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1.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(9): 783-788, 2019 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-31750818

RESUMO

Objective To investigate the function and differentiation of 1/17 type helper T (Th1/17) cells. Methods Bioinformatics analysis was performed using a gene chip dataset (GSE104021) in GEO which contains gene expression data from Th17 cells and Th1/17 cells of healthy human subjects. Taking Th17 cells as the control, R language software was used to analyze the differentially expressed genes (DEGs) between Th17 cells and Th1/17 cells, so as to explore the main functional molecules of Th1/17 cells. After that, gene ontology (GO) analysis and Kyoto encyclopedia of genes and genomes (KEGG) analysis of DEGs were conducted by R language software. Finally, the genes enriched into the target biological process in the GO analysis were selected for protein-protein interaction network (PPI) analysis to explore the differentiation process of Th1/17 cells. Results Analysis of DEGs showed that, compared with Th17 cells, the underexpressed genes in Th1/17 cells were interleukin 17A (IL-17A) and C-C motif chemokine receptor 4 (CCR4). The over-expressed genes were coiled-coil domain-containing 3 (CCDC3), C-C motif chemokine ligand 4 (CCL4), colony stimulating factor 2 receptor beta common subunit (CSF2RB), C-C motif chemokine ligand 5 (CCL5), interferon gamma (IFNG) and epithelial stromal interaction 1 (EPSTI1). In GO analysis, cell component analysis showed that the expression products of these DEGs were mainly located at external side of plasma membrane and the granulocyte-macrophage colony stimulating factor (GM-CSF) receptor complex; biological process analysis showed that the expression products of DEGs were involved in the upregulation of interleukin 23 (IL-23), the chemokine-mediated signaling pathway and the upregulated chemotaxis of natural killer (NK) cells; molecular function analysis showed that the expression products of these DEGs had C-C motif chemokine 5 receptor (CCR5) binding activity, cytokine activity and interferon gamma (IFN-γ) receptor binding activity. The results of KEGG analysis showed that the DEGs were enriched in the cytokine-cytokine receptor interaction, rheumatoid arthritis, inflammatory bowel disease and chemokine signaling pathways. The GO analysis showed that DEGs IL-17A and IFNG were enriched to the biological process of upregulating IL-23 production. PPI showed that IL-17A and IFNG had biological functions of regulating cytokine production and myeloid white blood cell differentiation. Conclusion Bioinformatics analysis showed that the protein products encoded by overexpressed genes CCL4, CSF2RB, CCL5, IFNG and EPSTI1 in Th1/17 cells were potential functional effectors of Th1/17 cells. Th1/17 cells could produce IFN-γ and IL-17A, which act on macrophages and dendritic cells (DCs) derived from myeloid white blood cells, thus promoting the differentiation of macrophages and DCs and the production of IL-23. IL-23 promotes trans-differentiation of Th17 cells into Th1/17 cells.


Assuntos
Diferenciação Celular , Mapas de Interação de Proteínas , Células Th1/citologia , Células Th17/citologia , Biologia Computacional , Ontologia Genética , Humanos
2.
Adv Exp Med Biol ; 1197: 45-54, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31732933

RESUMO

New strategies are critically needed to counter uncontrolled periodontal infection and inflammation in obesity-associated type 2 diabetes (T2D). However, mechanisms that explain the relationship between periodontitis (PD) and T2D remain poorly understood. Several lines of evidence indicate that destructive immune responses potentiate periodontitis (PD) in T2D. B cells are abundant in periodontal lesions, and our data show that B cells are required for PD in obese/insulin resistant but not lean/normoglycemic mice. In mice and in people, T2D-primed B cells supported Th17 cytokine profiles, but B cells had a modest effect on T-cell function in samples from normoglycemic individuals. Given the recently appreciated importance of Th17 cells in PD outside a T2D milieu, our data raise the possibility that B cells indirectly promote T2D-potentiated PD through support of Th17 cells, which in turn directly promote PD.Data herein thereby suggest unexpected mechanisms that explain the clinical observation that T2D potentiates PD.


Assuntos
Diabetes Mellitus Tipo 2 , Periodontite , Células Th17 , Animais , Diabetes Mellitus Tipo 2/complicações , Inflamação , Camundongos , Obesidade/fisiopatologia , Periodontite/complicações , Periodontite/patologia , Células Th17/citologia
3.
Adv Exp Med Biol ; 1197: 107-117, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31732938

RESUMO

T helper 17 (Th17) cells were first described as a T helper subset involved in the pathogenesis of experimental autoimmune inflammation. Since then, these cells have been described as orchestrators of immunopathology in several human inflammatory conditions including psoriasis, rheumatoid arthritis, and inflammatory bowel disease. More recently, the crucial role of Th17 cells in the regulation of immunity and protection of barrier sites has been unveiled. In the present work, we review the available evidence regarding Th17 cells in health and disease with a focus on the oral mucosa and their role in periodontitis pathogenesis. Recent mechanistic studies in animal models have demonstrated that interleukin-17A (IL-17A) and Th17 cells are critical mediators for alveolar bone destruction during periodontal inflammation. Observations in a cohort of patients with naturally occurring impaired Th17 cell differentiation supported these findings. However, interventional studies are needed to conclusively implicate Th17 cells in the immunopathogenesis of human alveolar bone and tissue destruction that characterize periodontitis.


Assuntos
Periodontite , Células Th17 , Animais , Diferenciação Celular , Modelos Animais de Doenças , Humanos , Inflamação , Interleucina-17/imunologia , Periodontite/fisiopatologia , Células Th17/citologia , Células Th17/imunologia
4.
Zhongguo Zhong Yao Za Zhi ; 44(15): 3330-3334, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31602891

RESUMO

Triptolide( TP) is isolated from the traditional Chinese medicine Tripterygium wilfordii,which exhibits notable immuneregulative effect. Th17 cells involve in inflammatory response and Treg cells contribute to immune tolerance. They both play an important role in immune response. Previous studies have investigated that TP induced hepatic Th17/Treg imbalance. However,the effect of TP on spleen Th17/Treg cells remains unclear. Therefore,the aim of present study was to investigate the effect of TP on Th17/Treg cells in spleen. In this study,the effect of TP on the proliferation of splenic lymphocyte was detected by cytotoxicity test in vitro. After different concentrations of TP( 2. 5,5,20,40 nmol·L~(-1)) were given to splenic lymphocyte,cytokines secreted from the supernatant of splenic lymphocyte were detected by cytometric bead array,and the expression of suppressor of cytokine signaling( SOCS) mRNA was detected by qRT-PCR. Female C57 BL/6 mice were continuously observed for 24 h after treatment of 500 µg·kg-1 TP. The effects of TP on the splenic tissue structure and the percentage of Th17/Treg cells were examined. The results showed that the IC50 of TP was19. 6 nmol·L~(-1) in spleen lymphocytes. TP inhibited the secretion of IL-2 and IL-10 and induced the expression of SOCS-1/3 mRNA in spleen lymphocytes at the dosage of 2. 5 and 5 nmol·L~(-1) after 24 h in vitro. Administration of TP at dosage of 500 µg·kg-1 had no significant spleen toxicity in vivo. TP treatment increased the percentage of Th17 cells after 12 h and inhibited the proportion of Treg cells after 12 and 24 h. In conclusion,TP reduced the secretion of IL-2 and IL-10 through SOCS-1/3 signaling pathway,thereby induced the percentage of Th17 cells and inhibited the percentage of Treg cells.


Assuntos
Diterpenos/farmacologia , Fenantrenos/farmacologia , Baço/efeitos dos fármacos , Linfócitos T Reguladores/citologia , Células Th17/citologia , Animais , Citocinas/metabolismo , Compostos de Epóxi/farmacologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais , Baço/citologia , Proteína 1 Supressora da Sinalização de Citocina/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo
5.
Nat Commun ; 10(1): 4698, 2019 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-31619674

RESUMO

T helper 17 (Th17) cells have crucial functions in mucosal immunity and the pathogenesis of several chronic inflammatory diseases. The lineage-specific transcription factor, RORγt, encoded by the RORC gene modulates Th17 polarization and function, as well as thymocyte development. Here we define several regulatory elements at the human RORC locus in thymocytes and peripheral CD4+ T lymphocytes, with CRISPR/Cas9-guided deletion of these genomic segments supporting their role in RORγt expression. Mechanistically, T cell receptor stimulation induces cyclosporine A-sensitive histone modifications and P300/CBP acetylase recruitment at these elements in activated CD4+ T cells. Meanwhile, NFAT proteins bind to these regulatory elements and activate RORγt transcription in cooperation with NF-kB. Our data thus demonstrate that NFAT specifically regulate RORγt expression by binding to the RORC locus and promoting its permissive conformation.


Assuntos
Regulação da Expressão Gênica , Fatores de Transcrição NFATC/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Elementos Reguladores de Transcrição/genética , Células Th17/metabolismo , Timócitos/metabolismo , Ativação Transcricional , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/metabolismo , Sistemas CRISPR-Cas , Linhagem da Célula , Citometria de Fluxo , Células HEK293 , Código das Histonas , Humanos , Células Jurkat , Células Th17/citologia , Timócitos/citologia , Fatores de Transcrição de p300-CBP/metabolismo
6.
Int J Mol Sci ; 20(17)2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31454926

RESUMO

Interleukin (IL)-23 is considered an effective therapeutic target for the treatment of psoriasis because of the crucial role of the IL-23/IL-17 axis in the pathogenesis of psoriasis, and it has recently been reported to be involved in ILC3 cell differentiation. In this study, we report that eukaryotically expressed rhIL23R-CHR/Fc, as an endogenous extracellular receptor analogue, could be a natural antagonist in an imiquimod (IMQ)-induced psoriasis-like mouse model, including the antagonizing effect of suppressed inflammation in the skin lesion, decreased production of pro-inflammatory cells, and reduced the expression of pro-inflammatory factors. The rhIL23R-CHR/Fc fusion protein inhibits both innate immune and adaptive immune-mediated inflammatory responses. These findings shed light on rhIL23R-CHR/Fc as a promising candidate therapy for the treatment of psoriasis.


Assuntos
Imunidade Inata/efeitos dos fármacos , Psoríase/etiologia , Psoríase/metabolismo , Proteínas Recombinantes de Fusão/farmacologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Células Th17/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Feminino , Humanos , Fragmentos Fc das Imunoglobulinas/genética , Linfócitos/imunologia , Linfócitos/metabolismo , Camundongos , Domínios e Motivos de Interação entre Proteínas , Psoríase/tratamento farmacológico , Psoríase/patologia , Receptores de Interleucina/química , Receptores de Interleucina/genética , Proteínas Recombinantes de Fusão/genética , Pele/efeitos dos fármacos , Pele/imunologia , Pele/metabolismo , Pele/patologia , Células Th17/citologia
7.
Biomed Khim ; 65(4): 347-355, 2019 Jun.
Artigo em Russo | MEDLINE | ID: mdl-31436177

RESUMO

We studied the effect of the native (non-recombinant) alpha-fetoprotein (AFP) on differentiation, proliferation, and cytokine profile of activated helper T cells 17 (Th17). The object of the study was a culture of isolated by immunomagnetic separation helper T cells (CD4+), induced into the Th17 phenotype by using TCR-activator and proinflammatory cytokines (IL-1ß and IL-6). AFP had not significant effect on the frequency of Th17 cells (ROR-γτ+) in the helper T cell culture, and did not affect proliferation of these cells, as measured by Ki-67 expression. Evaluation of the cytokine profile of culture supernatants by using the Luminex xMAP technology, revealed that AFP did not affect the levels of IL-4, IL-5, IL-7, IL-8, IL-10, IL-17, IFN-γ and TNF-α, but at concentrations of 50 IU/ml and 100 IU/ml it increased IL-2 production by activated helper T cells. At the same time, AFP suppressed the synthesis of G-CSF and GM-CSF (10 IU/ml), but stimulated the production of CCL4/MIP-1ß (100 IU/ml) and CCL2/MCP-1 chemokines (10 IU/ml and 50 IU/ml).


Assuntos
Citocinas/metabolismo , Linfócitos T Auxiliares-Indutores/citologia , Células Th17/citologia , alfa-Fetoproteínas/farmacologia , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Humanos , Fenótipo
8.
Arch Oral Biol ; 107: 104483, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31351339

RESUMO

OBJECTIVES: The persistence of T-helper 17 (Th17) cells has been shown to support chronic inflammation and mediate tissue destruction in periodontitis. However, little is known regarding the underlying mechanisms that regulate Th17 cell differentiation in the periodontal inflammatory context. The objective of this study was to explore the possible effect and mechanism of lipopolysaccharide (LPS) from Porphyromonas gingivalis on Th17 cell differentiation. METHODS: Activated human CD4+CD45RA+ naïve T cells were stimulated with different doses of LPS from virulent and avirulent P. gingivalis strains combined with Th17 driven cytokines in vitro. Flow cytometry was used to analyze the differentiation ratio of Th17 cells. IL-17A protein expression and IL-17, retinoid-related orphan receptor C (RORC) and toll-like receptor 2 (TLR2) mRNA transcription were analysed by ELISA and real-time qPCR, respectively. The role of TLR2 in Th17 cell differentiation was further confirmed by TLR2 blocking assay. RESULTS: LPS from P. gingivalis (Pg-LPS) up-regulated Th17 cell differentiation ratios, expression of IL-17 and RORC mRNA, and IL-17 concentration in culture supernatant, with 0.1 µg/mL LPS from the virulent P. gingivalis strain being the most effectively. Furthermore, Pg-LPS also up-regulated expression of TLR2 on T cells during Th17 differentiation, and the differentiation was attenuated by treatment with TLR2 antibody. CONCLUSIONS: These results suggest that Pg-LPS promotes Th17 cell differentiation in vitro, and TLR2 signalling may be involved in this process. LPS from the virulent P. gingivalis strain up-regulated Th17 cell differentiation more effectively, which may be associated with the pathogenicity of different P. gingivalis strains.


Assuntos
Diferenciação Celular , Lipopolissacarídeos/farmacologia , Porphyromonas gingivalis/química , Células Th17/citologia , Receptor 2 Toll-Like/metabolismo , Células Cultivadas , Citocinas/imunologia , Humanos , Periodontite , Células Th17/efeitos dos fármacos
9.
Int J Mol Sci ; 20(14)2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31295952

RESUMO

Innate immunity represents the semi-specific first line of defense and provides the initial host response to tissue injury, trauma, and pathogens. Innate immunity activates the adaptive immunity, and both act highly regulated together to establish and maintain tissue homeostasis. Any dysregulation of this interaction can result in chronic inflammation and autoimmunity and is thought to be a major underlying cause in the initiation and progression of highly prevalent immune-mediated inflammatory diseases (IMIDs) such as psoriasis, rheumatoid arthritis, inflammatory bowel diseases among others, and periodontitis. Th1 and Th2 cells of the adaptive immune system are the major players in the pathogenesis of IMIDs. In addition, Th17 cells, their key cytokine IL-17, and IL-23 seem to play pivotal roles. This review aims to provide an overview of the current knowledge about the differentiation of Th17 cells and the role of the IL-17/IL-23 axis in the pathogenesis of IMIDs. Moreover, it aims to review the association of these IMIDs with periodontitis and briefly discusses the therapeutic potential of agents that modulate the IL-17/IL-23 axis.


Assuntos
Inflamação/imunologia , Inflamação/metabolismo , Interleucina-17/metabolismo , Interleucina-23/metabolismo , Periodontite/etiologia , Periodontite/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Animais , Doenças Autoimunes/complicações , Autoimunidade , Diferenciação Celular , Citocinas/metabolismo , Gerenciamento Clínico , Suscetibilidade a Doenças/imunologia , Humanos , Imunomodulação , Mediadores da Inflamação/metabolismo , Periodontite/diagnóstico , Periodontite/terapia , Transdução de Sinais , Células Th17/citologia
10.
Nat Immunol ; 20(8): 1059-1070, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31308541

RESUMO

Dysfunction of virus-specific CD4+ T cells in chronic human infections is poorly understood. We performed genome-wide transcriptional analyses and functional assays of CD4+ T cells specific for human immunodeficiency virus (HIV) from HIV-infected people before and after initiation of antiretroviral therapy (ART). A follicular helper T cell (TFH cell)-like profile characterized HIV-specific CD4+ T cells in viremic infection. HIV-specific CD4+ T cells from people spontaneously controlling the virus (elite controllers) robustly expressed genes associated with the TH1, TH17 and TH22 subsets of helper T cells. Viral suppression by ART resulted in a distinct transcriptional landscape, with a reduction in the expression of genes associated with TFH cells, but persistently low expression of genes associated with TH1, TH17 and TH22 cells compared to the elite controller profile. Thus, altered differentiation is central to the impairment of HIV-specific CD4+ T cells and involves both gain of function and loss of function.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Expressão Gênica/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Células Th1/patologia , Células Th17/patologia , Perfilação da Expressão Gênica , Infecções por HIV/virologia , Humanos , Receptores CXCR5/metabolismo , Células Th1/citologia , Células Th1/imunologia , Células Th17/citologia , Células Th17/imunologia , Carga Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
11.
EMBO J ; 38(16): e101397, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31290162

RESUMO

NOD-like receptor (NLR) family CARD domain containing 3 (NLRC3), an intracellular member of NLR family, is a negative regulator of inflammatory signaling pathways in innate and adaptive immune cells. Previous reports have shown that NLRC3 is expressed in dendritic cells (DCs). However, the role of NLRC3 in DC activation and immunogenicity is unclear. In the present study, we find that NLRC3 attenuates the antigen-presenting function of DCs and their ability to activate and polarize CD4+ T cells into Th1 and Th17 subsets. Loss of NLRC3 promotes pathogenic Th1 and Th17 responses and enhanced experimental autoimmune encephalomyelitis (EAE) development. NLRC3 negatively regulates the antigen-presenting function of DCs via p38 signaling pathway. Vaccination with NLRC3-overexpressed DCs reduces EAE progression. Our findings support that NLRC3 serves as a potential target for treating adaptive immune responses driving multiple sclerosis and other autoimmune disorders.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Células Dendríticas/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Animais , Apresentação do Antígeno , Autoimunidade , Linfócitos T CD4-Positivos/transplante , Polaridade Celular , Células Cultivadas , Células Dendríticas/citologia , Encefalomielite Autoimune Experimental/terapia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Camundongos , Transdução de Sinais , Células Th1/citologia , Células Th1/metabolismo , Células Th17/citologia , Células Th17/metabolismo , Vacinação
12.
Medicine (Baltimore) ; 98(24): e15952, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31192933

RESUMO

This study aims at analyzing the Th17/Treg cell level and clinical characteristics of the peripheral blood of patients with Sjogren's syndrome (SS) complicated with primary biliary cirrhosis (PBC) so as to deepen the understanding of this disease and seek for its possible onset mechanism.A retrospective analysis was conducted on the clinical data of 24 patients [8 (33%) males and 16 (67%) females] with SS complicated with primary biliary cirrhosis, 50 patients with primary SS and 93 healthy volunteers. These patients were divided into 3 groups: experimental group (SS+PBC), control group (SS) and healthy group. Then, peripheral blood was collected and flow cytometry was conducted to detect level of Th17 cells and Treg cells. A fully automatic biochemical detector was used to detect the corresponding liver function index. The correlation analysis was made based on the clinical manifestations and biochemical characteristics.Compared with the healthy group and control group, the experimental group had the highest Th17/Treg cell ratio, and Th17 cell frequency was significantly increased (P <.05). Furthermore, ALT, AST, ALP, γ-GT, TBIL, and other indexes were positively correlated to the Th17/Treg ratio (P <.05).Th17/Treg cell level and its ratio in peripheral blood of patients with SS complicated with primary biliary cirrhosis were significantly unbalanced, indicating that Th17 cells participate in the onset of this disease to a large extent. Furthermore, the Th17/Treg ratio has a certain correlation with some of the liver function indexes, on which a stratified analysis could be made furtherly according to the seriousness of the conditions.


Assuntos
Cirrose Hepática Biliar/sangue , Síndrome de Sjogren/sangue , Linfócitos T Reguladores/citologia , Células Th17/citologia , Adulto , Idoso , Biomarcadores/metabolismo , Estudos de Casos e Controles , Feminino , Citometria de Fluxo , Humanos , Fígado/metabolismo , Cirrose Hepática Biliar/metabolismo , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Síndrome de Sjogren/complicações , Síndrome de Sjogren/metabolismo
13.
Cells ; 8(6)2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31167379

RESUMO

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). T helper (Th) 17 lymphocytes play a role in the pathogenesis of MS. Indeed, Th17 cells are abundant in the cerebrospinal fluid and peripheral blood of MS patients and promote pathogenesis in the mouse model of MS. To gain insight into the function of Th17 cells in MS, we tested whether Th17 cells polarized from naïve CD4 T cells of healthy donors and MS patients display different features. To this end, we analysed several parameters that typify the Th17 profile during the differentiation process of naïve CD4 T cells obtained from relapsing-remitting (RR)-MS patients (n = 31) and healthy donors (HD) (n = 28). Analysis of an array of cytokines produced by Th17 cells revealed that expression of interleukin (IL)-21, tumour necrosis factor (TNF)-ß, IL-2 and IL-1R1 is significantly increased in Th17 cells derived from MS patients compared to healthy donor-derived cells. Interestingly, IL-1R1 expression is also increased in Th17 cells circulating in the blood of MS patients compared to healthy donors. Since IL-2, IL-21, TNF-ß, and IL-1R1 play a crucial role in the activation of immune cells, our data indicate that high expression of these molecules in Th17 cells from MS patients could be related to their high inflammatory status.


Assuntos
Esclerose Múltipla Recidivante-Remitente/patologia , Células Th17/metabolismo , Adulto , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Interleucinas/metabolismo , Linfotoxina-alfa/metabolismo , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/imunologia , Esclerose Múltipla Recidivante-Remitente/metabolismo , Receptores Tipo I de Interleucina-1/metabolismo , Células Th17/citologia
14.
J Immunol Res ; 2019: 1418251, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31061831

RESUMO

The outbreak of avian influenza A (H7N9) virus infection, with a high mortality rate, has caused concern worldwide. Although interleukin-17- (IL-17-) secreting CD4+ T (Th17) and CD8+ T (Tc17) cells have been proven to play crucial roles in influenza virus infection, the changes and roles of Th17 and Tc17 cells in immune responses to H7N9 infection remain controversial. In this study, we found that the frequencies of Th17 and Tc17 cells among human peripheral blood mononuclear cells (PBMCs) as well as IL-17A protein and mRNA levels were markedly decreased in patients with acute H7N9 virus infection. A positive correlation was found between the serum IL-17A level and the frequency of these two cell groups. In vitro infection experiments revealed decreased Th17 and Tc17 cell frequency and IL-17A levels at various time points postinfection. In addition, Th17 cells were the predominant sources of IL-17A in PBMCs of patients infected with H7N9 virus. Taken together, our results indicate immune disorder in acute H7N9 infection and a restored Th17 and Tc17 cell frequency might serve as a biomarker for predicting recovery in patients infected with this virus.


Assuntos
Linfócitos T CD8-Positivos/citologia , Influenza Humana/imunologia , Interleucina-17/sangue , Células Th17/citologia , Doença Aguda , Adulto , Idoso , Animais , Células Cultivadas , Feminino , Humanos , Subtipo H7N9 do Vírus da Influenza A , Masculino , Pessoa de Meia-Idade , Aves Domésticas/virologia
15.
Chin J Nat Med ; 17(4): 252-263, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31076129

RESUMO

Astragalus membranaceus may be a potential therapy for childhood asthma but its driving mechanism remains elusive. The main components of A. membranaceus were identified by HPLC. The children with asthma remission were divided into two combination group (control group, the combination of budesonide and terbutaline) and A. membranaceus group (treatment group, the combination of budesonide, terbutaline and A. membranaceus). The therapeutic results were compared between two groups after 3-month therapy. Porcine peripheral blood mononuclear cells (PBMCs) were isolated from venous blood by using density gradient centrifugation on percoll. The levels of FoxP3, EGF-ß, IL-17 and IL-23 from PBMCs and serum IgE were measured. The relative percentage of Treg/Th17 cells was determined using flow cytometry. The main components of A. membranaceus were calycosin-7-O-glucoside, isoquercitrin, ononin, calycosin, quercetin, genistein, kaempferol, isorhamnetin and formononetin, all of which may contribute to asthma therapy. Lung function was significantly improved in the treatment group when compared with a control group (P < 0.05). The efficacy in preventing the occurrence of childhood asthma was higher in the treatment group than the control group (P < 0.05). The levels of IgE, IL-17 and IL-23 were reduced significantly in the treatment group when compared with the control group, while the levels of FoxP3 and TGF-ß were increased in the treatment group when compared with the control group (P < 0.05). A. membranaceus increased the percentage of Treg cells and reduced the percentage of Th17 cells. A. membranaceus is potential natural product for improving the therapeutic efficacy of combination therapy of budesonide and terbutaline for the children with asthma remission by modulating the balance of Treg/Th17 cells.


Assuntos
Asma/tratamento farmacológico , Astragalus propinquus/química , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/farmacologia , Fatores Imunológicos/administração & dosagem , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Animais , Asma/imunologia , Budesonida/administração & dosagem , Células Cultivadas , Criança , Pré-Escolar , Citocinas/metabolismo , Feminino , Humanos , Fatores Imunológicos/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/fisiologia , Masculino , Suínos , Linfócitos T Reguladores/citologia , Terbutalina/administração & dosagem , Células Th17/citologia , Resultado do Tratamento
16.
Cancer Sci ; 110(7): 2100-2109, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31100180

RESUMO

The presence of interleukin (IL)-17-producing T cells has recently been reported in non-small cell lung cancer (NSCLC) patients. However, the long-term prognostic significance of these populations in NSCLC patients remains unknown. In the present study, we collected peripheral blood from 82 NSCLC patients and 22 normal healthy donors (NC). Percentages of IL-17-producing CD4+ T (Th17), CD8+ T (Tc17) and γδT cells (γδT17) were measured to determine their association with clinical outcomes and overall survival (OS) in NSCLC. All NSCLC patients were followed up until July 2018. Median follow-up time was 13.5 months (range 1-87 months). The 3- and 5-year survival rate was 27% and 19.6%, respectively. We found that Th17 cells and γδT17 cells were significantly increased, whereas Tc17 cells were markedly decreased in patients with NSCLC compared with those in NC. In addition, Th17 cells were significantly positively associated with T helper type 1 cells (Th1), whereas γδT17 cells were significantly negatively associated with γδT + interferon (IFN)-γ+ cells. High percentages of peripheral Tc17 cells were significantly associated with favorable 5-year OS (P = .025), especially in patients with early TNM stage (P = .016). Furthermore, high percentages of peripheral Th17 cells were positively associated with favorable 5-year OS in patients with late TNM stage (P = .002). However, no significant association was observed between γδT17 cells and OS, regardless of the TNM stage. In conclusion, our findings suggest that enhanced Th17 and reduced Tc17 cells in the peripheral blood could be a significant predictor of a favorable prognosis for NSCLC patients.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Interleucina-17/metabolismo , Neoplasias Pulmonares/patologia , Linfócitos T/citologia , Células Th17/citologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Estudos de Casos e Controles , Feminino , Humanos , Interferon gama/metabolismo , Linfócitos Intraepiteliais/citologia , Linfócitos Intraepiteliais/imunologia , Neoplasias Pulmonares/imunologia , Contagem de Linfócitos , Masculino , Estadiamento de Neoplasias , Prognóstico , Análise de Sobrevida , Linfócitos T/imunologia , Células Th1/citologia , Células Th1/imunologia , Células Th17/imunologia
17.
PLoS One ; 14(4): e0215963, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31022269

RESUMO

The Tec kinases ITK (interleukin-2-inducible T-cell kinase) and RLK (resting lymphocyte kinase) are critical components of the proximal TCR/CD3 signal transduction machinery, and data in mice suggest that ITK negatively modulates regulatory T cell (TREG) differentiation. However, whether Tec kinases modulate TREG development and/or function in human T cells remains unknown. Using a novel self-delivery siRNA platform (sdRNA), we found that ITK knockdown in human primary naïve peripheral blood CD4 T cells increased Foxp3+ expression under both TREG and T helper priming conditions. TREG differentiated under ITK knockdown conditions exhibited enhanced expression of the co-inhibitory receptor PD-1 and were suppressive in a T cell proliferation assay. ITK knockdown decreased IL-17A production in T cells primed under Th17 conditions and promoted Th1 differentiation. Lastly, a dual ITK/RLK Tec kinase inhibitor did not induce Foxp3 in CD4 T cells, but conversely abrogated Foxp3 expression induced by ITK knockdown. Our data suggest that targeting ITK in human T cells may be an effective approach to boost TREG in the context of autoimmune diseases, but concomitant inhibition of other Tec family kinases may negate this effect.


Assuntos
Diferenciação Celular , Fatores de Transcrição Forkhead/metabolismo , Proteínas Tirosina Quinases/metabolismo , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/enzimologia , Polaridade Celular , Humanos , Ativação Linfocitária/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Células Th1/citologia , Células Th17/citologia , Regulação para Cima/efeitos dos fármacos
18.
Inflammation ; 42(4): 1401-1412, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30945038

RESUMO

Acute lung injury (ALI) is a syndrome characterized by damage to the alveolar-capillary wall, pulmonary edema and recruitment of inflammatory cells. Previous studies have indicated that aquaporin 4 (AQP4) plays a key role in brain edema formation and resolution. However, the role of AQP4 in the development and progression of ALI is not clear and needs to be resolved. In our current study, mouse ALI was induced by intratracheal instillation of lipopolysaccharide (LPS) at a concentration of 30 mg/kg. For the inhibition of AQP4, 200 mg/kg of TGN-020 (Sigma, USA) was administered intraperitoneally every 6 h starting at 30 min before intratracheal instillation of LPS. The results of the present work indicate, for the first time, that mice treated with the AQP4 inhibitor TGN-020 had attenuated LPS-induced lung injury, reduced proinflammatory cytokine release (including IL-1α, IL-1ß, IL-6, TNF-α, IL-23, and IL-17A), and an improved survival rate. Additionally, we found that the attenuated lung injury scores, increased survival rate, and decreased BALF total protein concentration in TGN-020-treated mice were all abrogated by rIL-17A administration. Furthermore, TGN-020 treatment downregulated the phosphorylation of PI3K and Akt, increased the expression of SOCS3, and decreased the expression of p-STAT3 and RORγt. In conclusion, inhibition of AQP4 by TGN-020 has a detectable protective effect against lung tissue injury induced by LPS, and this effect is associated with inhibition of IL-17A through the downregulation of the PI3K/Akt signaling pathway and upregulation of SOCS3 protein.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Aquaporina 4/antagonistas & inibidores , Proliferação de Células/efeitos dos fármacos , Interleucina-17/antagonistas & inibidores , Células Th17/efeitos dos fármacos , Animais , Lipopolissacarídeos/farmacologia , Camundongos , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Proteína Oncogênica v-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Células Th17/citologia , Tiadiazóis/farmacologia
19.
PLoS One ; 14(4): e0214596, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30934008

RESUMO

Stenotrophomonas maltophilia (S. maltophilia), a multi-drug resistant opportunistic pathogen, is associated with nosocomial and community-acquired infections. Preventive and therapeutic strategies for such infections are greatly needed. In this study, sequence alignment analysis revealed that Outer membrane protein A (OmpA) was highly conserved among S. maltophilia strains but shared no significant similarity with human and mouse proteomes. In mice, intranasal immunization with S. maltophilia recombinant OmpA (rOmpA) without additional adjuvant induced sustained mucosal and systemic rOmpA-specific antibody responses. Treatment with rOmpA stimulated significantly higher levels of secretion of IFN-γ, IL-2, and IL-17A (All P<0.05) from the primary splenocytes isolated from rOmpA-immunized mice than from the primary splenocytes isolated from PBS-immunized mice. Furthermore, mice immunized with rOmpA showed significantly reduced bacterial burden in the lung and reduced levels of pro-inflammatory cytokines (TNF-α and IL-6) in bronchoalveolar lavage fluid (BALF) 24 hours after intranasal S. maltophilia infection, indicating that immunization with rOmpA may have protective effects against S. maltophilia challenge in mice. Our findings suggest that intranasal immunization with rOmpA may induce mucosal and systemic immune responses in mice, trigger Th1- and Th17-mediated cellular immune responses, and thus stimulate host immune defense against S. maltophilia infection. These results also demonstrate that intranasal vaccination may offer an alternative approach to current strategies since it induces a mucosal as well as a systemic immune response.


Assuntos
Proteínas da Membrana Bacteriana Externa/imunologia , Vacinas Bacterianas/imunologia , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Infecções por Bactérias Gram-Negativas/prevenção & controle , Stenotrophomonas maltophilia , Adjuvantes Imunológicos , Administração Intranasal , Animais , Anticorpos Antibacterianos/imunologia , Formação de Anticorpos , Proteínas da Membrana Bacteriana Externa/administração & dosagem , Vacinas Bacterianas/administração & dosagem , Líquido da Lavagem Broncoalveolar , Biologia Computacional , Feminino , Interleucina-6/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/imunologia , Análise de Sequência de DNA , Baço/imunologia , Células Th1/citologia , Células Th17/citologia , Fator de Necrose Tumoral alfa/metabolismo
20.
Mol Med Rep ; 19(5): 4011-4018, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30896815

RESUMO

The aim of the present study was to confirm the effect of 2% rebamipide ophthalmic solution on a scopolamine­induced dry eye (DE) mouse model, and to investigate its effect on the ratio of T helper cell 17 (Th17)/regulatory T cell (Treg) numbers. C57BL/6 mice received subcutaneous injections of scopolamine and were exposed to a low­humidity environment in order to establish a DE model. Rebamipide eye drops (2%) administered four times daily for 2 weeks, significantly reduced the corneal staining scores and increased the tear film breakup time and tear production in the DE mice. Pathologically, the rebamipide restored the histological changes induced by DE in the cornea, conjunctiva and lacrimal gland. At a molecular level, it downregulated pro­inflammatory and upregulated anti­inflammatory cytokines in the conjunctiva and lacrimal gland. Furthermore, the increased Th17 and Treg levels were restored following treatment with rebamipide. In conclusion, the anti­inflammatory and Th17/Treg balance­preserving effects of rebamipide may contribute to the treatment of DE in mice.


Assuntos
Alanina/análogos & derivados , Síndromes do Olho Seco/patologia , Quinolonas/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Alanina/farmacologia , Alanina/uso terapêutico , Animais , Túnica Conjuntiva/patologia , Córnea/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Síndromes do Olho Seco/tratamento farmacológico , Síndromes do Olho Seco/imunologia , Feminino , Aparelho Lacrimal/patologia , Camundongos , Camundongos Endogâmicos C57BL , Soluções Oftálmicas/farmacologia , Soluções Oftálmicas/uso terapêutico , Quinolonas/uso terapêutico , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/metabolismo , Células Th17/citologia , Células Th17/metabolismo
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