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1.
Zhonghua Kou Qiang Yi Xue Za Zhi ; 55(8): 565-570, 2020 Aug 09.
Artigo em Chinês | MEDLINE | ID: mdl-32842348

RESUMO

Objetive: To investigate whether the methylation patterns of the interleukin-4 (IL-4) gene promoter changed and whether environmental factors affected the methylation level of IL-4 gene in the peripheral blood of patients with recurrent aphthous ulcer (RAU). Methods: Totally 20 patients, who were diagnosed with RAU, were recruited from May 2018 to May 2019 in the Department of Stomatology, First Hospital of Shanxi Medical University in the study (RAU group), including 12 females and 8 males, with mean age of 16-35 years. During the same period, 20 healthy volunteers matching the age and gender of the RAU group were selected from the medical personnel of the same hospital as the healty control group, including 11 females and 9 males, with mean age of 15-35 years. Peripheral blood samples of two groups were collected and the methylation levels of the IL-4 promoter were detected by bisulfite sequencing PCR (BSP). The IL-4 promoter methylation level of each sample was analyzed by direct sequencing and the IL-4 mRNA level was detected by real-time quantitative PCR. The data obtained were statistically analyzed. Results: The IL-4 gene promoter fragment contained 10 CPG sites from -1400 to -1625 bp. The methylation rates of CPG(-1556), CPG(-1483), CPG(-1479)and 10 CPG sites were significantly higher in RAU group ï¼»(32.0±19.9)%, (53.0±13.4)%, (46.0±19.8)% and (39.3±12.4)%ï¼½ than in healthy control group ï¼»(20.0±3.2)%, (35.5±12.3)%, (28.0±14.4)% and (32.6±5.8)%ï¼½, with statistically significant differences (P<0.05). The relative expression of IL-4 mRNA in the peripheral blood of RAU patients (1.0±0.1) was significantly lower than that of the healthy control group (1.5±0.2) (P<0.01). There was a significant negative correlation between the overall methylation rate of IL-4 gene promoter and the relative expression level of IL-4 mRNA in RAU group (r=-0.494, P<0.05). In the multivariate analysis, smoking, vitamin B12 and folic acid in the RAU group were significantly correlated with the overall methylation rate of the IL-4 gene promoter (P<0.01). Conclusions: The hypermethylation of IL-4 promoter in RAU patients may be related to the reduction of IL-4 gene transcription. Vitamin B12, folic acid and smoking may affect IL-4 gene methylation in peripheral blood of RAU patients.


Assuntos
Estomatite Aftosa/genética , Adolescente , Adulto , Metilação de DNA , Feminino , Humanos , Interleucina-4/genética , Masculino , Regiões Promotoras Genéticas , RNA Mensageiro , Adulto Jovem
2.
PLoS One ; 15(6): e0234493, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32520953

RESUMO

Multiple sclerosis (MS) is a neurodegenerative disease characterized by demyelination and inflammation. Dysregulated lipid metabolism and mitochondrial dysfunction are hypothesized to play a key role in MS. Carnitine Palmitoyl Transferase 1 (CPT1) is a rate-limiting enzyme for beta-oxidation of fatty acids in mitochondria. The therapeutic effect of pharmacological CPT1 inhibition with etomoxir was investigated in rodent models of myelin oligodendrocyte glycoprotein- and myelin basic protein-induced experimental autoimmune encephalitis (EAE). Mice receiving etomoxir showed lower clinical score compared to placebo, however this was not significant. Rats receiving etomoxir revealed significantly lower clinical score and lower body weight compared to placebo group. When comparing etomoxir with interferon-ß (IFN-ß), IFN-ß had no significant therapeutic effects, whereas etomoxir treatment starting at day 1 and 5 significantly improved the clinical scores compared to the IFN-ß and the placebo group. Immunohistochemistry and image assessments of brain sections from rats with EAE showed higher myelination intensity and decreased expression of CPT1A in etomoxir-treated rats compared to placebo group. Moreover, etomoxir mediated increased interleukin-4 production and decreased interleukin-17α production in activated T cells. In conclusion, CPT1 is a key protein in the pathogenesis of EAE and MS and a crucial therapeutic target for the treatment.


Assuntos
Carnitina O-Palmitoiltransferase/antagonistas & inibidores , Encefalomielite Autoimune Experimental/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Compostos de Epóxi/uso terapêutico , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Carnitina O-Palmitoiltransferase/metabolismo , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacologia , Compostos de Epóxi/administração & dosagem , Compostos de Epóxi/farmacologia , Feminino , Interleucina-17/genética , Interleucina-17/metabolismo , Interleucina-4/genética , Interleucina-4/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Bainha de Mielina/metabolismo , Ratos , Ratos Endogâmicos Lew
3.
PLoS One ; 15(6): e0234920, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32559224

RESUMO

Sanguinarine is a bioactive compound as a quaternary benzophenanthridine alkaloid from plant of the Macleaya cordata, Papaveraceae family. The present study was conducted to investigate the effects of dietary sanguinarine supplementation on growth performance, serum biochemistry parameters, intestinal mucosal morphology and gut microbiome in yellow feathered broilers. Two hundred and seventy 1-d-old female broilers were randomly assigned to 3 treatments ① Basal diet (NG); ② Basal diet containing bacitracin methylene disalicylate (50mg/Kg diet) (ANT); ③ Basal diet containing sanguinarine (0.7 mg/ kg of feed) (SAG). The statistical results showed that dietary sanguinarine supplementation enhanced growth performance and decreased glucose, uric acid as well as urea nitrogen levels of broilers at 28d of age (P<0.05). The 16S rRNA gene sequence analysis revealed that sanguinarine significantly decreased the species from the phyla Bacteroidetes, and increased the species from phyla Firmicutes. Moreover, dietary sanguinarine supplementation improved mucosal morphology to achieve higher ratio of intestinal villus height to crypt depth (P < 0.05), and decreased the concentrations of TNF-α and IL-4 in jejunum mucosal. This study demonstrated that sanguinarine supplementation in the diet of yellow feathered broilers improved intestinal morphology and microbiota community structure to promote growth performance on 1-28d.


Assuntos
Anti-Infecciosos/farmacologia , Benzofenantridinas/farmacologia , Galinhas/microbiologia , Microbioma Gastrointestinal , Isoquinolinas/farmacologia , Jejuno/efeitos dos fármacos , Animais , Anti-Infecciosos/administração & dosagem , Proteínas Aviárias/genética , Proteínas Aviárias/metabolismo , Bacteroidetes/efeitos dos fármacos , Bacteroidetes/patogenicidade , Benzofenantridinas/administração & dosagem , Glicemia/metabolismo , Galinhas/crescimento & desenvolvimento , Suplementos Nutricionais , Feminino , Firmicutes/efeitos dos fármacos , Firmicutes/patogenicidade , Interleucina-4/genética , Interleucina-4/metabolismo , Isoquinolinas/administração & dosagem , Jejuno/crescimento & desenvolvimento , Jejuno/metabolismo , Jejuno/microbiologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Ácido Úrico/sangue
4.
PLoS One ; 15(6): e0234731, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32544181

RESUMO

Airborne fungi are associated with upper and lower airway inflammatory diseases. Alternaria is commonly found in nasal secretions and induces the production of chemical mediators from sinonasal mucosa. This study aimed to establish an Alternaria-induced chronic rhinosinusitis (CRS) mouse model and determine the influence of host allergic background on the immunopathological characteristics of CRS. BALB/c mice were used for establishing the CRS model. Alternaria was intranasally instilled for 8 or 16 weeks with or without ovalbumin (OVA) presensitization. Total serum IgE and Alternaria-specific IgE levels were measured by enzyme-linked immunosorbent assay (ELISA). Interleukin (IL)-4, IL-10, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α levels in nasal lavage fluid (NLF) and splenocytes were measured by ELISA and their mRNAs and levels of associated transcription factors in sinonasal mucosa were determined with quantitative reverse-transcriptase polymerase chain reaction (RT-PCR). Hematoxylin-eosin staining and periodic acid-Schiff staining were performed to evaluate histological changes. Total serum IgE was increased in both allergic and non-allergic CRS. IL-4 was strongly expressed in NLF in both allergic and non-allergic CRS at 16 weeks and not only eosinophils but also neutrophils were increased in NLF of non-allergic CRS mice. The levels of Th1, Th2, and Treg cytokines and transcription factor mRNAs were significantly increased in sinonasal mucosa of non-allergic CRS mice. Both inflammatory cell infiltration and goblet cell hyperplasia were increased in CRS mice. Repeated intranasal instillation of Alternaria results in sinonasal inflammation with inflammatory cell infiltration. The sinonasal mucosal immune responses against Alternaria were shown to differ depending on the host allergic background.


Assuntos
Alternaria/patogenicidade , Rinite/patologia , Sinusite/patologia , Alternaria/imunologia , Animais , Doença Crônica , Modelos Animais de Doenças , Feminino , Imunoglobulina E/sangue , Interleucina-10/análise , Interleucina-10/genética , Interleucina-10/metabolismo , Interleucina-4/análise , Interleucina-4/genética , Interleucina-4/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Líquido da Lavagem Nasal/química , Mucosa Nasal/metabolismo , Mucosa Nasal/patologia , RNA Mensageiro/metabolismo , Rinite/imunologia , Sinusite/imunologia , Baço/metabolismo , Baço/microbiologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
5.
PLoS One ; 15(4): e0231101, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32302339

RESUMO

Mast cells and basophils are central players in allergic reactions triggered by immunoglobulin E (IgE). They have intracellular granules containing allergic mediators (e.g., histamine, serotonin, inflammatory cytokines, proteases and ß-hexosaminidase), and stimulation by IgE-allergen complex leads to the release of such allergic mediators from the granules, that is, degranulation. Mast cells are residents of mucosal surfaces, including those of nasal and oral cavities, and play an important role in the innate defense system. Members of the mitis group streptococci such as Streptococcus oralis, are primary colonizers of the human oral cavity. They produce hydrogen peroxide (H2O2) as a by-product of sugar metabolism. In this study, we investigated the effects of streptococcal infection on RBL-2H3 mast cell/basophil cell line. Infection by oral streptococci did not induce degranulation of the cells. Stimulation of the RBL-2H3 cells with anti-dinitrophenol (DNP) IgE and DNP-conjugated human serum albumin triggers degranulation with the release of ß-hexosaminidase. We found that S. oralis and other mitis group streptococci inhibited the IgE-triggered degranulation of RBL-2H3 cells. Since mitis group streptococci produce H2O2, we examined the effect of S. oralis mutant strain deficient in producing H2O2, and found that they lost the ability to suppress the degranulation. Moreover, H2O2 alone inhibited the IgE-induced degranulation. Subsequent analysis suggested that the inhibition of degranulation was related to the cytotoxicity of streptococcal H2O2. Activated RBL-2H3 cells produce interleukin-4 (IL-4); however, IL-4 production was not induced by streptococcal H2O2. Furthermore, an in vivo study using the murine pollen-induced allergic rhinitis model suggested that the streptococcal H2O2 reduces nasal allergic reaction. These findings reveal that H2O2 produced by oral mitis group streptococci inhibits IgE-stimulated degranulation by inducing cell death. Consequently, streptococcal H2O2 can be considered to modulate the allergic reaction in mucosal surfaces.


Assuntos
Alérgenos/metabolismo , Hipersensibilidade/imunologia , Imunoglobulina E/imunologia , Infecções Estreptocócicas/tratamento farmacológico , Alérgenos/imunologia , Animais , Basófilos/imunologia , Basófilos/microbiologia , Basófilos/patologia , Degranulação Celular/imunologia , Sobrevivência Celular/imunologia , Dinitrofenóis/farmacologia , Humanos , Peróxido de Hidrogênio/metabolismo , Hipersensibilidade/tratamento farmacológico , Hipersensibilidade/patologia , Imunoglobulina E/metabolismo , Interleucina-4/genética , Interleucina-4/metabolismo , Mastócitos/imunologia , Mastócitos/microbiologia , Mastócitos/patologia , Camundongos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Albumina Sérica Humana/imunologia , Albumina Sérica Humana/metabolismo , Infecções Estreptocócicas/imunologia , Streptococcus oralis/imunologia , Streptococcus oralis/patogenicidade , Açúcares/metabolismo
6.
PLoS One ; 15(4): e0225874, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32240169

RESUMO

We previously have reported that neonatal Bacillus Calmette-Guerin (BCG) vaccination improves neurogenesis and behavior in early life through affecting the neuroimmune milieu in the brain, but it is uncertain whether activation phenotypes and functional changes in T lymphocytes shape brain development. Here, we studied the effects of BCG vaccination via the adoptive transfer of T lymphocytes from the BALB/c wild-type mice into naive mice. Our results show that mice adoptive BCG-induced lymphocytes (BCG->naive mice) showed anxiolytic and antidepressant-like performance when completing an elevated plus maze (EPM) test. Meanwhile, BCG->naive mice possess more cell proliferation and newborn neurons than PBS->naive and nude mice in the hippocampus. IFN-γ and IL-4 levels in the serum of BCG->naive mice also increased, while TNF-α and IL-1ß levels were reduced relative to those of PBS->naive and nude mice. We further found that BCG->naive mice showed different repartition of CD4+ and CD8+ T cell to naive (CD62L+CD44low), effector memory (CD62L-CD44hi), central memory (CD62L+CD44hi) and acute/activated effector (CD62L-CD44low) cells in the spleen. Importantly, the adoptive transfer of BCG-induced T lymphocytes infiltrated into the dura mater and brain parenchyma of the nude mice. Activation phenotypes and functional changes in T lymphocytes are very likely to affect the neuroimmune milieu in the brain, and alterations in ratios of splenic CD4+ and CD8+ memory T cells may affect the expression of correlative cytokines in the serum, accounting for our behavioral results. We conclude thus that the adoptive transfer of BCG-induced T lymphocytes contributes to hippocampal cell proliferation and tempers anxiety-like behavior in immune deficient mice. Our work shows that BCG vaccination improves hippocampal cell proliferation outcomes and behaviors, likely as a result of splenic effector/memory T lymphocytes regulating the neuroimmune niche in the brain.


Assuntos
Ansiedade/tratamento farmacológico , Vacina BCG/farmacologia , Proliferação de Células/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Ansiedade/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Receptores de Hialuronatos/genética , Interferon gama/genética , Interleucina-4/genética , Selectina L/genética , Linfócitos/efeitos dos fármacos , Linfócitos/patologia , Camundongos , Camundongos Nus
7.
Artigo em Inglês | MEDLINE | ID: mdl-32130030

RESUMO

Mechanical tension and humoral stimuli can induce transitions in airway smooth muscle phenotype between a synthetic inflammatory state that promotes cytokine secretion and a differentiated state that promotes the expression of smooth muscle phenotype-specific proteins. When tissues are maintained under high tension, Akt activation and eotaxin secretion are suppressed, but expression of the differentiation marker protein, smooth muscle myosin heavy chain (SmMHC), is promoted. When tissues are maintained under low tension, Akt activation and eotaxin secretion are stimulated, and the differentiated phenotype is suppressed. We hypothesized that mechanical stimuli are differentially transduced to Akt-mediated signaling pathways that regulate phenotype expression by α-parvin and ß-parvin integrin-linked kinase/PINCH/parvin (IPP) signaling complexes within integrin adhesomes. High tension or ACh triggered paxillin phosphorylation and the binding of phospho-paxillin to ß-parvin IPP complexes. This inhibited Akt activation and promoted SmMHC expression. Low tension or IL-4 did not elicit paxillin phosphorylation and triggered the binding of unphosphorylated paxillin to α-parvin IPP complexes, which promoted Akt activation and eotaxin secretion and suppressed SmMHC expression. Expression of a nonphosphorylatable paxillin mutant or ß-parvin depletion by siRNA promoted the inflammatory phenotype, whereas the depletion of α-parvin promoted the differentiated phenotype. Results demonstrate that phenotype expression is regulated by the differential interaction of phosphorylated and unphosphorylated paxillin with α-parvin and ß-parvin IPP complexes and that these complexes have opposite effects on the activation of Akt. Our results describe a novel molecular mechanism for transduction of mechanical and humoral stimuli within integrin signaling complexes to regulate phenotype expression in airway smooth muscle.


Assuntos
Actinina/genética , Mecanotransdução Celular , Músculo Liso/metabolismo , Paxilina/genética , Proteínas Proto-Oncogênicas c-akt/genética , Traqueia/metabolismo , Acetilcolina/farmacologia , Actinina/metabolismo , Animais , Quimiocina CCL11/genética , Quimiocina CCL11/metabolismo , Cães , Feminino , Regulação da Expressão Gênica , Interleucina-4/genética , Interleucina-4/metabolismo , Proteínas com Domínio LIM/genética , Proteínas com Domínio LIM/metabolismo , Masculino , Contração Muscular/efeitos dos fármacos , Contração Muscular/genética , Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Paxilina/metabolismo , Fenótipo , Fosforilação/efeitos dos fármacos , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Miosinas de Músculo Liso/genética , Miosinas de Músculo Liso/metabolismo , Traqueia/efeitos dos fármacos
8.
Artigo em Inglês | MEDLINE | ID: mdl-32130032

RESUMO

We have previously demonstrated that upregulation of Sonic hedgehog (SHH) expression in allergic airway epithelia essentially contributes to the goblet cell metaplasia and mucous hypersecretion. However, the mechanism underlying the upregulation of SHH expression remains completely unknown. In cultured human airway epithelial cells, IL-4/IL-13 but not IL-5 robustly induces the mRNA and protein expression of SHH and in turn activates SHH signaling by promoting the JAK/STAT6-controlling transcription of SHH gene. Moreover, intratracheal instillation of IL-4 and/or IL-13 robustly activates STAT6 and concomitantly upregulates SHH expression in mouse airway epithelia, whereas, in Club cell 10-kDa protein (CC10)-positive airway epithelial cells of children with asthma, activated STAT6 closely correlates with the increased expression of SHH and high activity of SHH signaling. Finally, intratracheal inhibition of STAT6 by AS-1517499 significantly diminished the allergen-induced upregulation of SHH expression, goblet cell phenotypes, and airway hyperresponsiveness, in an ovalbumin- or house dust mite-induced mouse model with allergic airway inflammation,. Together, upregulation of SHH expression by IL-4/IL-13-induced JAK/STAT6 signaling contributes to allergic airway epithelial remodeling, and this study thus provides insight into how morphogen signaling is coordinated with Th2 cytokine pathways to regulate tissue remodeling in chronic airway diseases.


Assuntos
Asma/genética , Proteínas Hedgehog/genética , Interleucina-13/genética , Interleucina-4/genética , Mucosa Respiratória/imunologia , Animais , Antiasmáticos/farmacologia , Asma/induzido quimicamente , Asma/tratamento farmacológico , Asma/patologia , Linhagem Celular , Criança , Feminino , Regulação da Expressão Gênica , Células Caliciformes/efeitos dos fármacos , Células Caliciformes/imunologia , Células Caliciformes/patologia , Proteínas Hedgehog/imunologia , Humanos , Interleucina-13/imunologia , Interleucina-13/farmacologia , Interleucina-4/imunologia , Interleucina-4/farmacologia , Interleucina-5/genética , Interleucina-5/imunologia , Janus Quinases/genética , Janus Quinases/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/administração & dosagem , Cultura Primária de Células , Pirimidinas/farmacologia , Pyroglyphidae/química , Pyroglyphidae/imunologia , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/patologia , Fator de Transcrição STAT6/antagonistas & inibidores , Fator de Transcrição STAT6/genética , Fator de Transcrição STAT6/imunologia , Transdução de Sinais , Transcrição Genética , Uteroglobina/genética , Uteroglobina/imunologia
9.
Arch Virol ; 165(3): 593-607, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32016547

RESUMO

The eradication of hepatitis C virus (HCV) infection is a public health priority. Despite the efficiency of treatment with direct-acting antivirals, the high cost of the therapy and the lack of accurate data about the HCV-infected population worldwide constitute important factors hampering this task. Hence, an affordable preventive vaccine is still necessary for reducing transmission and the future disease burden globally. In this work, chimeric proteins (EnvCNS3 and NS3EnvCo) encompassing conserved and immunogenic epitopes from the HCV core, E1, E2 and NS3 proteins were produced in Escherichia coli, and their immunogenicity was evaluated in BALB/c mice. The impact of recombinant HCV E2.680 protein and oligodeoxynucleotide 39M (ODN39M) on the immune response to chimeric proteins was also assessed. Immunization with chimeric proteins mixed with E2.680 enhanced the antibody and cellular response against HCV antigens and chimeric proteins. Interestingly, the combination of NS3EnvCo with E2.680 and ODN39M as adjuvant elicited a potent antibody response characterized by an increase in antibodies of the IgG2a subclass against E2.680, NS3 and chimeric proteins, suggesting the induction of a Th1-type response. Moreover, a cytotoxic T lymphocyte response and a broad response of IFN-γ-secreting cells against HCV antigens were induced with this formulation as well. This T cell response was able to protect vaccinated mice against challenge with a surrogate model based on HCV recombinant vaccinia virus. Overall, the vaccine candidate NS3EnvCo/E2.680/ODN39M might constitute an effective immunogen against HCV with potential for reducing the likelihood of viral persistence.


Assuntos
Hepacivirus/imunologia , Anticorpos Anti-Hepatite C/sangue , Proteínas Recombinantes/imunologia , Sequência de Aminoácidos , Animais , Linfócitos T CD4-Positivos , Clonagem Molecular , Epitopos , Feminino , Regulação da Expressão Gênica/imunologia , Antígenos da Hepatite C/imunologia , Imunidade Celular , Interferon gama/genética , Interferon gama/metabolismo , Interleucina-4/genética , Interleucina-4/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Plasmídeos
10.
Int J Nanomedicine ; 15: 761-777, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32099364

RESUMO

Purpose: Salmonellosis in poultry is a serious economic burden. A major concern is the public health hazard caused by consumption of Salmonella-contaminated poultry products. Currently used Salmonella vaccines are ineffective in combating poultry Salmonellosis warranting the need of a potent vaccine, especially an oral vaccine that can elicit robust local intestinal immunity. Materials and Methods: A Salmonella subunit chitosan nanoparticles (NPs)-based vaccine was prepared that contained immunogenic outer membrane proteins (OMPs) and -flagellin (F) protein (OMPs-F-CS NPs). OMPs-F-CS NPs were administered as an oral vaccine in layer chickens and the resultant humoral and cell-mediated immune responses and localization of NPs were examined using standard detection methods. Results: We demonstrated targeting of surface F-protein coated chitosan NPs to immune cells when delivered orally to layer chickens, the particles were localized in ileal Peyer's patches. The OMPs-F-CS NPs vaccinated layer chickens had significantly higher OMPs-specific mucosal IgA production and lymphocyte proliferation response. The candidate vaccine increased the expression of toll-like receptor (TLR)-2, TLR-4, IFN-γ, TGF-ß and IL-4 mRNA expression in chicken cecal tonsils. Conclusion: Our study demonstrated that the chitosan-based oral Salmonella nanovaccine targets immune cells of chickens and induced antigen-specific B and T cell responses. This candidate oral Salmonella nanovaccine has the potential to mitigate Salmonellosis in poultry.


Assuntos
Galinhas , Salmonelose Animal/prevenção & controle , Vacinas contra Salmonella/administração & dosagem , Vacinas contra Salmonella/imunologia , Administração Oral , Animais , Galinhas/imunologia , Quitosana/química , Feminino , Imunidade Celular , Interleucina-4/genética , Mucosa Intestinal/efeitos dos fármacos , Nanopartículas/administração & dosagem , Nanopartículas/química , Porinas/química , Salmonelose Animal/imunologia , Salmonella enteritidis/imunologia , Receptores Toll-Like/genética , Fator de Crescimento Transformador beta/genética , Vacinas de Subunidades/administração & dosagem
11.
Parasitol Res ; 119(2): 491-499, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31907667

RESUMO

Following the emergence of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), the number of visceral leishmaniasis-HIV (VL-HIV) coinfections has increased worldwide, mainly in Brazil. The development of clinical forms of VL can be influenced by nutritional status, age, and host genetic factors, which are important variables determining susceptibility to disease. There are no studies with a candidate gene approach assayed directly in the VL-HIV-coinfected population. Herein, we determined and analyzed the associations of SLC11A1, LECT2, CCL1, CCL16, and IL4 genetic polymorphisms with susceptibility to VL-HIV coinfection in Northeastern Brazil. We analyzed 309 DNA samples extracted from the peripheral blood of HIV patients, and clinical and hematological data were collected from medical records. The diagnosis of VL was confirmed in 110 out of 309 patients; genotyping was carried out by TaqMan assays afterwards. Our results confirmed the association between the SLC11A1 polymorphism (rs3731865) and VL-HIV coinfection (p = 0.0206, OR 1.8126, 95% CI 1.1050-2.9727). In addition, the SLC11A1 genotype GG (p = 0.0050, OR 3.0395, 95% CI 1.4065-6.5789) and CD4+ T lymphocyte count (p = 0.0030, OR 0.9980, 95% CI 0.9970-0.9990) were associated with VL-HIV coinfection in a multivariate model. The polymorphism of the SLC11A1 gene (rs3731865) was associated with VL-HIV coinfection, suggesting a possible genetic mechanism involved in the susceptibility to VL in HIV patients. This finding can suggest new therapeutic targets and genetic markers for the VL-HIV-coinfected population.


Assuntos
Síndrome de Imunodeficiência Adquirida/epidemiologia , Proteínas de Transporte de Cátions/genética , Predisposição Genética para Doença/genética , Leishmaniose Visceral/epidemiologia , Adulto , Brasil/epidemiologia , Linfócitos T CD4-Positivos/imunologia , Quimiocina CCL1/genética , Quimiocinas CC/genética , Coinfecção/epidemiologia , Coinfecção/genética , Feminino , Genótipo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Interleucina-4/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético/genética
12.
Proc Natl Acad Sci U S A ; 117(6): 3103-3113, 2020 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-31980518

RESUMO

Neutrophils are the most abundant immune cells found in actively inflamed joints of patients with rheumatoid arthritis (RA), and most animal models for RA depend on neutrophils for the induction of joint inflammation. Exogenous IL-4 and IL-13 protect mice from antibody-mediated joint inflammation, although the mechanism is not understood. Neutrophils display a very strong basal expression of STAT6, which is responsible for signaling following exposure to IL-4 and IL-13. Still, the role of IL-4 and IL-13 in neutrophil biology has not been well studied. This can be explained by the low neutrophil surface expression of the IL-4 receptor α-chain (IL-4Rα), essential for IL-4- and IL-13-induced STAT6 signaling. Here we identify that colony stimulating factor 3 (CSF3), released during acute inflammation, mediates potent STAT3-dependent neutrophil IL-4Rα up-regulation during sterile inflammatory conditions. We further demonstrate that IL-4 limits neutrophil migration to inflamed joints, and that CSF3 combined with IL-4 or IL-13 results in a prominent neutrophil up-regulation of the inhibitory Fcγ receptor (FcγR2b). Taking these data together, we demonstrate that the IL-4 and CSF3 pathways are linked and play important roles in regulating proinflammatory neutrophil behavior.


Assuntos
Artrite/metabolismo , Interleucina-4 , Infiltração de Neutrófilos/fisiologia , Neutrófilos/metabolismo , Receptores de IgG/metabolismo , Animais , Modelos Animais de Doenças , Interleucina-4/genética , Interleucina-4/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout
13.
Immunology ; 159(4): 441-449, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31957000

RESUMO

Signaling by Kit has been extensively studied in hematopoietic cells and is essential for the survival, proliferation and maintenance of hematopoietic stem and progenitor cells. In addition to the activation of intrinsic signaling pathways, Kit has been shown to interact with lineage-restricted type I cytokine receptors and produce cross signals, e.g. erythropoietin receptor, interleukin-7 receptor (IL-7R), IL-3R. Based on the earlier studies, we hypothesize that Kit activate other type I cytokine receptors in a cell-specific manner and execute cell-specific function. To investigate other Kit-activated receptors, we tested Kit and IL-4R cross-receptor activation in murine bone-marrow-derived mast cells, which express both Kit and IL-4R at the surface level. Kit upon activation by Kit ligand (KL), activated IL-4Rα, γC , and signal transducer and activator of transcription 6 independent of its cognate ligand IL-4. Though KL and IL-4 are individually mitogenic, combinations of KL and IL-4 synergistically promoted mast cell proliferation. Furthermore, inhibition of lipid raft formation by methyl-ß-cyclodextrin resulted in loss of synergistic proliferation. Together the data suggest IL-4R as a novel Kit-activated receptor. Such cross-receptor activations are likely to be a universal mechanism of Kit signaling in hematopoiesis.


Assuntos
Interleucina-4/farmacologia , Mastócitos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-kit/genética , Receptores de Interleucina-4/genética , Fator de Transcrição STAT6/genética , Fator de Células-Tronco/farmacologia , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/imunologia , Proliferação de Células/efeitos dos fármacos , Regulação da Expressão Gênica , Hematopoese/efeitos dos fármacos , Hematopoese/genética , Hematopoese/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Mastócitos/citologia , Mastócitos/imunologia , Microdomínios da Membrana/efeitos dos fármacos , Microdomínios da Membrana/imunologia , Microdomínios da Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-kit/imunologia , Receptores da Eritropoetina/genética , Receptores da Eritropoetina/imunologia , Receptores de Interleucina-3/genética , Receptores de Interleucina-3/imunologia , Receptores de Interleucina-4/imunologia , Receptores de Interleucina-7/genética , Receptores de Interleucina-7/imunologia , Fator de Transcrição STAT6/imunologia , Transdução de Sinais , Fator de Células-Tronco/genética , Fator de Células-Tronco/imunologia , beta-Ciclodextrinas/farmacologia
14.
Cell ; 180(3): 502-520.e19, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-31983537

RESUMO

The tumor microenvironment (TME) is critical for tumor progression. However, the establishment and function of the TME remain obscure because of its complex cellular composition. Using a mouse genetic system called mosaic analysis with double markers (MADMs), we delineated TME evolution at single-cell resolution in sonic hedgehog (SHH)-activated medulloblastomas that originate from unipotent granule neuron progenitors in the brain. First, we found that astrocytes within the TME (TuAstrocytes) were trans-differentiated from tumor granule neuron precursors (GNPs), which normally never differentiate into astrocytes. Second, we identified that TME-derived IGF1 promotes tumor progression. Third, we uncovered that insulin-like growth factor 1 (IGF1) is produced by tumor-associated microglia in response to interleukin-4 (IL-4) stimulation. Finally, we found that IL-4 is secreted by TuAstrocytes. Collectively, our studies reveal an evolutionary process that produces a multi-lateral network within the TME of medulloblastoma: a fraction of tumor cells trans-differentiate into TuAstrocytes, which, in turn, produce IL-4 that stimulates microglia to produce IGF1 to promote tumor progression.


Assuntos
Astrócitos/metabolismo , Carcinogênese/metabolismo , Transdiferenciação Celular , Neoplasias Cerebelares/metabolismo , Meduloblastoma/metabolismo , Comunicação Parácrina , Animais , Linhagem da Célula , Neoplasias Cerebelares/patologia , Modelos Animais de Doenças , Feminino , Proteínas Hedgehog/metabolismo , Xenoenxertos , Humanos , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Interleucina-4/genética , Interleucina-4/metabolismo , Masculino , Meduloblastoma/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/metabolismo , Microambiente Tumoral
15.
Am J Chin Med ; 47(8): 1795-1814, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31795744

RESUMO

Asthma is a common allergic airway inflammatory disease, characterized by abnormal breathing due to bronchial inflammation. Asthma aggravates the patient's quality of life and needs continuous pharmacological treatment. Therefore, discovery of drugs for the treatment of asthma is an important area of human health. The aim of the present study was to evaluate whether Cynanchum atratum extract (CAE) modulates the asthma-like allergic airway inflammation and to study its possible mechanism of action using ovalbumin (OVA)-induced airway inflammation and lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice, as well as a mast cell-based in vitro model. The histological analysis showed that CAE reduced the airway constriction and immune cell infiltration. CAE also inhibited release of ß-hexosaminidase and expression of inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-4, and IL-5 in bronchoalveolar lavage fluid and lung tissues. In addition, CAE reduced the OVA-specific immunoglobulin (Ig) E, total IgE, IgG1, and IgG2a levels in the serum. In the LPS-induced ALI model, CAE suppressed the LPS-induced lung barrier dysfunction and the release of proinflammatory cytokines. Because allergic airway inflammatory responses are associated with the activation of mast cells, RBL-2H3 cells were used to evaluate the underlying mechanism of CAE effects. In RBL-2H3 cells, CAE down-regulated release of ß-hexosaminidase and histamine by reducing the intracellular calcium influx. In addition, CAE suppressed the expression of proinflammatory cytokines by inhibiting nuclear translocation of nuclear factor-κB. Taken together, our findings suggest that CAE may help in the prevention or treatment of airway inflammatory diseases.


Assuntos
Asma/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Mastócitos/efeitos dos fármacos , Mastócitos/imunologia , Alvéolos Pulmonares/imunologia , Vincetoxicum/química , Animais , Asma/genética , Asma/imunologia , Líquido da Lavagem Broncoalveolar/imunologia , Feminino , Humanos , Imunoglobulina E/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Interleucina-5/genética , Interleucina-5/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Alvéolos Pulmonares/efeitos dos fármacos , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
16.
Biomed Res Int ; 2019: 3104176, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31871935

RESUMO

Background: Several previous studies have assessed the relationship between IL-4-590C/T gene polymorphism and smoking-related cancer in recent years; however, the results remain controversial. Based on it, the study intends to clarify whether IL-4-590C/T variant increases the risk of smoking-related cancer through meta-analysis. Methods: We searched PubMed, EMBASE, Web of Science, Cochrane Library database, China National Knowledge Infrastructure, and Wanfang data information service platform to collect qualified case-control studies in strict accordance with the inclusion and exclusion standards. The 95% confidence interval (95% CI) and its odds ratio (OR) were adopted to access the relation between IL-4-590C/T gene polymorphism and smoking-related cancer; sensitivity analysis and publication bias assessment were carried out after the studies' quality evaluation. Results: 17 studies were included in total, with 5,061 patients and 6,346 control cases. A significant association between IL-4-590C/T variant and smoking-related cancer in total population was revealed in our meta-analysis results, and IL-4-590C/T variant might have a relatively protective effect on smoking-related cancer (CT vs. TT: P=0.026, OR = 0.900, 95% CI: 0.820-0.987). Subgroup analysis by ethnicity showed that the IL-4-590C/T polymorphism was associated with a decreased risk of smoking-related cancer in the Asian population (CT vs. TT: P=0.008, OR = 0.878, 95% CI: 0.798-0.967; CC + CT vs. TT: P=0.030, OR = 0.903, 95% CI: 0.824-0.990). Subgroup analysis based on types of cancer demonstrated the IL-4-590C/T variant achieved a lower risk in renal cell cancer (CC vs. TT: P=0.046, OR = 0.640, 95% CI: 0.412-0.993). Conclusion: There is a conspicuous association between IL-4-590C/T polymorphism and decreased risk of smoking-related cancer, particularly in Asians. And IL-4-590C/T polymorphism may have a protective effect on renal cell cancer.


Assuntos
Predisposição Genética para Doença , Interleucina-4/genética , Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Fumar/efeitos adversos , Grupo com Ancestrais do Continente Asiático/genética , Carcinoma de Células Renais/genética , Bases de Dados Factuais , Humanos , Neoplasias Renais/genética , Risco
17.
Biochemistry (Mosc) ; 84(9): 1040-1046, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31693463

RESUMO

Preterm birth is not only medical, but also a social problem. The global goal of medicine is prevention of preterm labor and identification of risk factors leading to preterm birth. The objective of our study was to find the association between polymorphic markers in the cytokine IL-1ß, TNF-α, IL-1Ra, and IL-4 genes and development of preterm labor. The prospective study was conducted in 108 pregnant women with the risk of preterm birth. The main group consisted of 66 women whose pregnancy ended with preterm delivery despite the ongoing therapy. The comparison group included 42 women with the full-term delivery. The dominant T allele of the cytokine IL-1ß gene polymorphism rs1143634 (3953C→T) was 7.6 times more common in women with preterm delivery vs. the comparison group (36.4 and 4.8%, respectively; RR, 1.802; 95% CI, 1.420-2.288; p < 0.05); its homozygous form was detected only in women with preterm delivery at the very early gestation age (less than 26 weeks). The dominant proinflammatory allele 2R of the IL-1 receptor antagonist gene (IL-1Ra) was 1.5 times more common in women with preterm delivery than in the comparison group (63.6 and 42.8%, respectively; RR, 1.400; 95% CI, 1.009-1.943; p < 0.05), which makes the 2R allele the risk factor for preterm birth. The 2R/2R and 2R/4R genotypes led to a very early and early preterm delivery, respectively. The combination of three or four proinflammatory genotypes was detected only in women with a very early preterm delivery, which confirms that the combination of several proinflammatory genotypes is an extremely unfavorable factor for the full-term pregnancy. Identification of genetic polymorphisms in the interleukin genes at the periconceptional stage will help to prevent the risk of preterm delivery, which will reduce the incidence of preterm births, as well as perinatal morbidity and mortality.


Assuntos
Proteína Antagonista do Receptor de Interleucina 1/genética , Interleucina-1beta/genética , Interleucina-4/genética , Polimorfismo Genético/genética , Nascimento Prematuro/genética , Fatores de Necrose Tumoral/genética , Alelos , Feminino , Humanos , Gravidez , Estudos Prospectivos , Fatores de Risco
18.
Arch Med Res ; 50(6): 384-392, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31678897

RESUMO

BACKGROUND: T helper 2 (Th2) lymphocytes and associated interleukin (IL) 4 and IL-13 play crucial roles in asthma pathogenesis. In this study, we explored an adeno-associated virus 5 (AAV5) based gene therapy by delivering truncated IL-4 protein to antagonize IL-4 receptor α chain and interrupt asthmatic signal pathway. RESULTS: A recombinant adeno-associated virus 5 (AAV5) vector harboring a truncated mouse IL-4 gene (AAV5-mIL-4ΔC22) was prepared. Western blotting showed that the IL-4 mutant protein lacking the C-terminal 22 amino acids was expressed well in AAV5-mIL-4ΔC22 infected 16HBE and BEAS-2B cells. AAV5-drivn green fluorescent protein (AAV5-GFP) served as a control. The biodistribution of vector DNA after AAV5 vector aerosol inhalation was examined by PCR and the result showed that foreign DNA was detectable in the lungs but not in other organs including gonads. The aerosol inhalation-mediated delivery of AAV5-expressed antagonistic IL-4 mutant protein improved the lung function of ovalbumin-induced asthma mice. CONCLUSIONS: The inhalation of aerosolized AAV5-mIL-4ΔC22 significantly improved the lung function and modulated the immune cell infiltration and associated cytokine expression in the bronchoalveolar lavage fluid (BALF) of ovalbumin-induced asthma mice.


Assuntos
Asma/terapia , Terapia Genética/métodos , Subunidade alfa de Receptor de Interleucina-4/antagonistas & inibidores , Interleucina-4/genética , Administração por Inalação , Animais , Asma/induzido quimicamente , Líquido da Lavagem Broncoalveolar/química , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Interleucina-4/imunologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/toxicidade , Parvovirinae/genética , Distribuição Tecidual
19.
Int J Rheum Dis ; 22(12): 2178-2184, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31701644

RESUMO

OBJECTIVE: SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, and osteitis) is an autoimmune disease of unknown etiology that seriously affects patients' daily lives. Family-based investigations support genetic contributions toward disease susceptibility. The present study evaluated whether the previously reported autoimmune disease-associated single nucleotide polymorphisms (SNPs) have any genetic overlap with SAPHO syndrome. METHOD: Genomic DNA was obtained from 71 SAPHO patients and 104 healthy controls. The SNP genotypes of each patient were determined with polymerase chain reaction and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Genotype, allele, and haplotype frequencies were analyzed with SPSS software. RESULTS: Three SNP sites (rs10889677 and rs2201841 of interleukin [IL]-23R, and rs2243248 of IL-4) showed significant correlation with the occurrence of SAPHO syndrome in additive and dominant genetic models, while rs7517847 of IL-23R showed substantial correlation with SAPHO in the dominant genetic model. The G allele of rs2243248 (IL-4) was a high risk factor for SAPHO (P = 2.41e-5, odds ratio [OR] =7.79, 95% CI: 2.59-23.3). The haplotype (A-G-C-G-T), comprising 5 SNPs of the IL-23R gene, had a significantly higher frequency in the SAPHO cohort than in the controls (P = .011, OR = 2.05, 95% CI: 1.12-3.60). CONCLUSION: Variants rs10889677, rs2201841, and rs7517847 of IL-23R, and variant rs2243248 of IL-4, showed strong associations with SAPHO syndrome. Patients carrying the A-G-C-G-T haplotype of IL-23 are significantly more likely to develop SAPHO syndrome.


Assuntos
Síndrome de Hiperostose Adquirida/genética , Polimorfismo de Nucleotídeo Único , Receptores de Interleucina/genética , Síndrome de Hiperostose Adquirida/diagnóstico , Síndrome de Hiperostose Adquirida/etnologia , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China/epidemiologia , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Interleucina-23/genética , Interleucina-4/genética , Masculino , Pessoa de Meia-Idade , Fenótipo , Medição de Risco , Fatores de Risco
20.
Turk J Med Sci ; 49(5): 1411-1417, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31650822

RESUMO

Background/aim: Sinonasal polyposis is a complex chronic disease displaying contributions from multiple genetic and environmental factors. In this study, we analyzed possible genetic factors that increase susceptibility to this widespread inflammatory disease. Materials and methods: A total of 176 adult patients, including 78 patients with sinonasal polyposis and 98 healthy controls, were analyzed for IL-1RN VNTR, IL-2(-330), and IL-4 VNTR gene polymorphisms using polymerase chain reaction and enzyme restriction. Results: IL-1RN and IL-4 VNTR polymorphisms were notably associated with sinonasal polyposis (P = 0.0001 and P = 0.036, respectively); however, regarding the IL-2(-330) gene polymorphism, no significant difference was shown between the patient and control groups (P = 0.235). Conclusions: Our study indicates that the RN2 allele of IL-1RN and the RP1 allele of IL-4 might be risk factors for developing sinonasal polyposis.


Assuntos
Proteína Antagonista do Receptor de Interleucina 1/genética , Interleucina-2/genética , Interleucina-4/genética , Repetições Minissatélites/genética , Pólipos Nasais/genética , Doenças dos Seios Paranasais/genética , Polimorfismo de Nucleotídeo Único/genética , Rinite/genética , Sinusite/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Estudos de Casos e Controles , Doença Crônica , Feminino , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
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