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Biol. Res ; 52: 22, 2019. graf
Article in English | LILACS | ID: biblio-1011424


BACKGROUND: Tumor microenvironment (TME) plays a vital role in determining the outcomes of radiotherapy. As an important component of TME, vascular endothelial cells are involved in the perivascular resistance niche (PVRN), which is formed by inflammation or cytokine production induced by ionizing radiation (IR). Protein kinase CK2 is a constitutively active serine/threonine kinase which plays a vital role in cell proliferation and inflammation. In this study, we investigated the potential role of CK2 in PVRN after IR exposure. RESULT: Specific CK2 inhibitors, Quinalizarin and CX-4945, were employed to effectively suppressed the kinase activity of CK2 in human umbilical vein endothelial cells (HUVECs) without affecting their viability. Results showing that conditioned medium from IR-exposed HUVECs increased cell viability of A549 and H460 cells, and the pretreatment of CK2 inhibitors slowed down such increment. The secretion of IL-8 and IL-6 in HUVECs was induced after exposure with IR, but significantly inhibited by the addition of CK2 inhibitors. Furthermore, IR exposure elevated the nuclear phosphorylated factor-κB (NF-κB) p65 expression in HUVECs, which was a master factor regulating cytokine production. But when pretreated with CK2 inhibitors, such elevation was significantly suppressed. CONCLUSION: This study indicated that protein kinase CK2 is involved in the key process of the IR induced perivascular resistant niche, namely cytokine production, by endothelial cells, which finally led to radioresistance of non-small cell lung cancer cells. Thus, the inhibition of CK2 may be a promising way to improve the outcomes of radiation in nonsmall cell lung cancer cells.

Humans , Carcinoma, Non-Small-Cell Lung/radiotherapy , Endothelial Cells/radiation effects , Casein Kinase II/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Lung Neoplasms/drug therapy , Endothelium, Vascular/cytology , Blotting, Western , Cytokines/biosynthesis , Anthraquinones/pharmacology , Naphthyridines/pharmacology
Rev. Soc. Bras. Med. Trop ; 51(2): 207-211, Mar.-Apr. 2018. tab, graf
Article in English | LILACS | ID: biblio-1041456


Abstract INTRODUCTION: Human T-cell lymphotropic virus type 1 (HTLV-1)induces exaggerated Th1 responses, whereas atopy is associated with exacerbated Th2 responses. METHODS: Here, a cross-sectional study compared the prevalence of atopy in HTLV-1 carriers and HAM/TSP patients. It also compared the spontaneous cytokine production in HTLV-1-infected individuals. A retrospective cohort study evaluated the development of neurological manifestations in atopic and non-atopic carriers. RESULTS: Atopic HAM/TSP patients with high IFN-γ production exhibited higher IL-5 levels than non-atopic patients. Allergic rhinitis accelerated the development of Babinski signals and overactive bladders. CONCLUSIONS: Abnormal Th1 and Th2 responses coexist in HTLV-1-infected individuals and allergic diseases may worsen the clinical course of HTLV-1 infections.

Humans , Male , Female , HTLV-I Infections/complications , Hypersensitivity, Immediate/epidemiology , Nervous System Diseases/virology , HTLV-I Infections/immunology , HTLV-I Infections/pathology , Paraparesis, Tropical Spastic/complications , Paraparesis, Tropical Spastic/immunology , Paraparesis, Tropical Spastic/pathology , Cross-Sectional Studies , Retrospective Studies , Cohort Studies , Cytokines/biosynthesis , Hypersensitivity, Immediate/immunology , Hypersensitivity, Immediate/blood , Middle Aged , Nervous System Diseases/immunology
Clinics ; 72(11): 652-660, Nov. 2017. tab, graf
Article in English | LILACS | ID: biblio-890691


OBJECTIVES: The impact of Chagas disease (CD) in HIV-infected patients is relevant throughout the world. In fact, the characterization of the adaptive immune response in the context of co-infection is important for predicting the need for interventions in areas in which HIV and Chagas disease co-exist. METHODS: We described and compared the frequency of cytokine-producing T cells stimulated with soluble antigen of Trypanosoma cruzi (T. cruzi) using a cytometric assay for the following groups: individuals with chronic Chagas disease (CHR, n=10), those with Chagas disease and HIV infection (CO, n=11), those with only HIV (HIV, n=14) and healthy individuals (C, n=15). RESULTS: We found 1) a constitutively lower frequency of IL-2+ and IFN-γ+ T cells in the CHR group compared with the HIV, CO and healthy groups; 2) a suppressive activity of soluble T. cruzi antigen, which down-regulated IL-2+CD4+ and IFN-γ+CD4+ phenotypes, notably in the healthy group; 3) a down-regulation of inflammatory cytokines on CD8+ T cells in the indeterminate form of Chagas disease; and 4) a significant increase in IL-10+CD8+ cells distinguishing the indeterminate form from the cardiac/digestive form of Chagas disease, even in the presence of HIV infection. CONCLUSIONS: Taken together, our data suggest the presence of an immunoregulatory response in chronic Chagas disease, which seems to be driven by T. cruzi antigens. Our findings provide new insights into immunotherapeutic strategies for people living with HIV/AIDS and Chagas disease.

Humans , Male , Female , Adult , CD4-Positive T-Lymphocytes/immunology , HIV Infections/immunology , Cytokines/biosynthesis , Chagas Disease/immunology , CD8-Positive T-Lymphocytes/immunology , Adaptive Immunity/immunology , HIV Infections/complications , Chronic Disease , Chagas Disease/complications , Coinfection/immunology , Flow Cytometry
Braz. j. med. biol. res ; 50(10): e6139, 2017. tab, graf
Article in English | LILACS | ID: biblio-888929


Augmenter of liver regeneration (ALR) is a thermostable cytokine that was originally identified to promote the growth of hepatocytes. This study was conducted to explore the expression and function of ALR in multiple myeloma (MM), a common hematologic malignancy. Real-time PCR and western blot analysis were performed to detect the expression of ALR in U266 human MM cells and healthy peripheral blood mononuclear cells (PBMCs). U266 MM cells were exposed to 20 or 40 μg/mL of recombinant ALR and tested for cell proliferation. Small interfering RNA-mediated silencing of ALR was done to investigate the role of ALR in cell proliferation, apoptosis, and cytokine production. Compared to PBMCs, U266 MM cells exhibited significantly higher levels of ALR at both the mRNA and protein levels. The addition of recombinant ALR protein significantly promoted the proliferation of U266 cells. In contrast, knockdown of ALR led to a significant decline in the viability and proliferation of U266 cells. Annexin-V/PI staining analysis demonstrated that ALR downregulation increased apoptosis in U266 MM cells, compared to control cells (20.1±1.1 vs 9.1±0.3%, P<0.05). Moreover, ALR depletion reduced the Bcl-2 mRNA level by 40% and raised the Bax mRNA level by 2-fold. Additionally, conditioned medium from ALR-depleted U266 cells had significantly lower concentrations of interleukin-6 than control cells (P<0.05). Taken together, ALR contributed to the proliferation and survival of U266 MM cells, and targeting ALR may have therapeutic potential in the treatment of MM.

Humans , Apoptosis/drug effects , Cell Proliferation/drug effects , Multiple Myeloma/metabolism , Proteins/pharmacology , Blotting, Western , Cell Line, Tumor , Cytokines/biosynthesis , Down-Regulation , Flow Cytometry , Leukocytes, Mononuclear/metabolism , Multiple Myeloma/immunology , Proteins/physiology , Real-Time Polymerase Chain Reaction , Recombinant Proteins/pharmacology , RNA, Small Interfering/metabolism
Rev. bras. epidemiol ; 18(supl.2): 238-255, Out.-Dez. 2015. tab
Article in English | LILACS | ID: lil-776697


RESUMO: Objetivo: Descrever as prevalências dos fatores de risco e proteção para doenças crônicas na população adulta brasileira no ano de 2014, e investigar os fatores sociodemográficos associados. Métodos: Análise dos dados provenientes do inquérito telefônico Vigitel 2014, a partir de amostras probabilísticas da população adulta (≥ 18 anos) das capitais dos 26 estados brasileiros e Distrito Federal, residentes em domicílios com telefone fixo. Apresentadas prevalências por sexo, idade e escolaridade e razões de prevalências (RP) ajustadas, por meio da Regressão de Poisson. Resultados: Entre 40.853 adultos entrevistados, 10,8% são fumantes atuais e 21,2% ex-fumantes. O consumo abusivo de bebidas alcoólicas foi relatado por 16,5 e 52,5% apresentaram excesso de peso, fatores mais frequentes entre os homens. A prevalência do consumo recomendado de frutas e hortaliças foi de 24%, de doces de 18,1% e de substituição das refeições por lanches de 16,2%, maiores entre as mulheres. Atividade física no tempo livre alcançou 35,3% e aumentou com a escolaridade. A hipertensão arterial foi a doença mais frequente, com 24,8%, foi maior entre as mulheres, aumentando com idade. Conclusão: Os resultados do Vigitel 2014 indicam que os fatores de risco investigados costumam ser mais frequentes entre os homens, adultos de maior idade, e menos escolarizados, caracterizando o gradiente socioeconômico e cultural na determinação de doenças crônicas.

ABSTRACT: Objective: To describe the prevalence of risk and protective factors for chronic diseases in Brazilian adult population in 2014 and investigate the associated sociodemographic factors. Methods: Analyses were performed based on data from telephone interviews (Vigitel 2014) on probabilistic samples of adult population (≥ 18 years old) from the capitals of the 26 Brazilian States and the Federal District, living in households with landline phones. Prevalence is presented by gender, age and educational level, and adjusted prevalence ratios (PR) are estimated using Poisson Regression model. Results: Among the 40.853 adults who were interviewed, 10.8% were smokers and 21.2% ex-smokers. Among the respondents, 16.5% reported alcohol abuse and 52.5% were overweight, factors that were more frequent among men. The prevalence of recommended intake of fruits and vegetables was 24%, intake of sweets was 18.1% and replacements of main meals for snacks was 16.2%, factors that were higher among women. Leisure time physical activity reached 35.3% and increased with the level of education. Hypertension was the most frequent disease achieving 24.8%, which was higher among women and increased with age. Conclusion: The results from Vigitel 2014 indicate that risk factors are, in general, more frequent among men, older adults and less educated individuals, characterizing the socioeconomic and cultural dimensions in determining chronic diseases.

Animals , Mice , Adjuvants, Immunologic/pharmacology , Biocompatible Materials , Docosahexaenoic Acids/pharmacology , Inflammation/therapy , Cytokines/biosynthesis , Tissue Scaffolds
Mem. Inst. Oswaldo Cruz ; 110(5): 655-661, Aug. 2015. ilus
Article in English | LILACS | ID: lil-755889


Dendritic cells (DCs) play a pivotal role in the connection of innate and adaptive immunity of hosts to mycobacterial infection. Studies on the interaction of monocyte-derived DCs (MO-DCs) using Mycobacterium leprae in leprosy patients are rare. The present study demonstrated that the differentiation of MOs to DCs was similar in all forms of leprosy compared to normal healthy individuals. In vitro stimulation of immature MO-DCs with sonicated M. leprae induced variable degrees of DC maturation as determined by the increased expression of HLA-DR, CD40, CD80 and CD86, but not CD83, in all studied groups. The production of different cytokines by the MO-DCs appeared similar in all of the studied groups under similar conditions. However, the production of interleukin (IL)-12p70 by MO-DCs from lepromatous (LL) leprosy patients after in vitro stimulation with M. lepraewas lower than tuberculoid leprosy patients and healthy individuals, even after CD40 ligation with CD40 ligand-transfected cells. The present cumulative findings suggest that the MO-DCs of LL patients are generally a weak producer of IL-12p70 despite the moderate activating properties ofM. leprae. These results may explain the poor M. leprae-specific cell-mediated immunity in the LL type of leprosy.


Female , Humans , Male , Cytokines/biosynthesis , Dendritic Cells/immunology , Leprosy, Lepromatous/immunology , Monocytes/immunology , Mycobacterium leprae/immunology , Antigens, Bacterial/immunology , Case-Control Studies , In Vitro Techniques , /immunology , Retrospective Studies
Rev. bras. ginecol. obstet ; 37(1): 16-23, 01/2015. tab
Article in Portuguese | LILACS | ID: lil-732876


OBJETIVO: Avaliar o hábito alimentar e nutricional de mulheres na pós-menopausa e compará-los com o perfil antropométrico, faixa etária e tempo de menopausa. MÉTODOS: No período de junho a agosto de 2011, 148 mulheres na pós-menopausa residentes no Estado de São Paulo (região Sudeste do Brasil) foram avaliadas com um questionário estruturado contendo dados socioeconômicos, clínicos, antropométricos e alimentares. Avaliou-se nível de atividade física, variáveis bioquímicas, Índice de Massa Corporal (IMC), circunferência abdominal (CA) e consumo alimentar (energia, proteínas, carboidratos e gorduras, fibra, colesterol, vitaminas A e C, minerais, cálcio e ferro) de acordo com a faixa etária e o tempo de pós-menopausa (TPM). RESULTADOS: A média de IMC foi 29,0±5,6 kg/m2 e da CA, 95,7±12,9 cm. O consumo médio calórico diário atingiu 1.406,3±476,5 kcal. A ingestão e a adequação calórica foram significantemente mais apropriadas entre as mulheres eutróficas e com CA<88 cm. O mesmo ocorreu quanto ao consumo de proteínas (p<0,001 e p=0,006, respectivamente). Na análise por faixa etária ou TPM não houve diferenças significantes, exceto a média do consumo proteico, maior no grupo com 5 anos ou menos de menopausa (p=0,048). CONCLUSÃO: O perfil antropométrico de mulheres na pós-menopausa mostrou predominância de sobrepeso ou obesidade. O consumo alimentar apresentou-se adequado quanto às calorias e percentuais de macronutrientes, entre as eutróficas e com CA<88 cm. .

PURPOSE: To evaluate eating in postmenopausal women and its relation to anthropometry, age and time since menopause in São Bernardo do Campo residents. METHODS: During the period from June to August of 2011, 148 postmenopausal women residents in state of São Paulo (Southeast region of Brazil) were evaluated using a structured questionnaire containing socioeconomic, clinical, anthropometric and food data. The level of physical activity, biochemical variables, Body Mass Index (BMI), abdominal circumference (AC) and dietary intake (energy, protein, carbohydrates and fats, fiber, cholesterol, vitamins A and C, minerals, calcium and iron) were analyzed according to age and time after menopause. RESULTS: Mean BMI was 29.0≤5.6 kg/m2 and abdominal circumference was 95.7±12.9 cm. The average daily caloric consumption was 1,406.3±476.5 kcal. The calorie intake was significantly more appropriate in normal-weight women and women with AC<88 cm. The same was observed for protein intake (p<0.001 and p=0.006, respectively). No association was observed with age or duration of the postmenopausal period, except for average protein consumption that was higher in the group with five years or less of menopause (p=0.048). CONCLUSION: The anthropometry of postmenopausal women showed a predominance of overweight and obesity. Dietary intake was adequate in relation to the percentage of calories and macronutrients and calories among most normal-weight women and women with AC<88 cm. .

Humans , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cytokines/biosynthesis , Floxuridine/therapeutic use , Picibanil/therapeutic use , Stomach Neoplasms/drug therapy , Thymidine Phosphorylase/biosynthesis , Antineoplastic Agents/administration & dosage , Enzyme Induction , Floxuridine/administration & dosage , Gastrectomy , Gene Expression , Interleukin-1/biosynthesis , Neoplasm Invasiveness , Neoplasm Staging , Picibanil/administration & dosage , Stomach Neoplasms/pathology , Stomach Neoplasms/physiopathology , Stomach Neoplasms/surgery , Stomach/pathology , Tumor Necrosis Factor-alpha/biosynthesis
Article in English | WPRIM | ID: wpr-223789


Eupatilin is the main active component of DA-9601, an extract from Artemisia. Recently, eupatilin was reported to have anti-inflammatory properties. We investigated the anti-arthritic effect of eupatilin in a murine arthritis model and human rheumatoid synoviocytes. DA-9601 was injected into collagen-induced arthritis (CIA) mice. Arthritis score was regularly evaluated. Mouse monocytes were differentiated into osteoclasts when eupatilin was added simultaneously. Osteoclasts were stained with tartrate-resistant acid phosphatase and then manually counted. Rheumatoid synoviocytes were stimulated with TNF-alpha and then treated with eupatilin, and the levels of IL-6 and IL-1beta mRNA expression in synoviocytes were measured by RT-PCR. Intraperitoneal injection of DA-9601 reduced arthritis scores in CIA mice. TNF-alpha treatment of synoviocytes increased the expression of IL-6 and IL-1beta mRNAs, which was inhibited by eupatilin. Eupatilin decreased the number of osteoclasts in a concentration dependent manner. These findings, showing that eupatilin and DA-9601 inhibited the expression of inflammatory cytokines and the differentiation of osteoclasts, suggest that eupatilin and DA-9601 is a candidate anti-inflammatory agent.

Animals , Anti-Inflammatory Agents/pharmacology , Arthritis, Experimental/chemically induced , Arthritis, Rheumatoid/drug therapy , Cell Differentiation/drug effects , Cells, Cultured , Collagen Type II , Cytokines/biosynthesis , Disease Models, Animal , Drugs, Chinese Herbal/therapeutic use , Female , Flavonoids/pharmacology , Humans , Inflammation/drug therapy , Interleukin-1beta/genetics , Interleukin-6/genetics , Lymph Nodes/cytology , Mice , Mice, Inbred DBA , Monocytes/cytology , Osteoclasts/cytology , Plant Extracts/pharmacology , RNA, Messenger/biosynthesis , Synovial Membrane/cytology , T-Lymphocytes, Regulatory/cytology , Tumor Necrosis Factor-alpha/pharmacology
Braz. j. microbiol ; 45(4): 1449-1454, Oct.-Dec. 2014. ilus, tab
Article in English | LILACS | ID: lil-741299


The Brazilian Purpuric Fever (BPF) is a systemic disease with many clinical features of meningococcal sepsis and is usually preceded by purulent conjunctivitis. The illness is caused by Haemophilus influenza biogroup aegyptius, which was associated exclusively with conjunctivitis. In this work construction of the las gene, hypothetically responsible for this virulence, were fusioned with ermAM cassette in Neisseria meningitidis virulent strains and had its DNA transfer to non BPF H. influenzae strains. The effect of the las transfer was capable to increase the cytokines TNFα and IL10 expression in Hec-1B cells line infected with these transformed mutants (in eight log scale of folding change RNA expression). This is the first molecular study involving the las transfer to search an elucidation of the pathogenic factors by horizontal intergeneric transfer from meningococci to H. influenzae.

Humans , Cytokines/biosynthesis , Epithelial Cells/immunology , Epithelial Cells/microbiology , Haemophilus Infections/immunology , Haemophilus influenzae/immunology , Virulence Factors/immunology , Brazil , Cell Line , Cloning, Molecular , Haemophilus Infections/microbiology , Haemophilus Infections/pathology , Haemophilus influenzae/genetics , Recombinant Proteins/genetics , Recombinant Proteins/immunology , Transformation, Bacterial , Virulence Factors/genetics
Rev. bras. enferm ; 67(5): 773-779, Sep-Oct/2014.
Article in Portuguese | LILACS, BDENF | ID: lil-731205


Pesquisa descritiva, qualitativa, com abordagem compreensiva, que teve por objetivo compreender o significado da instituição de longa permanência para idosos institucionalizados. Os dados foram coletados com 13 idosos institucionalizados, no período de 5 de abril a 25 de maio de 2013 por meio da entrevista narrativa, e submetidos a análise de conteúdo, na modalidade de análise temática. Os resultados indicam que ser idoso institucionalizado significa ter suas necessidades de cuidado atendidas, no que concerne a suas necessidades básicas; ao acesso a serviços e recursos de saúde, e a ter um lugar onde possam envelhecer e morrer. O estudo permitiu concluir que a instituição aparece como um lugar ambíguo para os idosos, pois ao mesmo tempo em que os acolhe, abriga e atende suas necessidades, é um ambiente que inviabiliza a vida independente e autônoma.

This is a descriptive, qualitative research, with comprehensive approach, which aimed to understand the meaning that the longterm institution has to institutionalized elderly. Data were collected with 13 institutionalized elderly in the period from April 5 to May 25, 2013, through narrative interview, and subjected to content analysis, in the form of thematic analysis. The results indicated that being elderly institutionalized means having their care needs met, with respect to their basic needs; access to health services and resources, and to have a place where they can grow old and die. The study concluded that the institution appears as an ambiguous place for the elderly because, even embracing and housing them and meeting their needs, is an environment that prevents the independent and autonomous life.

Investigación descriptiva, cualitativa con enfoque comprehensivo, que tuve como objetivo comprender el significado de la institución a largo plazo tiene para ancianos institucionalizados. Los datos fueron recolectados con 13 ancianos institucionalizados en el periodo comprendido entre el 5 abril-25 mayo de 2013, a través de entrevista narrativa, y tratados mediante análisis de contenido, en la modalidad de análisis temático. Los resultados indican que estar en edad avanzada y estar institucionalizado significa tener sus atendidas sus necesidades básicas; el acceso a los servicios de salud y los recursos, y tener un lugar donde pueden envejecer y morir. El estudio llegó a la conclusión de que la institución se presenta como un lugar ambiguo para las personas mayores, ya que si bien les acoja, albergue y atiendan sus necesidades, es un ambiente que impide la vida independiente y autónoma.

Humans , Male , Female , Adult , Middle Aged , Cytokines/biosynthesis , Hepatitis C, Chronic/immunology , Hepacivirus/immunology , In Vitro Techniques , Interleukin-1/biosynthesis , /biosynthesis , /biosynthesis , Monocytes/immunology , Tumor Necrosis Factor-alpha/biosynthesis , Viremia/immunology
Invest. clín ; 55(1): 61-81, mar. 2014. ilus
Article in Spanish | LILACS | ID: lil-746286


Las células del sistema inmunitario (SI) son capaces de reconocer una gran variedad de microorganismos, a través de los receptores que se encuentran expresados y distribuidos a lo largo de su arquitectura celular. La interacción entre los patrones moleculares asociados a microorganismos o a daño (PMAM o PMAD) y los receptores reconocedores de patrones (RRP) presentes en las células del hospedero es un evento crítico que implica procesos intracelulares de señalización que finalizan en la expresión de mediadores tanto proinflamatorios como antivirales. Por consiguiente, de la integridad de estos receptores dependerá el buen funcionamiento de los distintos mecanismos de transducción de señal desde las membranas celulares al citoplasma y por ende, de la respuesta que el SI desencadene contra los patógenos entre ellos los agentes virales. De allí que, en esta revisión se discutirá el papel de los receptores tipo toll (TLRs) y receptores para dominios de oligomerización para la unión a nucleótidos (NLRs) en las infecciones virales, tomando como evidencia los estudios en humanos y ratones que a la fecha se conocen.

The immune system (IS) cells are capable of recognizing a wide variety of microorganisms, through receptors that are expressed and distributed throughout the cell architecture. The interaction between the pathogen-associated molecular patterns or damage-associated molecular patterns (PAMPs or DAMPs) and pattern recognition receptors (PRR), present in host cells, is a critical event that involves intracellular signaling processes that end up in the expression of both, proinflammatory and antiviral mediators. Accordingly, the proper functioning of the different mechanisms of signal transduction from the cell membrane to the cytoplasm will depend on the integrity of these receptors (PRR); and therefore, the IS response triggered against pathogens including viral agents. Hence, in this review we discuss the role of toll-like receptors (TLRs) and nucleotide-binding oligomerization domain receptors (NLRs) in viral infections, using as evidence the studies in humans and mice known to date.

Animals , Humans , Mice , CARD Signaling Adaptor Proteins/physiology , Host-Pathogen Interactions/immunology , /physiology , Toll-Like Receptors/physiology , Virus Diseases/immunology , Carrier Proteins/physiology , Cytokines/biosynthesis , Cytokines/genetics , Evolution, Molecular , Forecasting , Immunity, Innate , Models, Immunological , Multigene Family , Nod1 Signaling Adaptor Protein/physiology , Protein Structure, Tertiary , Signal Transduction , Toll-Like Receptors/chemistry , Toll-Like Receptors/classification
Article in English | WPRIM | ID: wpr-53763


Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by abnormal proliferation of synoviocytes, leukocyte infiltration, and angiogenesis. The endoplasmic reticulum (ER) is the site of biosynthesis for all secreted and membrane proteins. The accumulation of unfolded proteins in the ER leads to a condition known as ER stress. Failure of the ER's adaptive capacity results in abnormal activation of the unfolded protein response. Recently, we have demonstrated that ER stress-associated gene signatures are highly expressed in RA synovium and synovial cells. Mice with Grp78 haploinsufficiency exhibit the suppression of experimentally induced arthritis, suggesting that the ER chaperone GRP78 is crucial for RA pathogenesis. Moreover, increasing evidence has suggested that GRP78 participates in antibody generation, T cell proliferation, and pro-inflammatory cytokine production, and is therefore one of the potential therapeutic targets for RA. In this review, we discuss the putative, pathophysiological roles of ER stress and GRP78 in RA pathogenesis.

Animals , Arthritis, Rheumatoid/genetics , Autoantibodies/immunology , Cell Proliferation , Cytokines/biosynthesis , Endoplasmic Reticulum/immunology , Endoplasmic Reticulum Stress/immunology , Haploinsufficiency/genetics , Heat-Shock Proteins/genetics , Humans , Lymphocyte Activation , Mice , Neovascularization, Pathologic/genetics , Protein Folding , Synovial Membrane/cytology , T-Lymphocytes/immunology , Unfolded Protein Response/immunology
Article in Spanish | LILACS | ID: lil-687663


Objetivo: Sobre la base de la antigenicidad del polisacárido O del LPS, en A. actinomycetemcomitans se describen distintos serotipos bacterianos y entre ellos se ha especulado una patogenicidad e inmunogenicidad diferente. El objetivo de este trabajo es analizar las diferencias en la síntesis de citoquinas producidas por células dendríticas cuando son estimuladas con los distintos serotipos de A. actinomycetemcomitans. Metodología: Células dendríticas diferenciadas a partir de monocitos circulantes periféricos humanos fueron estimuladas a MOIs=10-1-10-2 con los serotipos a, b y c de A. Actinomycetemcomitans. Mediante PCR y ELISA se evaluaron los niveles de expresión y secreción de citoquinas. Resultados: En las células dendríticas, la producción de citoquinas fue diferente ante los distintos serotipos de A. actinomycetemcomitans, con mayores niveles de secreción de IL-1beta, IL-6, IL-12, IL-23, IFN-gamma y TNF-alfa cuando el microorganismo estimulante fue la cepa ATCC® 43718™ (serotipo b). Conclusión: El serotipo b de A. actinomycetemcomitans posee un mayor potencial inmuno-estimulador de células dendríticas comparado con los otros serotipos bacterianos y potencialmente contribuiría a inducir un patrón de respuesta inmune tipo Th1 y/o Th17 durante las periodontitis.

Objective: A. actinomycetemcomitans expresses a number of virulence factors that contribute to direct tissue damage and, based on the antigenicity of LPS O-polysaccharide, distinct serotypes have been described. The aim of this study was to determine the pattern of cytokine expression and secretion on dendritic cells stimulated with A. actinomycetemcomitans serotypes a, b and c. Methods: Using different multiplicity of infections of the serotypes a, b, and c of A. actinomycetemcomitans, the mRNA expression and secretion levels for cytokines IL-1beta, IL-5, IL-6, IL-10, IL-12, IL-23, TNF-alpha, and IFN-gamma were determined in stimulated dendritic cells using PCR and ELISA. Results: A dose-dependent increase in the secretion levels for IL-1beta, IL-5, IL-6, IL-10, IL-12, IL-23, TNF-alpha, and IFN-gamma was elicited on dendritic cells following stimulation with each of the serotypes of A. actinomycetemcomitans. In addition, A. actinomycetemcomitans serotype b (ATCC® 43718™) induced higher levels of IL-1beta, IL-6, IL-12, IL-23, IFN-gamma y TNF-alpha compared with the other strains. Conclusion: These data demonstrate that the distinct A. actinomycetemcomitans LPS O-polysaccharide serotypes induce both quantitative and qualitative differences in the dendritic cell response. Furthermore, the observed dendritic cell response to A. actinomycetemcomitans b serotype was characteristic of a Th1 and Th17 pattern of cytokine expression.

Aggregatibacter actinomycetemcomitans , Dendritic Cells/metabolism , Cytokines/biosynthesis , Enzyme-Linked Immunosorbent Assay , Polymerase Chain Reaction
Braz. j. med. biol. res ; 46(5): 433-439, maio 2013. graf
Article in English | LILACS | ID: lil-675673


Primary biliary cirrhosis (PBC) is a chronic and slowly progressive cholestatic liver disease of autoimmune etiology. A number of questions regarding its etiology are unclear. CD4+CD25+ regulatory T cells (Tregs) play a critical role in self-tolerance and, for unknown reasons, their relative number is reduced in PBC patients. B-cell-activating factor (BAFF) is a key survival factor during B-cell maturation and its concentration is increased in peripheral blood of PBC patients. It has been reported that activated B cells inhibit Treg cell proliferation and there are no BAFF receptors on Tregs. Therefore, we speculated that excessive BAFF may result in Treg reduction via B cells. To prove our hypothesis, we isolated Tregs and B cells from PBC and healthy donors. BAFF and IgM concentrations were then analyzed by ELISA and CD40, CD80, CD86, IL-10, and TGF-β expression in B cells and Tregs were measured by flow cytometry. BAFF up-regulated CD40, CD80, CD86, and IgM expression in B cells. However, BAFF had no direct effect on Treg cell apoptosis and cytokine secretion. Nonetheless, we observed that BAFF-activated B cells could induce Treg cell apoptosis and reduce IL-10 and TGF-β expression. We also showed that BAFF-activated CD4+ T cells had no effect on Treg apoptosis. Furthermore, we verified that bezafibrate, a hypolipidemic drug, can inhibit BAFF-induced Treg cell apoptosis. In conclusion, BAFF promotes Treg cell apoptosis and inhibits cytokine production by activating B cells in PBC patients. The results of this study suggest that inhibition of BAFF activation is a strategy for PBC treatment.

Female , Humans , Male , Middle Aged , Apoptosis/drug effects , B-Lymphocytes, Regulatory/drug effects , B-Lymphocytes/drug effects , Bezafibrate/pharmacology , Cytokines/biosynthesis , Liver Cirrhosis, Biliary/immunology , B-Cell Activating Factor , B-Lymphocytes, Regulatory/metabolism , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Lymphocyte Activation
J. pediatr. (Rio J.) ; 89(1): 40-47, jan.-fev. 2013. ilus, tab
Article in Portuguese | LILACS | ID: lil-668824


OBJETIVO: Comparar o estado imunológico de 44 pacientes pediátricos com fibrose cística (FC)a umgrupo-controle formado por 16 indivíduos saudáveis. MÉTODOS: Foram selecionados para o estudo pacientes com FC com idade entre 3 e 12 anos, apresentando um escore clínico moderado e bom. Foram avaliados a glutationa eritrocitária, a produção de espécies reativas de oxigênio, citocinas (TNF-α, IFN-γ, IL-8, IL-6, IL-10) em culturas de células mononucleares do sangue periférico em condições espontâneas e estimuladas por BCG ou PHA, a concentração sérica de TGF-β2, IgA, IgG, IgM, IgE e IgA salivar. RESULTADOS :A produção espontânea de TNF-α, IL-6 e IL-10, a produção de IL-6 estimulada por PHA e TGF-β2, IgA e IgG séricas aumentaram em amostras de pacientes com FC. Indivíduos saudáveis tiveram uma produção mais elevada de TNF-α em resposta a BCG. CONCLUSÃO: Apesar de os pacientes com FC parecerem clinicamente estáveis, os resultados de seus exames de sangue periférico mostraram que houve um impacto sobre o sistema imunológico.

OBJECTIVE: To compare the immunologic state of 44 pediatric patients with cystic fibrosis (CF) with a control group consisting of 16 healthy individuals. METHODS: CF patients aged 3 to 12 years with moderate to good clinical score were selected for the study. Erythrocytic glutathione, production of reactive oxygen species, cytokines (TNF-α, IFN-γ, IL-8, IL-6, IL-10) in peripheral blood mononuclear cells cultures under spontaneous and BCG- or PHA-stimulated conditions, serum concentrations of TGF-β2, IgA, IgG, IgM, IgE, and salivary IgA were evaluated. RESULTS: The spontaneous production of TNF-α, IL-6, and IL-10, the PHA-stimulated production of IL-6, and the serum TGF-β2, IgA, and IgG were increased in samples from CF patients. Healthy subjects had a higher production of TNF-α in response to BCG. CONCLUSION: Although CF patients appearedclinically stable, the results of their peripheral blood examinations demonstrated an impact on the immune system.

Child , Child, Preschool , Female , Humans , Male , Cystic Fibrosis/immunology , Cytokines/biosynthesis , Glutathione/biosynthesis , Immunoglobulins/blood , Case-Control Studies , Cell Culture Techniques , Cross-Sectional Studies , Cystic Fibrosis/blood , Enzyme-Linked Immunosorbent Assay , Inflammation Mediators/blood , Leukocytes, Mononuclear/chemistry , Monitoring, Immunologic , Reactive Oxygen Species/blood , Saliva/immunology , /blood
An. bras. dermatol ; 88(1): 32-40, fev. 2013. tab, graf
Article in English | LILACS | ID: lil-667938


BACKGROUND: The histopathology and immune responses of the healing process of leishmaniasis are still poorly studied. OBJECTIVES: This study aimed to examine the histopathological and immunological aspects of lesions of patients with cutaneous leishmaniasis before and after different therapeutic methods. METHODS: We studied 23 individuals grouped according to the treatments: Glucantime, Glucantime + Leishvacin and Glucantime + Leishvacin associated with Bacillus Calmette-Guerin. For analysis of the histopathological changes present in the dermis and epidermis, histological sections were stained with hematoxylin and eosin. The samples were immunostained before and after treatment to analyze the expression of interferon (IFN)-γ, interleukin (IL) 12, IL-10 and IL-4. RESULTS: Before treatment the presence of intense infiltrates of mononuclear cells was noticed and after treatment, even with a diagnosis of clinical cure, the subjects still showed a moderate inflammatory process. In the immunohistochemical analyses, we noticed a difference between the cytokines, with increased expression of cytokines IFN-γ and IL-12 compared to IL 10 and IL-4, both before and after treatment and, comparatively, the difference in this expression was more intense before treatment. However, the cytokine expression analyzed by treatment group showed no statistically significant difference. CONCLUSION: We conclude that a clinical cure does not always coincide with the histopathological ...

FUNDAMENTOS: A histopatologia e as respostas imunológicas do processo de cura da leishmaniose são ainda pouco estudadas. OBJETIVOS: Este estudo teve como objetivo avaliar os aspectos histopatológicos e imunológicos das lesões de pacientes com leishmaniose tegumentar, antes e após diferentes métodos terapêuticos. MÉTODOS: Foram estudados 23 indivíduos agrupados de acordo com os tratamentos: Glucantime, Glucantime + Leishvacin e Glucantime + Leishvacin associado com Bacilo Calmette-Guerin. Para a análise das alterações histopatológicas presentes na derme e epiderme, cortes histológicos foram corados com hematoxilina e eosina. Para avaliar a expressão de interferon (IFN)-γ, interleucina (IL) 12, IL-10 e IL-4 foi utilizada a técnica de imuno-histoquímica antes e após o tratamento. RESULTADOS: Antes do tratamento houve um intenso infiltrado de células mononucleares, após o tratamento, mesmo com um diagnóstico de cura clínica, apresentou-se ainda um moderado processo inflamatório. Na análise imuno-histoquímica, notamos uma diferença entre as citocinas, com expressão aumentada de citocinas IFN-γ e IL-12 em comparação com IL-10 e IL-4 tanto antes quanto depois do tratamento, e comparativamente, a diferença nesta expressão mostrou-se mais intensa antes do tratamento. No entanto, a expressão das citocinas analisadas por grupo de tratamento não mostraram diferenças ...

Adolescent , Adult , Aged , Child , Female , Humans , Male , Middle Aged , Young Adult , Antiprotozoal Agents/therapeutic use , Cytokines/biosynthesis , Immunotherapy, Active/methods , Leishmaniasis , Adjuvants, Immunologic/therapeutic use , BCG Vaccine/therapeutic use , Immunohistochemistry , Leishmania/immunology , Leishmaniasis Vaccines/therapeutic use , Leishmaniasis/drug therapy , Leishmaniasis/immunology , Leishmaniasis/pathology , Meglumine/therapeutic use , Organometallic Compounds/therapeutic use , Retrospective Studies , Treatment Outcome , Wound Healing/drug effects
Article in English | WPRIM | ID: wpr-199831


Toll-like receptors (TLRs) are pivotal components of the innate immune response, which is responsible for eradicating invading microorganisms through the induction of inflammatory molecules. These receptors are also involved in responding to harmful endogenous molecules and have crucial roles in the activation of the innate immune system and shaping the adaptive immune response. However, TLR signaling pathways must be tightly regulated because undue TLR stimulation may disrupt the fine balance between pro- and anti-inflammatory responses. Such disruptions may harm the host through the development of autoimmune and inflammatory diseases, such as rheumatoid arthritis and systemic lupus erythematosus. Several studies have investigated the regulatory pathways of TLRs that are essential for modulating proinflammatory responses. These studies reported several pathways and molecules that act individually or in combination to regulate immune responses. In this review, we have summarized recent advancements in the elucidation of the negative regulation of TLR signaling. Moreover, this review covers the modulation of TLR signaling at multiple levels, including adaptor complex destabilization, phosphorylation and ubiquitin-mediated degradation of signal proteins, manipulation of other receptors, and transcriptional regulation. Lastly, synthetic inhibitors have also been briefly discussed to highlight negative regulatory approaches in the treatment of inflammatory diseases.

Animals , Cytokines/biosynthesis , Humans , Ligands , Models, Immunological , Signal Transduction/immunology , Toll-Like Receptors/antagonists & inhibitors
Article in English | WPRIM | ID: wpr-199828


We evaluated the effectiveness of rhamnogalacturonan II (RG-II)-stimulated bone marrow-derived dendritic cells (BMDCs) vaccination on the induction of antitumor immunity in a mouse lymphoma model using EG7-lymphoma cells expressing ovalbumin (OVA). BMDCs treated with RG-II had an activated phenotype. RG-II induced interleukin (IL)-12, IL-1beta, tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) production during dendritic cell (DC) maturation. BMDCs stimulated with RG-II facilitate the proliferation of CD8+ T cells. Using BMDCs from the mice deficient in Toll-like receptors (TLRs), we revealed that RG-II activity is dependent on TLR4. RG-II showed a preventive effect of immunization with OVA-pulsed BMDCs against EG7 lymphoma. These results suggested that RG-II expedites the DC-based immune response through the TLR4 signaling pathway.

Acute-Phase Proteins/metabolism , Adaptor Proteins, Vesicular Transport/metabolism , Animals , Lipopolysaccharide Receptors/metabolism , Bone Marrow Cells/cytology , CD8-Positive T-Lymphocytes/immunology , Carrier Proteins/metabolism , Cell Differentiation/drug effects , Cell Nucleus/drug effects , Cell Proliferation/drug effects , Cytokines/biosynthesis , Dendritic Cells/cytology , Enzyme Activation/drug effects , Lymphocyte Activation/drug effects , Membrane Glycoproteins/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Mitogen-Activated Protein Kinases/metabolism , Myeloid Differentiation Factor 88/metabolism , NF-kappa B/metabolism , Neoplasms/immunology , Pectins/pharmacology , Phenotype , Protein Transport/drug effects , Receptors, Chemokine/metabolism , Signal Transduction/drug effects , T-Lymphocytes, Cytotoxic/cytology , Toll-Like Receptor 4/agonists
Article in English | IMSEAR | ID: sea-144771


Background & objectives: In congestive heart failure (CHF), increased concentrations of several cytokines including cardiotrophin-1 (CT-1) and immunactivation are found. This study was performed to evaluate whether CT-1 can induce in vitro cytokines in monocytes and CD4+ T-lymphocytes of healthy volunteers. Methods: The study was performed in vitro to see whether CT-1 can modulate monocyte or CD4+ T-lymphocyte interleukin (IL)-1β, -2, -4, -5, -10, interferon γ (IFNγ), and tumour necrosis factor α (TNFα) expression by flow cytometry following stimulation with CT-1 alone or together with lipopolysaccharide (LPS) or phorbol myristate acetate (PMA)/ionomycine (iono). Results: CT-1 increased the number of TNFα and IL-1β positive monocytes. LPS induced IL-10, TNFα, and IL-1β in monocytes but only IL-2 in CD4+ T-lymphocytes, whereas PMA/iono induced all cytokines besides IL-5 in monocytes and IL-1β in CD4+ T-lymphocytes. In LPS activated monocytes, CT-1 induced a concentration-dependent reduction in the number of TNFα positive monocytes. After LPS activation, CT-1 decreased the number of CD4+ lymphocytes positive for IL-2, IL-4, and IL-5. In addition, following PMA/iono stimulation, CT-1 initiated a concentration-dependent decrease of CD4+ T-lymphocytes positive for TNFα, IL-4, IL-5, and IL-10. Interpretation & conclusions: The present data show that in vitro CT-1 can activate monocytes and modulate cytokine production of activated CD4+ T-lymphocytes. We speculate that CT-1 may at least be partly responsible for immunactivation in CHF.

Adjuvants, Pharmaceutic , Adult , CD4-Positive T-Lymphocytes/immunology , Cytokines/biosynthesis , Cytokines/immunology , Cytokines/pharmacokinetics , Heart Failure , Humans , Immunosuppressive Agents/pharmacokinetics , Tumor Necrosis Factor-alpha
Mem. Inst. Oswaldo Cruz ; 107(3): 348-355, May 2012. graf
Article in English | LILACS | ID: lil-624016


We investigated the cytokine profile of peripheral mononuclear cells from chronic osteomyelitis (OST) patients following in vitro stimulation with staphylococcal enterotoxin A (SEA). We demonstrate that stimulation with SEA induced prominent lymphocyte proliferation and high levels of tumour necrosis factor (TNF)-α, interleukin (IL)-4 and IL-10 secretion in both OST and non-infected individuals (NI). Even though stimulation with SEA had no impact on IL-6 production in either patient group, the baseline level of IL-6 production by cells from OST patients was always significantly less than that produced by cells from NI. After classifying the osteomyelitic episodes based on the time after the last reactivation event as "early" (1-4 months) or "late" osteomyelitis (5-12 months), we found that increased levels of TNF-α and IL-4 in combination with decreased levels of IL-6 were observed in the early episodes. By contrast, increased levels of IL-10, IL-2 and IL-6 were hallmarks of late episodes. Our data demonstrate that early osteomyelitic episodes are accompanied by an increased frequency of "high producers" of TNF-α and IL-4, whereas late events are characterised by increased frequencies of "high producers" of IL-10, IL-6 and IL-2. These findings demonstrate the distinct cytokine profiles in chronic osteomyelitis, with a distinct regulation of IL-6 production during early and late episodes.

Adolescent , Adult , Child , Female , Humans , Male , Middle Aged , Young Adult , Cytokines/biosynthesis , Enterotoxins/immunology , Leukocytes, Mononuclear/immunology , Nitric Oxide/biosynthesis , Osteomyelitis/immunology , Staphylococcal Infections/immunology , Staphylococcus aureus/immunology , Case-Control Studies , Chronic Disease , Interleukins/biosynthesis , Lymphocyte Activation , Osteomyelitis/microbiology , Tumor Necrosis Factor-alpha/biosynthesis