Peruvian plant known as Red Maca (RM) (Lepidium meyenii) inhibits BPH in rats and mice. The aim of the study was to assess the inflammatory effect of RM and finasteride in rats with testosterone enanthate (TE)-induced BPH. Thirty rats were divided into 5 groups: Control, TE (50 mg/rat), TE + F (0.6 mg/kg), and two groups of TE + RM 40/80 (40 or 80 mg). After treatments, tumour necrosis factor alpha (TNFa), interleukin 4 (IL4) and interferon gamma (INFg) as well as testosterone and oestradiol were evaluated and inflammatory cells (neutrophils, mast cells and lymphocytes) in prostate were quantified. Red Maca and finasteride treatments decreased inflammatory cells counts in prostate, inhibiting TNFa by different pathways. Finasteride increased IL4 whereas Red Maca increased INFg. In conclusion, data suggest that finasteride acts on Th2 response by increasing IL4 in prostate, while Red Maca acts on Th1 response mediated by INFg.


Assuntos
Lepidium/química , Extratos Vegetais/farmacologia , Próstata/efeitos dos fármacos , Hiperplasia Prostática/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Inibidores de 5-alfa Redutase/farmacologia , Inibidores de 5-alfa Redutase/uso terapêutico , Animais , Modelos Animais de Doenças , Finasterida/farmacologia , Finasterida/uso terapêutico , Humanos , Interferon gama/metabolismo , Interleucina-4/metabolismo , Masculino , Extratos Vegetais/uso terapêutico , Próstata/citologia , Próstata/imunologia , Próstata/patologia , Hiperplasia Prostática/induzido quimicamente , Hiperplasia Prostática/imunologia , Hiperplasia Prostática/patologia , Ratos , Transdução de Sinais/imunologia , Testosterona/análogos & derivados , Testosterona/toxicidade , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th1/metabolismo , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Células Th2/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
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