Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.012
Filtrar
1.
Nat Commun ; 12(1): 1285, 2021 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-33627652

RESUMO

The host defence peptide cathelicidin (LL-37 in humans, mCRAMP in mice) is released from neutrophils by de-granulation, NETosis and necrotic death; it has potent anti-pathogen activity as well as being a broad immunomodulator. Here we report that cathelicidin is a powerful Th17 potentiator which enhances aryl hydrocarbon receptor (AHR) and RORγt expression, in a TGF-ß1-dependent manner. In the presence of TGF-ß1, cathelicidin enhanced SMAD2/3 and STAT3 phosphorylation, and profoundly suppressed IL-2 and T-bet, directing T cells away from Th1 and into a Th17 phenotype. Strikingly, Th17, but not Th1, cells were protected from apoptosis by cathelicidin. We show that cathelicidin is released by neutrophils in mouse lymph nodes and that cathelicidin-deficient mice display suppressed Th17 responses during inflammation, but not at steady state. We propose that the neutrophil cathelicidin is required for maximal Th17 differentiation, and that this is one method by which early neutrophilia directs subsequent adaptive immune responses.


Assuntos
Peptídeos Catiônicos Antimicrobianos/farmacologia , Neutrófilos/citologia , Neutrófilos/efeitos dos fármacos , Células Th17/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação/genética , Fosforilação/fisiologia , Proteínas Citotóxicas Formadoras de Poros/farmacologia , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Proteína Smad2/genética , Proteína Smad2/metabolismo , Proteína Smad3/genética , Proteína Smad3/metabolismo , Células Th1/citologia , Células Th1/efeitos dos fármacos , Células Th1/metabolismo , Células Th17/citologia , Células Th17/efeitos dos fármacos
2.
Cell Res ; 31(3): 272-290, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33473155

RESUMO

How the innate and adaptive host immune system miscommunicate to worsen COVID-19 immunopathology has not been fully elucidated. Here, we perform single-cell deep-immune profiling of bronchoalveolar lavage (BAL) samples from 5 patients with mild and 26 with critical COVID-19 in comparison to BALs from non-COVID-19 pneumonia and normal lung. We use pseudotime inference to build T-cell and monocyte-to-macrophage trajectories and model gene expression changes along them. In mild COVID-19, CD8+ resident-memory (TRM) and CD4+ T-helper-17 (TH17) cells undergo active (presumably antigen-driven) expansion towards the end of the trajectory, and are characterized by good effector functions, while in critical COVID-19 they remain more naïve. Vice versa, CD4+ T-cells with T-helper-1 characteristics (TH1-like) and CD8+ T-cells expressing exhaustion markers (TEX-like) are enriched halfway their trajectories in mild COVID-19, where they also exhibit good effector functions, while in critical COVID-19 they show evidence of inflammation-associated stress at the end of their trajectories. Monocyte-to-macrophage trajectories show that chronic hyperinflammatory monocytes are enriched in critical COVID-19, while alveolar macrophages, otherwise characterized by anti-inflammatory and antigen-presenting characteristics, are depleted. In critical COVID-19, monocytes contribute to an ATP-purinergic signaling-inflammasome footprint that could enable COVID-19 associated fibrosis and worsen disease-severity. Finally, viral RNA-tracking reveals infected lung epithelial cells, and a significant proportion of neutrophils and macrophages that are involved in viral clearance.


Assuntos
Imunidade Adaptativa , Lavagem Broncoalveolar , /imunologia , Imunidade Inata , Análise de Célula Única , Líquido da Lavagem Broncoalveolar , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD8-Positivos/citologia , Comunicação Celular , Perfilação da Expressão Gênica , Humanos , Pulmão/virologia , Macrófagos Alveolares/citologia , Monócitos/citologia , Neutrófilos/citologia , Fenótipo , Análise de Componente Principal , RNA-Seq , Células Th17/citologia
3.
Gene ; 757: 144931, 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-32640308

RESUMO

OBJECTIVE: The aim of this study is to investigate the role of close homolog of L1 (CHL1) on inflammatory bowel disease (IBD), and the correlation with the balance of Th17/Treg. METHODS: Dextran sodium sulfate (DSS)-induced IBD mice model was established. CHL1 knockout (KO) mice and CHL1 wild-type (WT) mice were subjected to DSS. CHL1 expression was detected using qRT-PCR. Weight was recorded daily, and disease activity index (DAI) score was assessed. The colon length and histological changes were measured. The number of neutrophils, macrophages and T cells was observed by immunohistochemistry. The expression of inflammatory cytokines and the proportion of Th17/Treg cells were detected by qRT-PCR and flow cytometry. The expression of RORγt, STAT3 and Foxp3 was detected by using immunohistochemistry and Western blot. RESULTS: CHL1 expression was upregulated in DSS-induced IBD mice. DSS-CHLl-KO mice exhibited less weight loss than the DSS-CHLl-WT mice. The DAI score and histological score were decreased in DSS-CHLl-KO mice compared with DSS-CHLl-WT mice, while colon length was increased. Number of neutrophils, macrophages and T cells, and expression of TNF-α, IL-6, IL-17A, IL-21 and IL-23 were decreased in DSS-CHLl-KO mice, while IL-10 expression was increased. Moreover, CHL1-deficient inhibited Th17 cells differentiation and promoted Treg cells differentiation in IBD mice. CHL1-deficient also inhibited the expression of RORγt and STAT3, and promoted the expression of Foxp3 in IBD mice. CONCLUSION: CHL1-deficient reduces the inflammatory response by regulating the balance of Th17/Treg in mice with IBD. CHL1 is expected to be a new target for the treatment of IBD.


Assuntos
Moléculas de Adesão Celular/genética , Doenças Inflamatórias Intestinais/genética , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Animais , Moléculas de Adesão Celular/deficiência , Diferenciação Celular , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Doenças Inflamatórias Intestinais/sangue , Doenças Inflamatórias Intestinais/imunologia , Interleucinas/genética , Interleucinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Linfócitos T Reguladores/citologia , Células Th17/citologia
4.
PLoS One ; 15(6): e0234479, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32542025

RESUMO

There are differences in disease susceptibility to whirling disease (WD) among strains of rainbow trout. The North American strain Trout Lodge (TL) is highly susceptible, whereas the German Hofer (HO) strain is more resistant. The suppressor of cytokine signaling (SOCS) proteins are key in inhibiting cytokine signaling. Their role in modulating the immune response against whirling disease is not completely clear. This study aimed at investigating the transcriptional response of SOCS1 and SOCS3 genes to Myxobolus cerebralis along with that of several upstream regulators and immune response genes. M. cerebralis induced the expression of SOCS1, the IL-6-dependent SOCS3, the anti-inflammatory cytokine IL-10 and the Treg associated transcription factor FOXP3 in TL fish at multiple time points, which likely caused a restricted STAT1 and STAT3 activity affecting the Th17/Treg17 balance. The expression of SOCS1 and the IL-6-dependent SOCS3 was induced constraining the activation of STAT1 and STAT3 in TL fish, thereby causing Th17/Treg17 imbalance and leaving the fish unable to establish a protective immune response against M. cerebralis or control inflammatory reactions increasing susceptibility to WD. Conversely, in HO fish, the expression of SOCS1 and SOCS3 was restrained, whereas the expression of STAT1 and IL-23-mediated STAT3 was induced potentially enabling more controlled immune responses, accelerating parasite clearance and elevating resistance. The induced expression of STAT1 and IL-23-mediated STAT3 likely maintained a successful Th17/Treg17 balance and enabled fish to promote effective immune responses favouring resistance against WD. The results provide insights into the role of SOCS1 and SOCS3 in regulating the activation and magnitude of host immunity in rainbow trout, which may help us understand the mechanisms that underlie the variation in resistance to WD.


Assuntos
Suscetibilidade a Doenças/imunologia , Doenças dos Peixes/imunologia , Myxobolus/imunologia , Oncorhynchus mykiss/imunologia , Doenças Parasitárias em Animais/imunologia , Fator de Transcrição STAT3/imunologia , Proteína 3 Supressora da Sinalização de Citocinas/imunologia , Animais , Oncorhynchus mykiss/parasitologia , Fator de Transcrição STAT1/imunologia , Proteína 1 Supressora da Sinalização de Citocina/imunologia , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Células Th17/citologia , Células Th17/imunologia
5.
Exp Mol Pathol ; 115: 104447, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32380055

RESUMO

BACKGROUND: The purpose of this research is to reveal the improvement effect and potential mechanism of Huagan tongluo Fang (HGTLF) on liver fibrosis. METHODS: A mouse model of liver fibrosis induced by CCl4 was established to analyze the effect of HGTLF on liver fibrosis. The expression changes of miRNA after HGTLF stimulation were detected by qRT-PCR. After interference with miR-184 in Th17 cells, the concentration of IL-17A in cell culture supernatants was detected by ELISA and the proportion of Th17 cells was analyzed by flow cytometry. The relationship between miR-184 and FOXO1 was verified by online software and dual-luciferase reporter system. After HGTLF treatment of Th17 cells overexpressing miR-184, the protein level of FOXO1 was detected by Western blot. RESULTS: HGTLF could significantly improve liver fibrosis in mice. By qRT-PCR, miR-184 was most significantly expressed after HGTLF drug stimulation, and miR-184 was considered to be the major RNA involved in Th17 cell differentiation. Interference with miR-184 in Th17 cells inhibited the differentiation of Th17 cells. By online software and dual-luciferase reporter system assay, the direct interaction of miR-184 with FOXO1 was confirmed. After HGTLF treatment of Th17 cells overexpressing miR-184, FOXO1 protein levels were significantly up-regulated and inhibited the differentiation of Th17 cells, which was reversed by miR-184 inhibitors. The Vivo experiments also confirmed the improvement effect of HGTLF on liver fibrosis in mice. CONCLUSION: Our results indicated that HGTLF could improve liver fibrosis via down-regulating miR-184 and up-regulating of FOXO1 to inhibit Th17 cell differentiation.


Assuntos
Diferenciação Celular , Regulação para Baixo/genética , Medicamentos de Ervas Chinesas/uso terapêutico , Proteína Forkhead Box O1/metabolismo , Cirrose Hepática/tratamento farmacológico , MicroRNAs/genética , Células Th17/citologia , Regulação para Cima/genética , Animais , Sequência de Bases , Tetracloreto de Carbono , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/farmacologia , Proteína Forkhead Box O1/genética , Cirrose Hepática/genética , Cirrose Hepática/imunologia , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo
6.
Zhongguo Xue Xi Chong Bing Fang Zhi Za Zhi ; 32(2): 154-158, 2020 Apr 28.
Artigo em Chinês | MEDLINE | ID: mdl-32458604

RESUMO

OBJECTIVE: To investigate the clinical characteristics and the distribution of peripheral blood T lymphocyte sub-sets in patients with schistosomal hepatic cirrhosis in Suzhou City. METHODS: A total of 32 inpatients with liver diseases due to advanced schistosomiasis at the Department of Infectious Diseases, The First Affiliated Hospital of Soochow University from January 2016 to January 2018 were recruited and assigned into the infection and non-infection groups according to presence of co-infections, and 20 old healthy volunteers served as controls. Venous blood samples were collected on the day of admission, and the proportions of CD4+ T cells, CD8+ T cells, regulatory T (Treg) cells and Th17 cells were detected in peripheral blood using flow cytometry. RESULTS: Most patients with liver disorders due to advanced schistosomiasis were admitted to hospital in Suzhou City because of portal hypertension-associated complications, with a high prevalence of co-infections (59.38%, 19/32). The proportions of peripheral CD4+ and CD8+ T cells and Th17 cells were all significantly lower in patients with liver disorders due to advanced schistosomiasis than in controls (t = -5.111, -4.470 and -2.749, all P < 0.05), and a higher proportion of Treg cells was detected in patients than in controls (t = 5.628, P < 0.05). In addition, there were significant differences among the infection group, non-infection group and controls in terms of the percentage of CD4+ T cells, CD8+ T cells, Th17 cells and Treg cells (F = 15.837, 16.594, 9.290 and 27.866, all P < 0.05). CONCLUSIONS: Portal hypertension-associated complications are predominantly seen in patients with liver diseases due to advanced schistosomiasis at admission in Suzhou City, and co-infections are common. Imbalance of peripheral T cell subsets is detected in patients with liver diseases due to advanced schistosomiasis in Suzhou City.


Assuntos
Hepatopatias Parasitárias , Esquistossomose , Subpopulações de Linfócitos T , Contagem de Células Sanguíneas , Linfócitos T CD8-Positivos/citologia , China , Citometria de Fluxo , Humanos , Hepatopatias Parasitárias/sangue , Hepatopatias Parasitárias/etiologia , Esquistossomose/sangue , Esquistossomose/complicações , Subpopulações de Linfócitos T/citologia , Linfócitos T Reguladores/citologia , Células Th17/citologia
7.
Braz J Med Biol Res ; 53(4): e9282, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32267311

RESUMO

Vitiligo is an acquired pigmentary disorder resulting from selective destruction of melanocytes. Emerging studies have suggested that T helper cell 17 (Th17) is potentially implicated in vitiligo development and progression. It was recently discovered that metabotropic glutamate receptor 4 (mGluR4) can modulate Th17-mediated adaptive immunity. However, the influence of mGluR4 on melanogenesis of melanocytes has yet to be elucidated. In the present study, we primarily cultured mouse bone marrow-derived dendritic cells (BMDC) and then knocked down and over-expressed mGluR4 using transfection. Transduced BMDC were co-cultured with CD4+ T cells and the expression of Th17-related cytokines were measured. The morphology and melanogenesis of B16 cells were observed after being treated with co-culture medium of CD4+ T cells and transduced BMDC. We found that mGluR4 knockdown did not affect the co-stimulatory CD80 and CD86 upregulation after lipopolysaccharide stimulation but did increase the expression of Th17-related cytokines, and further down-regulated the expression of microphthalmia-associated transcription factor (MITF) and the downstream genes, decreased melanin production, and destroyed the morphology of B16 cells. Conversely, over-expression of mGluR4 reduced the expression of CD80 and CD86, suppressed the production of Th17-related cytokines, increased the expression of MITF, and did not destroy the morphology of B16 cells. Our study confirmed that mGluR4 modulated the Th17 cell polarization and resulted in the alteration of melanogenesis and morphology of B16 cells. Collectively, these findings suggest mGluR4 might be a potent target involved in the immune pathogenesis of vitiligo.


Assuntos
Células da Medula Óssea/citologia , Diferenciação Celular/fisiologia , Células Dendríticas/citologia , Receptores de Glutamato Metabotrópico/fisiologia , Células Th17/imunologia , Vitiligo/imunologia , Animais , Citometria de Fluxo , Masculino , Melaninas/biossíntese , Melanócitos/citologia , Camundongos Endogâmicos C57BL , RNA Interferente Pequeno/imunologia , Células Th17/citologia , Vitiligo/genética
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.
Minerva Med ; 111(3): 254-265, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32166932

RESUMO

With the discovery of the IL-23 / Th17 axis, the treatment of psoriasis has entered a new era. The aim of this study was to explore the progress of biologics and janus kinases (JAK) inhibitors targeting IL-23/Th17 axis in the treatment of psoriasis. review of English-language article was performed. Search terms included IL-17, IL-23, biologics, monoclonal antibodies, neutralizing antibodies, JAK, inhibitors, Psoriasis Area Severity Index and psoriasis. Data were selected from two phase 2 clinical trials; and nine phase 3 randomized, double-blind clinical trials; and other clinical trials. This review analyzes skin lesion clearance and major adverse reactions of 9 mAbs including mirikizumab and bimekizumab. At the same time, the research progress and prospects of three non-IgG small molecule biologics are analyzed too. This paper also compares the efficacy and limitations of biologics targeting the IL-23/Th17 axis with non-biologics acting on the JAK-signal transducer and activator of transcription pathway. The IL-17A/F inhibitors and non-IgG small molecule biologics that are being studied will bring a revolutionary development to the treatment of psoriasis. Topical application of JAK inhibitors can not only achieve the purpose of treating psoriasis, but also reduce the amounts of systemic medication, and reduces side effects. Each drug has its own indication, and the effect of the drug can be better achieved by selecting the indication for the drug.


Assuntos
Produtos Biológicos/uso terapêutico , Interleucina-17/antagonistas & inibidores , Subunidade p19 da Interleucina-23/antagonistas & inibidores , Inibidores de Janus Quinases/uso terapêutico , Psoríase/terapia , Anticorpos Monoclonais Humanizados , Anticorpos Neutralizantes/uso terapêutico , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Humanos , Subunidade p19 da Interleucina-23/metabolismo , Psoríase/patologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores de Interleucina-17/antagonistas & inibidores , Índice de Gravidade de Doença , Células Th17/citologia , Células Th17/imunologia
10.
J Vis Exp ; (156)2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-32150154

RESUMO

Immune cell subtype population frequencies can have a large effect on the efficacy of T cell therapies. Current methods, like flow cytometry, have specific sample requirements, high sample input, are low throughput, and are difficult to standardize, all of which are detrimental to characterization of cell therapy products during their development and manufacturing. The assays described herein accurately identify and quantify immune cell types in a heterogeneous mixture of cells using isolated genomic DNA (gDNA). DNA methylation patterns are revealed through bisulfite conversion, a process in which unmethylated cytosines are converted to uracils. Unmethylated DNA regions are detected through qPCR amplification using primers targeting converted areas. One unique locus per assay is measured and serves as an accurate identifier for a specific cell type. The assays are robust and identify CD8+, regulatory, and Th17 T cells in a high throughput manner. These optimized assays can potentially be used for in-process and product release testing for cell therapy process.


Assuntos
Linfócitos T CD8-Positivos/citologia , Metilação de DNA , Epigênese Genética , Reação em Cadeia da Polimerase em Tempo Real/métodos , Linfócitos T Reguladores/citologia , Células Th17/citologia , Linfócitos T CD8-Positivos/metabolismo , Células Cultivadas , Humanos , Análise de Sequência de DNA/métodos , Sulfitos/química , Linfócitos T Reguladores/metabolismo , Células Th17/metabolismo
11.
PLoS One ; 15(2): e0228745, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32023301

RESUMO

HIV-1 infection is characterized by generalized deregulation of the immune system, resulting in increased chronic immune activation. However, some individuals called HIV controllers (HICs) present spontaneous control of viral replication and have a more preserved immune system. Among HICs, discordant results have been observed regarding immune activation and the frequency of different T cell subsets, including Treg and Th17 cells. We evaluated T cell immune activation, differentiation and regulatory profiles in two groups of HICs-elite controllers (ECs) and viremic controllers (VCs)-and compared them to those of cART-treated individuals (cART) and HIV-1-negative (HIV-neg) individuals. ECs demonstrated similar levels of activated CD4+ and CD8+ T cells in comparison to HIV-neg, while cART and VCs showed elevated T cell activation. CD4+ T cell subset analyses showed differences only for transitional memory T cell frequency between the EC and HIV-neg groups. However, VC individuals showed higher frequencies of terminally differentiated, naïve, and stem cell memory T cells and lower frequencies of transitional memory and central memory T cells compared to the HIV-neg group. Among CD8+ T cell subsets, ECs presented higher frequencies of stem cell memory T cells, while VCs presented higher frequencies of terminally differentiated T cells compared to the HIV-neg group. HICs showed lower frequencies of total Treg cells compared to the HIV-neg and cART groups. ECs also presented higher frequencies of activated and a lower frequency of resting Treg cells than the HIV-neg and cART groups. Furthermore, we observed a high frequency of Th17 cells in ECs and high Th17/Treg ratios in both HIC groups. Our data showed that ECs had low levels of activated T cells and a high frequency of activated Treg and Th17 cells, which could restrict chronic immune activation and be indicative of a preserved mucosal response in these individuals.


Assuntos
Infecções por HIV/imunologia , HIV-1/fisiologia , Ativação Linfocitária , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Adulto , Feminino , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Linfócitos T Reguladores/citologia , Células Th17/citologia
12.
J Agric Food Chem ; 68(9): 2664-2672, 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32033515

RESUMO

The immunomodulatory activity of a few Lactobacillus exopolysaccharides (EPS) has been reported. However, whether Lactobacillus EPS can promote the differentiation of CD4 T lymphocytes (CD4+T) cells into T-helper 17 cells (Th17 cells) in the Peyer's Patches (PPs) of mice has not been addressed. In this study, we found the molecular weight (Mw) of the purified EPS from L. casei ranged from 2.7 × 106 Da to 1.7 × 107 Da, and the average Mw was approximately 8.4 × 106 Da. In healthy BALB/c mice, EPS elevated the numbers of Th17 cells and levels of Th17-related cytokines. In vitro, EPS induced BMDCs to stimulate the differentiation of CD4+T cells of PPs into Th17 cells and the related cytokine secretions. Results suggest that L. casei EPS can effectively induce and promote the differentiation of CD4+T cells of PPs into Th17 cells in healthy mice and has the potential ability to improve intestinal mucosa immunity.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Lactobacillus casei/química , Nódulos Linfáticos Agregados/efeitos dos fármacos , Polissacarídeos Bacterianos/farmacologia , Células Th17/imunologia , Animais , Citocinas/genética , Citocinas/imunologia , Feminino , Fatores Imunológicos/química , Fatores Imunológicos/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Lactobacillus casei/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Peso Molecular , Nódulos Linfáticos Agregados/citologia , Nódulos Linfáticos Agregados/imunologia , Polissacarídeos Bacterianos/química , Polissacarídeos Bacterianos/metabolismo , Células Th17/citologia , Células Th17/efeitos dos fármacos
13.
Zhonghua Kou Qiang Yi Xue Za Zhi ; 55(2): 80-85, 2020 Feb 09.
Artigo em Chinês | MEDLINE | ID: mdl-32074667

RESUMO

Objective: To investigate the effects of exogenous interleukin (IL)-35 on the balance of helper T cell 17 (Th17) and regulatory T cell (Treg) in peripheral blood of patients with oral lichen planus (OLP). Methods: Totally 12 peripheral blood samples of OLP patients (OLP group, one male and 11 female, 26-68 years old; four cases of reticular OLP and eight cases of erosive OLP) were collected from patients of Department of Oral Mucosal Specialist of the Affiliated Hospital of Guizhou Medical University from October to December 2016. During the same period, thirteen normal peripheral blood samples were collected from the Physical Examination Center of the Affiliated Hospital of Guizhou Medical University (normal control group, one male and 12 female, 20-68 years old). The peripheral blood mononuclear cells (PBMC) were extracted in sterile condition and CD4+ T cells were sorted by flow cytometry (FCM). Quantitative real-time PCR (qPCR) technique was used to detect the mRNA expression levels of retinoid-related orphan nuclear γt (RORγt) and forkhead box3 (Foxp3). The CD4+ T cells were divided into experimental group and control group. The CD4+ T cells of experimental group were cultured in vitro by adding rhIL-35, and the CD4+ T cells of control group were cultured with the same volume of phosphate buffered saline (PBS). After the completion of the culture, the cells were collected. The expression levels of the same factors were detected by qPCR. Results: The expression [M(Q(25), Q(75))] of Foxp3 [0.15 (0.09, 0.30)] and RORγt mRNA [1.04 (0.45, 2.15)] in the CD4+ T cells of OLP were significantly higher than those in normal control group [0.04 (0.02, 0.06), 0.10 (0.05, 0.11)] (Z=-4.134, P<0.01; Z=-3.699, P<0.01). The ratio of ROR γt/Foxp3 mRNA in OLP group [6.22(3.67, 15.34)] was higher than that in normal control group [2.50 (1.24, 5.23)] (Z=-2.665, P=0.007). In the CD4+ T cells of OLP patients, the expression of Foxp3 mRNA in the experiment group [0.40 (0.21, 1.22)] was higher than that in the control group [0.15 (0.11, 0.26)](Z=-2.510, P=0.012), and the expression of ROR γt mRNA between two groups showed no significant difference (P>0.05). The ROR γt/Foxp3 mRNA ratio [3.44 (1.55, 8.16)] of the experiment group was lower than that in the control group [6.22 (4.43, 12.21)] (Z=-2.746, P=0.006). Conclusions: There was a Th17/Treg imbalance with predominated by Th17 cells in the peripheral blood of patients with OLP. Exogenous rhIL-35 had an immunomodulatory effect on the balance of Th17/Treg.


Assuntos
Interleucinas/farmacologia , Líquen Plano Bucal/imunologia , Linfócitos T Reguladores/citologia , Células Th17/citologia , Adulto , Idoso , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Leucócitos Mononucleares , Líquen Plano Bucal/sangue , Masculino , Pessoa de Meia-Idade , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Proteínas Recombinantes/farmacologia , Adulto Jovem
14.
Food Funct ; 11(1): 221-235, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31915776

RESUMO

Lactobacillus salivarius is a species of lactic acid bacteria with probiotic potency. Compared to such well-known probiotics as L. rhamnosus and L. casei, the genomic characteristics and health-beneficial effects of L. salivarius are inadequately researched. For this study, a medium with enhanced selectivity for the isolation of L. salivarius was developed by optimizing the carbon source and antibiotics in the medium. Seventy-three L. salivarius strains were isolated from 472 fecal samples from Chinese populations, and their pan-genomic and phylogenetic characterizations were analyzed. Three strains (L. salivarius HN26-4, NT4-8, and FXJCJ7-2) that were clearly categorized in different sub-phylotypes of the phylogenetic tree were randomly selected for further studies. Compared to the other two tested strains, L. salivarius FXJCJ7-2 showed higher tolerance to simulated gastrointestinal tract conditions and more significant anti-inflammatory effects in lipopolysaccharides (LPS)-treated RAW264.7 murine macrophages. This strain was also more effective in reversing LPS-induced alterations in gut barrier function, colonic histopathology, Treg/Th-17 balance, immunomodulatory indicators, nuclear factor kappa B pathway activation, and the intestinal microenvironment of the mice than the other two tested strains. Comparative genomic analysis indicated that these protective effects may be related to the specific genes of L. salivarius FXJCJ7-2 that were involved in the tolerance to the gastrointestinal environment, short-chain fatty acid production, and host-bacterium interaction.


Assuntos
Fezes/microbiologia , Trato Gastrointestinal/microbiologia , Inflamação/metabolismo , Lactobacillus salivarius/isolamento & purificação , Animais , China , Humanos , Lactobacillus salivarius/classificação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células RAW 264.7 , Linfócitos T Reguladores/citologia , Células Th17/citologia
15.
PLoS One ; 15(1): e0227993, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31990927

RESUMO

OBJECTIVES: The regulatory mechanisms affecting the modulation of the immune system accompanying the progressive effort to exhaustion, particularly associated with T cells, are not fully understood. We analysed the impact of two progressive effort protocols on T helper (Th) cell distribution and selected cytokines. METHODS: Sixty-two male soccer players with a median age of 17 (16-29) years performed different protocols for progressive exercise until exhaustion: YO-YO (YYRL1) and Beep. Blood samples for all analyses were taken three times: at baseline, post-effort, and in recovery. RESULTS: The percentage of Th1 cells increased post-effort and in recovery. The post-effort percentage of Th1 cells was higher in the Beep group compared to the YYRL1 group. Significant post-effort increase in Th17 cells was observed in both groups. The post-effort percentage of regulatory T cells (Treg) increased in the Beep group. An increased post-effort concentration of IL-2, IL-6, IL-8 and IFN-γ in both groups was observed. Post-effort TNF-α and IL-10 levels were higher than baseline in the YYRL1 group, while the post-effort IL-17A concentration was lower than baseline only in the Beep group. The recovery IL-2, IL-4, TNF-α and IFN-γ levels were higher than baseline in the YYRL1 group. The recovery IL-4, IL-6, IL-8, TNF-α and IFN-γ values were higher than baseline in the Beep group. CONCLUSION: The molecular patterns related to cytokine secretion are not the same between different protocols for progressive effort. It seems that Treg cells are probably the key cells responsible for silencing the inflammation and enhancing anti-inflammatory pathways.


Assuntos
Esforço Físico/imunologia , Futebol/fisiologia , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th17/imunologia , Células Th2/imunologia , Adolescente , Adulto , Atletas , Expressão Gênica/imunologia , Humanos , Interferon gama/genética , Interferon gama/imunologia , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-17/genética , Interleucina-17/imunologia , Interleucina-2/genética , Interleucina-2/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Interleucina-8/genética , Interleucina-8/imunologia , Masculino , Esforço Físico/genética , Recuperação de Função Fisiológica/imunologia , Linfócitos T Reguladores/citologia , Células Th1/citologia , Células Th17/citologia , Células Th2/citologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
16.
Int J Mol Sci ; 21(1)2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31948053

RESUMO

Diffusion-weighted magnetic resonance imaging (DW-MRI) is a diagnostic tool that is increasingly used for the detection and characterization of focal masses in the abdomen, among these, pancreatic ductal adenocarcinoma (PDAC). DW-MRI reflects the microarchitecture of the tissue, and changes in diffusion, which are reflected by changes in the apparent diffusion coefficient (ADC), are mainly attributed to variations in cellular density, glandular formation, and fibrosis. When analyzing the T cell infiltrates, we found an association of a tumor-promoting subpopulation, characterized by the expression of interleukin (IL) 21 and IL26, with high ADC values. Moreover, the presence of IL21+ and IL26+ positive T cells was associated with poor prognosis. Pancreatic cancers-but not healthy pancreatic tissue-expressed receptors for IL21 and IL26, a finding that could be confirmed in pancreatic cell lines. The functionality of these receptors was demonstrated in pancreatic tumor cell lines, which showed phosphorylation of ERK1/2 and STAT3 pathways in response to the respective recombinant interleukins. Moreover, in vitro data showed an increased colony formation of tumor cells. In summary, our data showed an association of IL21+ and IL26+ immune cell infiltration, increased ADC, and aggressive tumor disease, most likely due to the activation of the key cancer signaling pathways ERK1/2 and STAT3 and formation of tumor colonies.


Assuntos
Carcinoma Ductal Pancreático/diagnóstico por imagem , Carcinoma Ductal Pancreático/imunologia , Imagem de Difusão por Ressonância Magnética , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/imunologia , Células Th17/imunologia , Idoso , Complexo CD3/metabolismo , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Imuno-Histoquímica , Subunidade beta de Receptor de Interleucina-10/metabolismo , Interleucinas/metabolismo , Masculino , Pessoa de Meia-Idade , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Prognóstico , Receptores de Interleucina/metabolismo , Fator de Transcrição STAT3/metabolismo , Células Th17/citologia , Células Th17/metabolismo , Células Th17/patologia , Microambiente Tumoral
17.
Biochem Biophys Res Commun ; 522(4): 1030-1036, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-31818460

RESUMO

Rheumatoid arthritis (RA) is a systemic, chronic inflammatory disease that is characterized by T helper 17 (Th17) cell- and osteoclast-induced joint destruction and inflammation. In RA, several cytokines (interleukin (IL)-1, 6,17, and tumor necrosis factor (TNF)) are involved in almost all aspects of articular inflammation and destruction. This study aimed to evaluate the combinatorial effect of TNF and IL-6 inhibitors on the differentiation and activation of Th17 cells and osteoclasts in the context of RA, and to identify the RA-related mechanisms through IL-6 signaling. Tetrahydropapaverine (THP) showed direct binding to TNF in screening-ELISA, and SPR and TNF-neutralization assays. In a previous study, the therapeutic effect of gp130-targeting LMT-28 was confirmed in RA. Combinatorial treatment with LMT-28 and THP reduced the arthritis index and showed protective effects against bone and cartilage destruction in CIA mice. The secretion levels of TNF, IL-6, and IL-1ß significantly decreased upon combinatorial treatment with LMT-28 and THP. Further, the LMT-28 and THP combination suppressed the differentiation and activation of Th17 cells in mouse splenocytes and human PBMCs. In human RA-FLS, the LMT-28 and THP combination inhibited cell proliferation and downregulated IL-6 and/or TNF-mediated signaling relative to that observed upon independent treatment with LMT-28 or THP. Furthermore, the combination of LMT-28 and THP significantly inhibited the differentiation of mouse bone marrow monocytes (BMMs) into osteoclasts. In conclusion, the LMT-28 and THP combination can attenuate RA through the inhibition of Th17 differentiation and osteoclastogenesis, and suppression of IL-6 or TNF-induced signaling pathways. This combinatorial therapy could be used as a new strategy for the treatment of RA.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Diferenciação Celular , Receptor gp130 de Citocina/antagonistas & inibidores , Regulação para Baixo , Osteogênese , Bibliotecas de Moléculas Pequenas/uso terapêutico , Células Th17/citologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Artrite Experimental/patologia , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Receptor gp130 de Citocina/metabolismo , Citocinas/metabolismo , Regulação para Baixo/efeitos dos fármacos , Quimioterapia Combinada , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Humanos , Mediadores da Inflamação/metabolismo , Isoquinolinas/farmacologia , Isoquinolinas/uso terapêutico , Masculino , Camundongos , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Osteoclastos/patologia , Osteogênese/efeitos dos fármacos , Oxazolidinonas/farmacologia , Oxazolidinonas/uso terapêutico , Ligação Proteica/efeitos dos fármacos , Ligante RANK/farmacologia , Receptores do Fator de Necrose Tumoral/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Sinoviócitos/efeitos dos fármacos , Sinoviócitos/patologia , Células Th17/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
18.
Cell Immunol ; 347: 104025, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31837749

RESUMO

B10 cells, a specific subset of regulatory B cells, are capable of regulating immune response and restricting inflammation and autoimmune disease progression by producing IL-10. B10 cells frequently change significantly during inflammation and autoimmunity. However, how B10 cell populations change in viral myocarditis (VMC) remains unclear. Therefore, this work was conducted to clarify the changes in B10 cells and their potential mechanisms. Our results showed that the B10 cell frequency significantly changed in the VMC model. Changes in prostaglandin E2 (PGE2) levels in VMC model hearts were consistent with B10 expansion. PGE2 induced B10 cell expansion via the MAPKs/AKT-AP1 axis or AhR signaling. Additionally, PGE2-pretreated B10 cells inhibited naïve CD4+ T cell differentiation into Th17 cells. In vivo, PGE2 treatment or adoptive B10 cell transfer significantly restricted VMC development. Our results provide sufficient evidence that PGE2-induced B10 cell expansion may become a promising therapeutic approach for VMC and acute inflammatory injury.


Assuntos
Linfócitos B Reguladores/imunologia , Dinoprostona/farmacologia , Infecções por Enterovirus/patologia , Interleucina-10/imunologia , Miocardite/prevenção & controle , Células Th17/citologia , Transferência Adotiva , Animais , Subpopulações de Linfócitos B/imunologia , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Dinoprostona/sangue , Enterovirus Humano B , Ativação Linfocitária/imunologia , Contagem de Linfócitos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Miocardite/tratamento farmacológico , Miocardite/virologia , Miocárdio/imunologia , Peptídeos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/imunologia , Células Th17/imunologia
19.
Microb Pathog ; 139: 103903, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31790794

RESUMO

The contribution of Th17 and Treg in the pathogenesis of septic arthritis is well known. The imbalance of Th17/Treg ratio, especially the skewed CD4+ T cell differentiation towards pathogenic Th17 lineage is a major reason that mediates bone damage through one of its prime cytokine member IL-17A. The neutralization of released IL-17A, as well as exogenous administration of IL-2 at a lower dose, was seen to be potent in dampening the inflammatory response in many cases. Interestingly the effect of IL-17A neutralization to limit IL-17 mediated inflammation and induction of Tregs by the administration of IL-2 has not been studied in experimental arthritis. So in this study, we have treated arthritic mice with IL-17A Ab and recombinant mouse IL-2 either alone or in combination at 3, 9 and 15 days post-infection. We have found a marked decrease in Th17 cell population and their related pro-inflammatory cytokine levels at 15DPI in arthritic mice after IL-17 neutralization. An increased Treg cell population was also observed in mice after application of rIL-2 with a significantly heightened TGF-ß level in serum and synovial joints compared to the untreated one. However, in the case of combination therapy of IL-17A Ab and rIL-2 we have observed a beneficial effect in ameliorating the disease outcome as the arthritic index was decreased maximally at 15DPI with a significant reduction of arthritis compared to individual treatment. Overall the inflammatory microenvironment was counterbalanced most effectively in combination treatment by lowering the Th17/Treg ratio and their related cytokines that resulted in reducing the immunopathogenesis of the destructive arthritis.


Assuntos
Anticorpos/administração & dosagem , Artrite Infecciosa/tratamento farmacológico , Interleucina-17/imunologia , Interleucina-2/administração & dosagem , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Animais , Artrite Infecciosa/imunologia , Artrite Infecciosa/microbiologia , Diferenciação Celular , Humanos , Masculino , Camundongos , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/genética , Staphylococcus aureus/fisiologia , Células Th17/citologia , Células Th17/imunologia , Fator de Crescimento Transformador beta/imunologia
20.
Int J Lab Hematol ; 42(1): 68-76, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31825162

RESUMO

INTRODUCTION: Chemokine receptors (CRs) and the prostaglandin D2 receptor, CRTH2, have been used as surrogate markers for cytoplasmic Th1 and Th2 cytokines. The presence of regulatory T (Treg) and Th17 cells may affect the analysis of such surrogate markers, as they share several CRs with Th1 and Th2 cells. This study aimed to determine the optimal surrogate markers of Th1 and Th2 cells under physiological conditions. METHODS: Surface and cytoplasmic markers of CD4+ peripheral lymphocytes were analyzed in healthy volunteers by flow cytometry. Th1, Th2, Th17, and Treg cells were identified as IFN-γ+ , IL-4+ IL-13+ , IL-17+ , and CD25+ FoxP3+ CD4+ lymphocytes, respectively. RESULTS: The percentages of CXCR3+ and CCR5+ CD4+ lymphocytes clearly correlated with those of Th1 cells. The percentage of CRTH2+ CD4+ lymphocytes showed the closest correlation with that of Th2 cells. The percentages of Th2 cells correlated with those of CCR3+ or CCR8+ CD4+ lymphocytes, with the majority of CCR3+ and CCR8+ cells unlikely to be Th2 cells, themselves. The proportions of CCR4+ or CCR7+ CD4+ lymphocytes did not correlate with those of Th2 cells, possibly due to their expression on the surface of Treg and Th17 cells. Th2-related receptors were classified into three different groups for better understanding. CONCLUSION: CXCR3 and CCR5 are useful markers of Th1 cells. With the exception of CCR4 and CCR7 expressed at measurable levels on Treg and Th17 cells, CRTH2 and CRs, CCR3, and CCR8 may be employed as surrogate markers of Th2 cells. The proposed surrogate markers may help physicians in interpreting the disease state.


Assuntos
Regulação da Expressão Gênica , Receptores de Quimiocinas/biossíntese , Células Th1/metabolismo , Células Th2/metabolismo , Adulto , Citocinas/biossíntese , Humanos , Masculino , Pessoa de Meia-Idade , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/metabolismo , Células Th1/citologia , Células Th17/citologia , Células Th17/metabolismo , Células Th2/citologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...