Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.042
Filtrar
1.
Cancer Sci ; 110(10): 3068-3078, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432577

RESUMO

The programmed cell death 1/programmed cell death 1 ligand 1 pathway was successfully targeted in cancer immunotherapy. Elevated interleukin-17 (IL-17), which is known in autoimmune diseases, has recently been recognized in cancer patients. We investigated the role of IL-17 in the regulation of expression of programmed cell death 1 ligand 1 in ovarian cancer by evaluating changes in the number of IL-17-producing cluster of differentiation 4 helper T cells (Th17) and γδT cells (γδT17) in PBMC of 52 gynecological cancer patients (including 30 ovarian cancer patients) and 18 healthy controls. The occupancy ratio of Th17 and γδT17 was higher in ovarian cancer and endometrial cancer patients than in controls, determined by multi-color flow cytometry (Th17: P < 0.0001 and P = 0.0002, respectively; γδT17: P = 0.0020 and P = 0.0084, respectively). IL-17 mRNA level was elevated in PBMC of ovarian cancer patients (P = 0.0029), as measured by RT-PCR. The neutrophil-to-lymphocyte ratio, which is a prognostic biomarker of ovarian cancer, correlated with Th17 occupancy ratio in patients (P = 0.0068). We found that programmed cell death 1 ligand 1 expression and its associated factors (IL-6 and phospho-signal transducer and activator of transcription 3) were induced by IL-17 in an ovarian cancer cell line. These results suggest that increased Th17 counts and IL-17 level, which correlated with high neutrophil-to-lymphocyte ratio and programmed cell death 1 ligand 1 expression, are potential biomarkers for poor prognosis in ovarian cancer and likely indications for application of programmed cell death 1 ligand 1 pathway inhibitors.


Assuntos
Antígeno B7-H1/genética , Neoplasias do Endométrio/genética , Interleucina-16/metabolismo , Interleucina-17/genética , Neoplasias Ovarianas/genética , Fator de Transcrição STAT3/metabolismo , Adulto , Idoso , Estudos de Casos e Controles , Linhagem Celular Tumoral , Neoplasias do Endométrio/imunologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Interleucina-17/metabolismo , Linfócitos Intraepiteliais/metabolismo , Neoplasias Ovarianas/imunologia , Fosforilação , Prognóstico , Células Th17/metabolismo , Regulação para Cima
2.
Korean J Parasitol ; 57(3): 225-232, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31284344

RESUMO

Innate lymphoid cells (ILCs) are key players during an immune response at the mucosal surfaces, such as lung, skin, and gastrointestinal tract. Giardia lamblia is an extracellular protozoan pathogen that inhabits the human small intestine. In this study, ILCs prepared from the lamina propria of mouse small intestine were incubated with G. lamblia trophozoites. Transcriptional changes in G. lamblia-exposed ILCs resulted in identification of activation of several immune pathways. Secretion of interleukin (IL)-17A, IL-17F, IL-1ß, and interferon-γ was increased, whereas levels of IL-13, IL-5, and IL22, was maintained or reduced upon exposure to G. lamblia. Goup 3 ILC (ILC3) was found to be dominant amongst the ILCs, and increased significantly upon co-cultivation with G. lamblia trophozoites. Oral inoculation of G. lamblia trophozoites into mice resulted in their presence in the small intestine, of which, the highest number of parasites was detected at the 5 days-post infection. Increased ILC3 was observed amongst the ILC population at the 5 days-post infection. These findings indicate that ILC3 from the lamina propria secretes IL-17 in response to G. lamblia, leading to the intestinal pathology observed in giardiasis.


Assuntos
Giardia lamblia/fisiologia , Giardíase/imunologia , Interleucina-17/imunologia , Linfócitos/imunologia , Membrana Mucosa/parasitologia , Animais , Células Cultivadas , Giardíase/genética , Giardíase/parasitologia , Humanos , Imunidade Inata , Interleucina-17/genética , Linfócitos/parasitologia , Camundongos , Camundongos Endogâmicos C57BL , Membrana Mucosa/imunologia
3.
Artigo em Chinês | MEDLINE | ID: mdl-31256521

RESUMO

Objective: To explore the relationship between polymorphisms of interleukin 17(IL-17) gene (rs4711998, rs763780) and the susceptibility of pneumoconiosis, and to provide a basis for prevention of high-risk groups of pneumoconiosis. Methods: A total of 219 pneumoconiosis patients and 242 workers without pneumoconiosis were enrolled in the study. All subjects were photographed with high undulating X-rays anterior chest radiographs, diagnosed according to diagnostic criteria for pneumoconiosis. We collected 3 ml of peripheral venous blood of the study subjects. Polymorphism in IL-17A rs4711998 and IL-17F rs763780 locus were evaluated by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results: The IL-17A rs4711998 locus has AA, AG and GG genotypes, there was no the significant difference between case and control groups (P>0.05). IL-17F rs763780 had AA, AG and GG genotypes, there was a significant difference between case and control groups (P<0.05). Allele A and allele G were statistically significant difference between the case group and the control group (P<0.05). Conclusion: No relationship was found between IL-17A gene polymorphisms at rs4711998 and silicosis. IL-17F rs763780 locus gene polymorphism is associated with susceptibility to pneumoconiosis. AG genotype and G allele may have a protective effect.


Assuntos
Interleucina-17/genética , Pneumoconiose , Estudos de Casos e Controles , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Pneumoconiose/genética , Polimorfismo de Nucleotídeo Único
4.
Zhonghua Yi Xue Za Zhi ; 99(24): 1870-1874, 2019 Jun 25.
Artigo em Chinês | MEDLINE | ID: mdl-31269582

RESUMO

Objective: To investigate the association between single nucleotide polymorphisms (SNP) of IL-17A (rs2275913) and IL-17F (rs763780) genes and susceptibility to knee osteoarthritis (KOA) in Chinese Han and Tibetan populations. Methods: A case-control study was conducted. Total of 122 Han KOA patients and 124 Han healthy controls and 76 Tibetan KOA patients and 68 Tibetan healthy controls in Qinghai Province were selected between 2015 and 2017. SNP typing was performed on four groups of rs2275913 and rs763780 polymorphisms by polymerease chain reaction (PCR)-sequencing to detect IL-17A and IL-17 F genotype frequencies and allele frequencies. The t test was used to compare data between groups. Results: The genotype AA frequency of IL-17A (rs2275913) was significantly different between the Han KOA and the control group (OR=2.625, P=0.016). Compared with the frequency of allele A in healthy control group, the allele A frequency in Han KOA group was significantly higher(OR=1.445, P=0.047); the genotype frequency of IL-17A,however,was comparable between the KOA and the healthy control in Tibetan population (OR=1.696, 1.355, both P>0.05); there were also not difference in the IL-17F (rs763780) genotype frequency and allele frequency between the Han KOA and Tibetan KOA groups and two control groups,respectively (OR=1.346, 1.126, both P>0.05). Conclusion: It is highly likely that the pathogenesis of KOA in Chinese Han population is positively related to the genotype AA and allele A of IL-17A (rs2275913).


Assuntos
Interleucina-17/genética , Osteoartrite do Joelho , Polimorfismo de Nucleotídeo Único , Grupo com Ancestrais do Continente Asiático , Estudos de Casos e Controles , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Osteoartrite do Joelho/genética
5.
J Agric Food Chem ; 67(24): 6773-6784, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31154759

RESUMO

The aim of this study was to evaluate the immunomodulatory effects of atractylodin, a polyethylene alkyne, on the maturation of bone marrow-derived dendritic cells (BM-DC) as well as its antirheumatic effect on collagen-induced arthritis (CIA) in DBA/1 mice. Our results indicate that atractylodin effectively suppressed the secretion of pro-inflammatory cytokines, expression of costimulatory molecules, and p38 MAPK, ERK, and NF-κBp65 signaling pathways in LPS-incubated dendritic cells (DCs). Additionally, the proliferation and cytokine secretion (IFN-γ and IL-17A) of CD8+ and CD4+ T cells were reduced. In a murine CIA model, intraperitoneal injection of atractylodin significantly alleviated the severity of the disease progression, as indicated by reduced paw swelling, clinical arthritis scores, and pathological changes of joint tissues. In addition, the overall proliferation of T cells stimulated by type II collagen and the abundance of Th1 and Th17 in the spleens were also significantly decreased with atractylodin treatments. Furthermore, atractylodin significantly downregulated the expression levels of CD40, CD80, and CD86 of DCs in the spleens. In conclusion, this study shows for the first time that atractylodin has potential to manipulate the maturation of BM-DCs and should be further explored as a therapeutic agent in the treatment of rheumatoid arthritis (RA).


Assuntos
Artrite Reumatoide/tratamento farmacológico , Atractylodes/química , Diferenciação Celular/efeitos dos fármacos , Colágeno Tipo II/efeitos adversos , Células Dendríticas/citologia , Furanos/administração & dosagem , Animais , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/imunologia , Artrite Reumatoide/fisiopatologia , Proliferação de Células/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Modelos Animais de Doenças , Humanos , Interferon gama/genética , Interferon gama/imunologia , Interleucina-17/genética , Interleucina-17/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Células Th17/imunologia , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/imunologia
6.
Vet Res ; 50(1): 48, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31221216

RESUMO

Enterotoxigenic Escherichia coli (ETEC) are an important cause of post-weaning diarrhea (PWD) in piglets. The IL-17 cytokine family is well known to play important roles in the host defense against bacterial infections at the mucosa. Previously, we reported the potential role of IL-17A in clearing an ETEC infection in piglets. IL-17C, another member of the IL-17 family, is highly expressed in the intestinal epithelium, however, its role during an ETEC infection is still unclear. In this study, we demonstrate that F4+ ETEC induce IL-17C mRNA and protein expression in intestinal tissues as well as in porcine intestinal epithelial cells (IPEC-J2). This IL-17C production is largely dependent on TLR5 signaling in IPEC-J2 cells. Both F4+ ETEC infection and exogenous IL-17C increased the expression of antimicrobial peptides and tight junction proteins, such as porcine beta-defensin (pBD)-2, claudin-1, claudin-2 and occludin in IPEC-J2 cells. Taken together, our data demonstrate that TLR5-mediated IL-17C expression in intestinal epithelial cells enhances mucosal host defense responses in a unique autocrine/paracrine manner in the intestinal epithelium against ETEC infection.


Assuntos
Escherichia coli Enterotoxigênica/fisiologia , Infecções por Escherichia coli/veterinária , Interleucina-17/genética , Doenças dos Suínos/genética , Receptor 5 Toll-Like/genética , Animais , Infecções por Escherichia coli/genética , Infecções por Escherichia coli/metabolismo , Infecções por Escherichia coli/microbiologia , Interleucina-17/metabolismo , Mucosa Intestinal/fisiopatologia , Suínos , Doenças dos Suínos/metabolismo , Doenças dos Suínos/microbiologia , Receptor 5 Toll-Like/metabolismo
7.
Virol J ; 16(1): 79, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-31196204

RESUMO

BACKGROUND: The increased levels of blood cytokines is the main immunopathological process that were attributed to severe clinical outcomes in cases of influenza A, influenza B and people with influenza-like illness (ILI). Functional genetic polymorphisms caused by single nucleotide polymorphisms (SNPs) in inflammatory cytokines genes can influence their functions either qualitatively or quantitatively, which is associated with the possibility of severe influenza infections. The aim of the present case-control study was to investigate the association of polymorphisms in inflammatory cytokines genes with influenza patients and ILI group in an Iranian population. METHODS: Total number of 30 influenza B, 50 influenza A (H1N1) and 96 ILI inpatient individuals were confirmed by Real-time RT-PCR and HI assays. The genotype determination was assessed for defined SNPs in IL-1ß, IL-17, IL-10 and IL-28 genes. RESULTS: The frequencies of the IL-1ß rs16944 (P = 0.007) and IL-17 rs2275913 (P = 0.006) genotypes were associated with severe influenza disease, while the frequencies of IL-10 rs1800872 and IL-28 rs8099917 were not associated with the disease (P > 0.05). Also, the absence of A allele in IL-17 rs2275913 SNP increased the risk of influenza A (H1N1) infection (P = 0.008). CONCLUSIONS: This study demonstrated that influenza A- (H1N1) and B-infected patients and also ILI controls have different profiles of immune parameters, and individuals carrying the specific cytokine-derived polymorphisms may show different immune responses towards severe outcome.


Assuntos
Citocinas/genética , Influenza Humana/epidemiologia , Influenza Humana/imunologia , Polimorfismo de Nucleotídeo Único , Adulto , Alelos , Estudos de Casos e Controles , Citocinas/imunologia , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Vírus da Influenza A Subtipo H1N1 , Vírus da Influenza B , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-17/genética , Interleucina-17/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Irã (Geográfico)/epidemiologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
8.
Acta Virol ; 63(2): 186-194, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31230447

RESUMO

Little is known about the role of genetic variation in the genes for cytokines and susceptibility to viral infection especially torque teno virus (TTV) following allogeneic hematopoietic stem cell transplantation. In this study, the association between interleukin-12, interleukin-17, interleukin-10 (IL-12,-17,-10) and tumor necrosis factor-α (TNF-α) polymorphisms was evaluated in patients with TTV infection who underwent allogeneic hematopoietic stem cell transplantation from South of Iran. The single nucleotide polymorphisms in the cytokine genes including IL-12 (-1188A/C), IL-17 (-197G/A), IL-10 (-1082G/A, -819C/T and -592C/A) and TNF-α (-308 G/A) were analyzed by PCR-RFLP methods. While our results did not show any association between IL-17, IL-12 and IL-10 (-819C/T and -1082G/A) polymorphisms and TTV infection status, heterozygote genotype of IL-10 (-592C/A) had direct correlation with TTV infection and A allele of TNF-α (-308G/A) showed a protective effect against TTV infection (P = 0.05 and P = 0.025, respectively). Within the group of patients who experienced acute graft-versus-host disease, the AA genotype and the A allele of IL-17 (-197 G/A) were significantly higher in non-infected patients compared to infected ones (P = 0.024 and P = 0.057, respectively). It was also observed that among infected patients, the GG genotype of IL-17 and AA genotype of TNF-α were significantly increased in hematopoietic stem cell transplanted patients with low grade (grade I+II) acute graft-versus-host disease compared to high grade (grade III and IV) disease (P = 0.056 and P = 0.056, respectively). Taken together, genetic variation of IL-10 (-592C/A) and TNF-α (-308G/A) genes might be associated with susceptibility to TTV infection post hematopoietic stem cell transplantation. Keywords: TNF-α; interleukins; torque teno virus (TTV); hematopoietic stem cell transplantation (HSCT); graft versus host disease (GvHD).


Assuntos
Citocinas , Infecções por Vírus de DNA , Transplante de Células-Tronco Hematopoéticas , Torque teno virus , Citocinas/genética , Infecções por Vírus de DNA/genética , Humanos , Interleucina-10/genética , Interleucina-12/genética , Interleucina-17/genética , Irã (Geográfico) , Fator de Necrose Tumoral alfa/genética
9.
MBio ; 10(3)2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31088921

RESUMO

Staphylococcus aureus is a major cause of skin and soft tissue infections and aggravator of the inflammatory skin disease atopic dermatitis (AD [eczema]). Epicutaneous exposure to S. aureus induces Th17 responses through skin Langerhans cells (LCs), which paradoxically contribute to host defense but also to AD pathogenesis. The molecular mechanisms underlying the interaction between S. aureus and LCs are poorly understood. Here we demonstrate that human LCs directly interact with S. aureus through the pattern recognition receptor langerin (CD207). Human, but not mouse, langerin interacts with S. aureus through the conserved ß-N-acetylglucosamine (GlcNAc) modifications on wall teichoic acid (WTA), thereby discriminating S. aureus from other staphylococcal species. Importantly, the specific S. aureus WTA glycoprofile strongly influences the level of proinflammatory cytokines that are produced by in vitro-generated LCs. Finally, in a murine epicutaneous infection model, S. aureus strongly upregulated transcripts of Cxcl1, Il6, and Il17, which required the presence of both human langerin and WTA ß-GlcNAc. Our findings provide molecular insight into the unique proinflammatory capacities of S. aureus in relation to skin inflammation.IMPORTANCE The bacterium Staphylococcus aureus is an important cause of skin infections and is also associated with the occurrence and severity of eczema. Langerhans cells (LCs), a specific subset of skin immune cells, participate in the immune response to S. aureus, but it is yet unclear how LCs recognize S. aureus Therefore, we investigated the molecular mechanism underlying the interaction between LCs and S. aureus We identified that wall teichoic acid, an abundant polymer on the S. aureus surface, is recognized by langerin, a receptor unique to LCs. This interaction allows LCs to discriminate S. aureus from other related staphylococcal species and initiates a proinflammatory response similar to that observed in patients with eczema. Our data therefore provide important new insights into the relationship between S. aureus, LCs, and eczema.


Assuntos
Antígenos CD/genética , Antígenos de Superfície/genética , Células de Langerhans/imunologia , Lectinas Tipo C/genética , Lectinas de Ligação a Manose/genética , Infecções Estafilocócicas/imunologia , Ácidos Teicoicos/imunologia , Acetilglucosamina , Animais , Antígenos CD/imunologia , Antígenos de Superfície/imunologia , Células Cultivadas , Citocinas/genética , Citocinas/imunologia , Humanos , Inflamação , Interleucina-17/genética , Interleucina-17/imunologia , Lectinas Tipo C/imunologia , Lectinas de Ligação a Manose/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Pele/imunologia , Pele/microbiologia , Staphylococcus aureus
10.
PLoS Negl Trop Dis ; 13(5): e0007247, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31107882

RESUMO

Cutaneous leishmaniasis (CL) is a parasitic disease causing chronic, ulcerating skin lesions. Most humans infected with the causative Leishmania protozoa are asymptomatic. Leishmania spp. are usually introduced by sand flies into the dermis of mammalian hosts in the presence of bacteria from either the host skin, sand fly gut or both. We hypothesized that bacteria at the dermal inoculation site of Leishmania major will influence the severity of infection that ensues. A C57BL/6 mouse ear model of single or coinfection with Leishmania major, Staphylococcus aureus, or both showed that single pathogen infections caused localized lesions that peaked after 2-3 days for S. aureus and 3 weeks for L. major infection, but that coinfection produced lesions that were two-fold larger than single infection throughout 4 weeks after coinfection. Coinfection increased S. aureus burdens over 7 days, whereas L. major burdens (3, 7, 28 days) were the same in singly and coinfected ears. Inflammatory lesions throughout the first 4 weeks of coinfection had more neutrophils than did singly infected lesions, and the recruited neutrophils from early (day 1) lesions had similar phagocytic and NADPH oxidase capacities. However, most neutrophils were apoptotic, and transcription of immunomodulatory genes that promote efferocytosis was not upregulated, suggesting that the increased numbers of neutrophils may, in part, reflect defective clearance and resolution of the inflammatory response. In addition, the presence of more IL-17A-producing γδ and non-γδ T cells in early lesions (1-7 days), and L. major antigen-responsive Th17 cells after 28 days of coinfection, with a corresponding increase in IL-1ß, may recruit more naïve neutrophils into the inflammatory site. Neutralization studies suggest that IL-17A contributed to an enhanced inflammatory response, whereas IL-1ß has an important role in controlling bacterial replication. Taken together, these data suggest that coinfection of L. major infection with S. aureus exacerbates disease, both by promoting more inflammation and neutrophil recruitment and by increasing neutrophil apoptosis and delaying resolution of the inflammatory response. These data illustrate the profound impact that coinfecting microorganisms can exert on inflammatory lesion pathology and host adaptive immune responses.


Assuntos
Coinfecção/imunologia , Interleucina-17/imunologia , Leishmania major/fisiologia , Leishmaniose Cutânea/imunologia , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/fisiologia , Animais , Coinfecção/microbiologia , Coinfecção/parasitologia , Coinfecção/patologia , Feminino , Humanos , Interleucina-17/genética , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Leishmania major/genética , Leishmania major/isolamento & purificação , Leishmaniose Cutânea/genética , Leishmaniose Cutânea/parasitologia , Leishmaniose Cutânea/patologia , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/imunologia , Infecções Estafilocócicas/genética , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/patologia , Staphylococcus aureus/genética , Staphylococcus aureus/isolamento & purificação , Células Th17/imunologia
11.
Mol Med Rep ; 19(6): 4906-4918, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059089

RESUMO

The six members of the interleukin (IL)­17 gene family (IL­17A­F) have been identified in various types of cancer. Although lung cancer is the leading cause of cancer­related death worldwide and IL­17A was found to play a critical role in lung cancer, there is little knowledge concerning the association between the other five members of the IL­17 family and lung cancer. The genetic mutations and expression of IL­17 family members were investigated using the Catalogue of Somatic Mutations in Cancer (COSMIC), Oncomine, and cBio Cancer Genomics Portal (cBioPortal) databases. Prognostic values and interaction networks of the members were assessed by the Kaplan­Meier plotter, Search Tool for the Retrieval of Interacting Genes (STRING) database and FunRich software. The results found that, across 5,238 lung cancer patients in the cBioPortal, the results of IL­17 family gene alteration frequencies and types showed that IL­17A, IL­25 and IL­17F exhibited higher alteration frequencies (2, 2.1 and 1.9%, respectively), and gene amplification accounted for the majority of changes. IL­17B, IL­17C and IL­17D exhibited lower alteration frequencies (0.8, 1.1 and 1.1%, respectively), and deep deletion accounted for the majority of changes. The rates of point mutations in IL­17A through IL­17F family genes in lung cancer were 0.66, 0.18, 0.13, 0.09, 0.27 and 0.44% in the COSMIC database. Within the Oncomine database, five datasets showed that IL­17D was significantly decreased in lung cancer, while no dataset showed a significant difference in the expression of IL­17A, IL­17B, IL­17C, IL­25 or IL17­F between lung cancer and normal controls. The frequencies of IL­17A, IL­17B and IL­17C mRNA upregulation in lung squamous cell carcinoma were lower than those in lung adenocarcinoma (2.7, 1.9 and 2.1%, respectively), whereas the frequencies of IL­17D, IL­25 and IL­17F mRNA upregulation were higher in lung squamous cell carcinoma than those in lung adenocarcinoma (3, 6 and 6%, respectively). IL­17A and IL­17B were unrelated to overall survival (p=0.11; P=0.17), whereas IL­17C, IL­17D, IL­25 and IL­17F influenced prognosis (P=0.0023, P=0.0059, P=0.039 and P=0.0017, respectively) according to the Kaplan­Meier plotter. Moreover, the expression level of IL­17C was the highest in lung tissues, and IL­17 family genes mainly participate in the 'IFN­Î³ pathway' according to the STRING database and Funrich software. In conclusion, we performed the first comprehensive investigation of the IL­17 gene family in lung cancer, including gene mutation, mRNA expression levels, prognostic values and network pathways. Our results revealed that IL­17 family gene mutation rates were in general low and that amplification and deep deletion were the main mutation type. The expression and function of IL­17A and IL­17B in lung cancer are still not fully elucidated and warrant research with larger sample sizes. IL­17D was significantly decreased in lung cancer and was correlated with better OS. Studies of IL­17C­F in lung cancer are limited. Further experimental studies on the association between IL­17D and lung cancer progression are needed to identify more effective therapeutic targets for lung cancer.


Assuntos
Interleucina-17/genética , Neoplasias Pulmonares/patologia , Adenocarcinoma/genética , Adenocarcinoma/patologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Bases de Dados Factuais , Deleção de Genes , Frequência do Gene , Genótipo , Humanos , Interleucina-17/metabolismo , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Mutação Puntual , Prognóstico , Mapas de Interação de Proteínas , Regulação para Cima
12.
Infect Immun ; 87(7)2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31061145

RESUMO

Tissue-resident memory T cells (TRM cells) are a novel population of tissue-restricted antigen-specific T cells. TRM cells are induced by pathogens and promote host defense against secondary infections. Although TRM cells cannot be detected in circulation, they are the major memory CD4+ and CD8+ T-cell population in tissues in mice and humans. Murine models of CD8+ TRM cells have shown that CD8+ TRM cells maintain tissue residency via CD69 and though tumor growth factor ß-dependent induction of CD103. In contrast to CD8+ TRM cells, there are few models of CD4+ TRM cells. Thus, much less is known about the factors regulating the induction, maintenance, and host defense functions of CD4+ TRM cells. Citrobacter rodentium is known to induce IL-17+ and IL-22+ CD4+ T cells (Th17 and Th22 cells, respectively). Moreover, data from IL-22 reporter mice show that most IL-22+ cells in the colon 3 months after C. rodentium infection are CD4+ T cells. This collectively suggests that C. rodentium may induce CD4+ TRM cells. Here, we demonstrate that C. rodentium induces a population of IL-17A+ CD4+ T cells that are tissue restricted and antigen specific, thus meeting the criteria of CD4+ TRM cells. These cells expand and are a major source of IL-22 during secondary C. rodentium infection, even before the T-cell phase of the host response in primary infection. Finally, using FTY 720, which depletes circulating naive and effector T cells but not tissue-restricted T cells, we show that these CD4+ TRM cells can promote host defense.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Citrobacter rodentium/imunologia , Infecções por Enterobacteriaceae/imunologia , Animais , Citrobacter rodentium/genética , Infecções por Enterobacteriaceae/genética , Infecções por Enterobacteriaceae/microbiologia , Humanos , Memória Imunológica , Interleucina-17/genética , Interleucina-17/imunologia , Interleucinas/genética , Interleucinas/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Células Th17/imunologia
13.
Nat Immunol ; 20(5): 534-545, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30962593

RESUMO

Lymph-node (LN) stromal cell populations expand during the inflammation that accompanies T cell activation. Interleukin-17 (IL-17)-producing helper T cells (TH17 cells) promote inflammation through the induction of cytokines and chemokines in peripheral tissues. We demonstrate a critical requirement for IL-17 in the proliferation of LN and splenic stromal cells, particularly fibroblastic reticular cells (FRCs), during experimental autoimmune encephalomyelitis and colitis. Without signaling via the IL-17 receptor, activated FRCs underwent cell cycle arrest and apoptosis, accompanied by signs of nutrient stress in vivo. IL-17 signaling in FRCs was not required for the development of TH17 cells, but failed FRC proliferation impaired germinal center formation and antigen-specific antibody production. Induction of the transcriptional co-activator IκBζ via IL-17 signaling mediated increased glucose uptake and expression of the gene Cpt1a, encoding CPT1A, a rate-limiting enzyme of mitochondrial fatty acid oxidation. Hence, IL-17 produced by locally differentiating TH17 cells is an important driver of the activation of inflamed LN stromal cells, through metabolic reprogramming required to support proliferation and survival.


Assuntos
Proliferação de Células , Fibroblastos/imunologia , Interleucina-17/imunologia , Linfonodos/imunologia , Células Estromais/imunologia , Animais , Formação de Anticorpos/genética , Formação de Anticorpos/imunologia , Sobrevivência Celular/genética , Sobrevivência Celular/imunologia , Células Cultivadas , Colite/genética , Colite/imunologia , Colite/metabolismo , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Fibroblastos/metabolismo , Interleucina-17/genética , Interleucina-17/metabolismo , Linfonodos/citologia , Linfonodos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Receptores de Interleucina-17/genética , Receptores de Interleucina-17/imunologia , Receptores de Interleucina-17/metabolismo , Células Estromais/metabolismo , Células Th17/imunologia , Células Th17/metabolismo
14.
Genes Immun ; 20(5): 415-425, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31000797

RESUMO

Chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, spondyloarthritis, and psoriasis cause significant morbidity and are a considerable burden for the patients in terms of pain, impaired function, and diminished quality of life, as well as for society, because of the associated high health-care costs and loss of productivity. Our limited understanding of the pathogenic mechanisms involved in these diseases currently hinders early diagnosis and the development of more specific and effective therapies. The past years have been marked by considerable progress in our insight of the genetic basis of many diseases. In particular, genome-wide association studies (GWAS) performed with thousands of patients have provided detailed information about the genetic variants associated with a large number of chronic inflammatory diseases. These studies have brought to the forefront many genes linked to signaling pathways that were not previously known to be involved in pathogenesis, pointing to new directions in the study of disease mechanisms. GWAS also provided fundamental evidence for a key role of the immune system in the pathogenesis of these diseases, because many of the identified loci map to genes involved in different immune processes. However, the mechanisms by which disease-associated genetic variants act on disease development and the targeted cell populations remain poorly understood. The challenge of the post-GWAS era is to understand how these variants affect pathogenesis, to allow translation of genetic data into better diagnostics and innovative treatment strategies. Here, we review recent results that document the importance of the IL-23/IL-17 pathway for the pathogenesis of several chronic inflammatory diseases and summarize data that demonstrate how therapeutic targeting of this pathway can benefit affected patients.


Assuntos
Predisposição Genética para Doença , Doenças do Sistema Imunitário/genética , Interleucina-17/imunologia , Interleucina-23/imunologia , Animais , Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Humanos , Doenças do Sistema Imunitário/tratamento farmacológico , Doenças do Sistema Imunitário/imunologia , Interleucina-17/genética , Interleucina-23/genética
15.
Inflamm Res ; 68(6): 493-509, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30972425

RESUMO

OBJECTIVE AND DESIGN: To evaluate the potency of RORγt blockade for treatment of Inflammatory Bowel Disease (IBD), the efficacy of TAK-828F, a novel RORγt inverse agonist, in anti-TNF-α mAb non-responsive mouse colitis model and effect of TAK-828F on IL-17 production in peripheral mononuclear blood cells (PBMCs) of anti-TNF-α naive and treatment-failure patients of IBD was investigated. METHODS AND RESULTS: The colitis model showed Th17-dependent pathogenicity and response to anti-IL-12/23p40 monoclonal antibody (mAb), but no response to anti-TNF-α mAb. In the model, TAK-828F, at oral dosages of 1 and 3 mg/kg, inhibited progression of colitis and reduced the immune reaction that characterize Th17 cells. Anti-IL-17A mAb showed neither efficacy nor change in the T cell population and colonic gene expression in the model. In the normal mouse, a 4-week treatment of TAK-828F at 30 mg/kg did not severely reduce lymphocyte cell counts in peripheral and intestinal mucosa, which was observed in RORγ-/- mice. TAK-828F strongly inhibited IL-17 gene expression with IC50 values from 21.4 to 34.4 nmol/L in PBMCs from anti-TNF mAb naive and treatment-failure patients of IBD. CONCLUSIONS: These results indicate that RORγt blockade would provide an effective approach for treating refractory patients with IBD by blocking IL-23/Th17 pathway.


Assuntos
Acetatos/farmacologia , Acetatos/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Leucócitos Mononucleares/efeitos dos fármacos , Naftiridinas/farmacologia , Naftiridinas/uso terapêutico , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Adolescente , Adulto , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Células Cultivadas , Colo/efeitos dos fármacos , Colo/imunologia , Colo/patologia , Modelos Animais de Doenças , Feminino , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia , Interleucina-17/antagonistas & inibidores , Interleucina-17/genética , Interleucina-17/imunologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Leucócitos Mononucleares/imunologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Knockout , Camundongos SCID , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto Jovem
16.
Cell Physiol Biochem ; 52(2): 354-367, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30816679

RESUMO

BACKGROUND/AIMS: Although a cross-talk between immune and endocrine systems has been well established, the precise pathways by which these signals co-regulate pro- and antiinflammatory responses on antigen-presenting cells remain poorly understood. In this work we investigated the mechanisms by which triiodothyronine (T3) controls T cell activity via dendritic cell (DC) modulation. METHODS: DCs from wild-type (WT) and IL-6-deficient mice were pulsed with T3. Cytokine production and programmed death protein ligands (PD-L) 1 and 2 expression were assayed by flow cytometry and ELISA. Interferon-regulatory factor-4 (IRF4) expression was evaluated by RT-qPCR and flow cytometry. The ability of DCs to stimulate allogenic splenocytes was assessed in a mixed lymphocyte reaction and the different profile markers were analyzed by flow cytometry and ELISA. For in vivo experiments, DCs treated with ovalbumin and T3 were injected into OTII mice. Proliferation, cytokine production, frequency of FoxP3+ regulatory T (Treg) cells and PD-1+ cells were determined by MTT assay, ELISA and flow cytometry, respectively. RESULTS: T3 endows DCs with pro-inflammatory potential capable of generating IL-17-dominant responses and down-modulating expression of PD-L1 and 2. T3-stimulated WT-DCs increased the proportion of IL-17-producing splenocytes, an effect which was eliminated when splenocytes were incubated with T3-treated DCs derived from IL-6-deficient mice. Enhanced IL-17 expression was recorded in both, CD4- and CD4+ populations and involved the IRF-4 pathway. Particularly, γδ-T cells but not natural killer (NK), NKT, B lymphocytes nor CD8+ T cells were the major source of IL-17-production from CD4- cells. Moreover, T3-conditioned DCs promoted a decrease of the FoxP3+ Treg population. Furthermore, T3 down-modulated PD-1 expression on CD4- cells thereby limiting inhibitory signals driven by this co-inhibitory pathway. Thus, T3 acts at the DC level to drive proinflammatory responses in vitro. Accordingly, we found that T3 induces IL-17 and IFNγ-dominant antigen-specific responses in vivo. CONCLUSION: These results emphasize the relevance of T3 as an additional immune-endocrine checkpoint and a novel therapeutic target to modulate IL-17-mediated pro-inflammatory responses.


Assuntos
Células Dendríticas/imunologia , Interleucina-17/imunologia , Transdução de Sinais/efeitos dos fármacos , Tri-Iodotironina/farmacologia , Animais , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Células Dendríticas/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/imunologia , Interleucina-17/genética , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Camundongos , Camundongos Knockout , Proteína 2 Ligante de Morte Celular Programada 1/genética , Proteína 2 Ligante de Morte Celular Programada 1/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/genética , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Transdução de Sinais/imunologia
17.
Gene ; 702: 107-113, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-30898714

RESUMO

Osteopontin (OPN) is involved in the regulation of the immune response and is accused in the pathogenesis of several autoimmune diseases including systemic lupus erythematosus (SLE). An obvious link between OPN and T cells, particularly T helper 17 cells is reported, where OPN produced by dendritic cells supports interleukin-17 (IL-17) expression, contributing to pathology of autoimmune disorders. The aim of the study was to investigate the association of genotypes and alleles frequencies of OPN 9250 (rs1126616) and IL-17A 197 (rs2275913) genes polymorphisms with their serum levels, susceptibility, disease activity and severity in Egyptian SLE patients. A total of 80 SLE patients and 80 healthy subjects were enrolled. The PCR-RFLP technique was used to detect OPN 9250 C/T and IL-17A 197 G/A genes polymorphisms. Serum OPN and IL- 17 levels were measured by the enzyme-linked immunosorbent assay. OPN TT genotype and T allele were significantly detected in SLE patients more than controls (P = 0.003, P < 0.001 respectively). IL-17A AA genotype showed non-significant higher frequency in SLE patients than in their controls (P = 0.07). While only the A allele of IL-17A polymorphism was significantly elevated in patients (P = 0.048). There was statistical significant association between OPN CT and TT genotypes and both renal and mucocutaneous manifestations. Also IL-17A AG and AA genotypes was significantly associated with renal, mucocutaneous in addition to the hematological manifestations. Serum OPN levels were significantly increased with TT genotype while serum IL-17 levels were significantly increased with AA genotype. Disease activity and severity scores were significantly elevated with both OPN TT and IL-17A AA genotypes. In conclusion, OPN 9250 C/T and IL-17A 197 G/A genes polymorphisms and their serum levels seemed to have a role in pathogenesis of SLE.


Assuntos
Interleucina-17/genética , Lúpus Eritematoso Sistêmico/genética , Osteopontina/genética , Adulto , Estudos de Casos e Controles , Egito , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Interleucina-17/sangue , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/diagnóstico , Masculino , Osteopontina/sangue , Adulto Jovem
18.
Microbiol Immunol ; 63(3-4): 139-146, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30851127

RESUMO

IL-17is one of the most important inflammatory cytokines that stimulate immunity responses in humans infected with Brucella species, acting as a regulator that reduces release of γ-IFN, thus increasing resistance to brucellosis. Gene polymorphisms in the regulatory regions of cytokine-encoding genes affect the amountsof cytokines produced and play a fundamental role in infectious diseases. The aim of this study was to determine the association between IL-17 gene polymorphisms and susceptibility to brucellosis. In this case-control study, 86 patients with brucellosis and 86 healthy persons in Hamadan, western Iran, from September 2014 to September 2016, were included. IL-17 genetic variants at positions rs4711998 A/G, rs8193036 C/T, rs3819024 A/G, rs2275913 A/G, rs3819025 A/G, rs8193038 A/G, rs3804513 A/T, rs1974226 A/G and rs3748067 A/G were analyzed by restriction fragment length polymorphism-PCR. Serum IL-17 titers were measured by sandwich ELISA. GG genotypes at positions rs4711998 and rs3748067 were present significantly more frequently in patients with brucellosis than in controls (P < 0.05). The AA genotype at positions rs4711998, rs2275913 and rs3748067 and GG genotype at position rs19744226 were present significantly more frequently in controls than in the patient group. These results suggest that the AA genotype at positions rs3748067, rs3819025 and rs4711998 and GG genotype at position rs3819024 are likely protective factors against brucellosis, whereas the GG genotype at positions rs3748067, rs3819025 and rs4711998 and AA genotype at position rs3819024 may be risk factors against the disease. No significant relationships were found between serum IL-17 titers and genotypes of the single-nucleotide polymorphisms.


Assuntos
Brucelose/genética , Predisposição Genética para Doença , Interleucina-17/genética , Adulto , Brucella/imunologia , Brucelose/imunologia , Brucelose/microbiologia , Estudos de Casos e Controles , Feminino , Frequência do Gene/genética , Genótipo , Humanos , Interleucina-17/sangue , Irã (Geográfico) , Masculino , Pessoa de Meia-Idade , Polimorfismo de Fragmento de Restrição , Polimorfismo de Nucleotídeo Único/genética
19.
Iran J Immunol ; 16(1): 53-61, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30864555

RESUMO

BACKGROUND: Interleukin 17 (IL-17) is a pro-inflammatory cytokine that plays an important role in cancer pathogenesis. OBJECTIVE: To investigate the association of two IL-17 gene polymorphisms (rs2275913 and rs763780), as well as IL-17 serum levels with susceptibility to Basal Cell Carcinoma (BCC) of skin. METHODS: Two hundred subjects with BCC and 200 healthy controls were recruited. DNA was extracted from peripheral blood leukocytes and genotypes were determined using PCR-RFLP methods. Serum levels were assessed by ELISA. RESULTS: At position rs2275913 in IL-17A, the frequencies of GG, AG and AA genotypes were 99 (49.5%), 76 (38%) and 25 (12.5%) in patients and 97 (48.5%), 84 (42%) and 19 (9.5%) in the control group. The distribution of AA, GA and GG genotypes at position rs763780 in IL-17F were 166 (83%), 34 (17%) and 0 (0%) in patients and 158 (79%), 40 (20%) and 2 (1%) in the control group. Haplotype analysis by Arlequin software package revealed that GA haplotype was the most frequent haplotype in both groups. No significant differences were found in alleles, genotypes, and haplotypes frequencies between study groups at both positions (P>0.05). While no difference in IL-17 serum levels was observed between individuals with different genotypes, statistical analysis showed higher IL-17A serum levels, but not IL-17F, in patients compared to controls (0.65 ± 0.11 and 0.03 ± 0.02 pg/ml), respectively, (P<0.001). CONCLUSION: Our findings do not support the association of rs763780 and rs2275913 gene polymorphisms in IL-17gene with susceptibility of Iranians with BCC. Increased IL-17A serum levels may still play a role in pathogenesis of BCC.


Assuntos
Carcinoma Basocelular/sangue , Carcinoma Basocelular/genética , Interleucina-17/sangue , Interleucina-17/genética , Polimorfismo de Nucleotídeo Único , Neoplasias Cutâneas/sangue , Neoplasias Cutâneas/genética , Idoso , Alelos , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances
20.
Infect Immun ; 87(6)2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30910792

RESUMO

CD4+ T-cell mechanisms are implied in protection against pneumococcal colonization; however, their target antigens and function are not well defined. In contrast to high-throughput protein arrays for serology, basic antigen tools for CD4+ T-cell studies are lacking. Here, we evaluate the potential of a bioinformatics tool for in silico prediction of immunogenicity as a method to reveal domains of pneumococcal proteins targeted by human CD4+ T cells. For 100 pneumococcal proteins, CD4+ T-cell immunogenicity was predicted based on HLA-DRB1 binding motifs. For 20 potentially CD4+ T-cell immunogenic proteins, epitope regions were verified by testing synthetic peptides in T-cell assays using peripheral blood mononuclear cells from healthy adults. Peptide pools of 19 out of 20 proteins evoked T-cell responses. The most frequent responses (detectable in ≥20% of donors tested) were found to SP_0117 (PspA), SP_0468 (putative sortase), SP_0546 (BlpZ), SP_1650 (PsaA), SP_1923 (Ply), SP_2048 (conserved hypothetical protein), SP_2216 (PscB), and SPR_0907 (PhtD). Responding donors had diverging recognition patterns and profiles of signature cytokines (gamma interferon [IFN-γ], tumor necrosis factor alpha [TNF-α], interleukin-13 [IL-13], and/or IL-17A) against single-epitope regions. Natural HLA-DR-restricted presentation and recognition of a predicted SP_1923-derived epitope were validated through the isolation of a CD4+ T-cell clone producing IFN-γ, TNF-α, and IL-17A in response to the synthetic peptide, whole protein, and heat-inactivated pneumococcus. This proof of principle for a bioinformatics tool to identify pneumococcal protein epitopes targeted by human CD4+ T cells provides a peptide-based strategy to study cell-mediated immune mechanisms for the pneumococcal proteome, advancing the development of immunomonitoring assays and targeted vaccine approaches.


Assuntos
Proteínas de Bactérias/química , Proteínas de Bactérias/imunologia , Linfócitos T CD4-Positivos/imunologia , Infecções Pneumocócicas/microbiologia , Streptococcus pneumoniae/imunologia , Proteínas de Bactérias/genética , Epitopos de Linfócito T/química , Epitopos de Linfócito T/genética , Epitopos de Linfócito T/imunologia , Humanos , Interferon gama/genética , Interferon gama/imunologia , Interleucina-17/genética , Interleucina-17/imunologia , Leucócitos Mononucleares/imunologia , Infecções Pneumocócicas/genética , Infecções Pneumocócicas/imunologia , Domínios Proteicos , Streptococcus pneumoniae/química , Streptococcus pneumoniae/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA