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1.
Nat Commun ; 11(1): 4457, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32901017

RESUMO

Innate lymphoid cells (ILCs) and CD4+ T cells produce IL-22, which is critical for intestinal immunity. The microbiota is central to IL-22 production in the intestines; however, the factors that regulate IL-22 production by CD4+ T cells and ILCs are not clear. Here, we show that microbiota-derived short-chain fatty acids (SCFAs) promote IL-22 production by CD4+ T cells and ILCs through G-protein receptor 41 (GPR41) and inhibiting histone deacetylase (HDAC). SCFAs upregulate IL-22 production by promoting aryl hydrocarbon receptor (AhR) and hypoxia-inducible factor 1α (HIF1α) expression, which are differentially regulated by mTOR and Stat3. HIF1α binds directly to the Il22 promoter, and SCFAs increase HIF1α binding to the Il22 promoter through histone modification. SCFA supplementation enhances IL-22 production, which protects intestines from inflammation. SCFAs promote human CD4+ T cell IL-22 production. These findings establish the roles of SCFAs in inducing IL-22 production in CD4+ T cells and ILCs to maintain intestinal homeostasis.


Assuntos
Ácidos Graxos Voláteis/imunologia , Microbioma Gastrointestinal/imunologia , Imunidade Inata , Interleucinas/biossíntese , Animais , Butiratos/imunologia , Butiratos/metabolismo , Butiratos/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/microbiologia , Citrobacter rodentium , Colite/imunologia , Colite/microbiologia , Colite/prevenção & controle , Infecções por Enterobacteriaceae/imunologia , Infecções por Enterobacteriaceae/microbiologia , Infecções por Enterobacteriaceae/prevenção & controle , Ácidos Graxos Voláteis/metabolismo , Ácidos Graxos Voláteis/farmacologia , Microbioma Gastrointestinal/fisiologia , Inibidores de Histona Desacetilases/farmacologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Técnicas In Vitro , Interleucinas/deficiência , Interleucinas/genética , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Linfócitos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Regiões Promotoras Genéticas , Receptores de Hidrocarboneto Arílico/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo
2.
Antiviral Res ; 180: 104860, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32565134

RESUMO

Middle East Respiratory Syndrome Coronavirus (MERS-CoV) causes severe respiratory in human with high mortality and it has been a challenge to determine optimum treatment for MERS-CoV-induced respiratory infection. Here, we observed the distribution of MERS-CoV receptors using human respiratory mucosa and also evaluated the contribution of interferon-lambdas (IFN-λs) in response to MERS-CoV infection using in vitro normal human nasal epithelial (NHNE) and bronchial epithelial (NHBE) cells. We found that the gene and protein expression of DPPIV, MERS-CoV receptor, were more dominantly located in nasal and bronchial epithelium although human nasal mucosa exhibited relatively lower DPPIV expression than lung parenchymal tissues. The quantitative mRNA level of the MERS-CoV envelope (upE) gene was significantly induced in MERS-CoV-infected cultured NHNE and NHBE cells until 3 days after infection. The induction of IFNs was identified in NHNE and NHBE cells after MERS-CoV infection and IFN-λs were predominantly increased in MERS-CoV-infected respiratory epithelial cells. Inoculation of IFN-λs to NHNE and NHBE cells suppressed MERS-CoV replication and in particular, IFN-λ4 showed a strong therapeutic effect in reducing MERS-CoV infection with higher induction of IFN-stimulated genes. Thus, IFN-λ has a decisive function in the respiratory epithelium that greatly limits MERS-CoV replication, and may be a key cytokine for better therapeutic outcomes against MERS-CoV infection in respiratory tract.


Assuntos
Antivirais/uso terapêutico , Interferons/uso terapêutico , Interleucinas/uso terapêutico , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Mucosa Respiratória/virologia , Replicação Viral/efeitos dos fármacos , Brônquios/virologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Citocinas/metabolismo , Células Epiteliais/virologia , Regulação Viral da Expressão Gênica , Humanos , Imunidade Inata/imunologia , Interferons/biossíntese , Interleucinas/biossíntese , Mucosa Laríngea/virologia , Pulmão/virologia , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Reação em Cadeia da Polimerase , Mucosa Respiratória/efeitos dos fármacos
3.
Medicine (Baltimore) ; 99(18): e19967, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32358369

RESUMO

The present study aimed to investigate the association between the expressions of serum progranulin (PGRN) and serum soluble Oxford 40 ligand (sOX40L) and determine their clinical significances in primary Sjögren's syndrome (pSS).The present study included a total of 68 patients with pSS and 50 healthy controls. Demographic data and clinical basic information were collected. Enzyme-linked immunosorbent assay (ELISA) was performed to determine serum levels of PGRN, sOX40L and interleukins. Spearman's correlation coefficient and Mann-Whitney U test were used to determine the correlation between PGRN, and sOX40L and the association between PGRN and sOX40L and disease activity and disease severity.Serum interleukin (IL)-4, IL-6, IL-10, PGRN, and sOX40L levels were significantly higher in pSS patients as compared to the healthy controls. A positive correlation was observed between PGRN and sOX40L. Patients with elevated levels of PGRN or sOX40L exhibited higher disease activity compared to those with lower levels. Patients with III to IV stages of pSS or multiple system damage showed higher serum levels of PGRN and sOX40L.Elevated serum PGRN, and sOX40L levels were relevant with disease activity and severity in patients with pSS.


Assuntos
Progranulinas/sangue , Receptores do Fator de Necrose Tumoral/sangue , Síndrome de Sjogren/fisiopatologia , Adulto , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Interleucinas/biossíntese , Interleucinas/sangue , Masculino , Pessoa de Meia-Idade , Progranulinas/biossíntese , Estudos Prospectivos , Receptores do Fator de Necrose Tumoral/biossíntese , Índice de Gravidade de Doença , Síndrome de Sjogren/sangue , Fatores Socioeconômicos
4.
Nat Commun ; 11(1): 2608, 2020 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-32451418

RESUMO

IL-22 has dual functions during tumorigenesis. Short term IL-22 production protects against genotoxic stress, whereas uncontrolled IL-22 activity promotes tumor growth; therefore, tight regulation of IL-22 is essential. TGF-ß1 promotes the differentiation of Th17 cells, which are known to be a major source of IL-22, but the effect of TGF-ß signaling on the production of IL-22 in CD4+ T cells is controversial. Here we show an increased presence of IL-17+IL-22+ cells and TGF-ß1 in colorectal cancer compared to normal adjacent tissue, whereas the frequency of IL-22 single producing cells is not changed. Accordingly, TGF-ß signaling in CD4+ T cells (specifically Th17 cells) promotes the emergence of IL-22-producing Th17 cells and thereby tumorigenesis in mice. IL-22 single producing T cells, however, are not dependent on TGF-ß signaling. We show that TGF-ß, via AhR induction, and PI3K signaling promotes IL-22 production in Th17 cells.


Assuntos
Colite/complicações , Neoplasias do Colo/etiologia , Interleucinas/biossíntese , Células Th17/imunologia , Fator de Crescimento Transformador beta/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carcinogênese/imunologia , Diferenciação Celular , Colite/imunologia , Neoplasias do Colo/imunologia , Neoplasias do Colo/patologia , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Modelos Animais de Doenças , Feminino , Humanos , Interleucina-17/genética , Interleucina-17/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fosfatidilinositol 3-Quinases/metabolismo , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais/imunologia , Células Th17/patologia , Fator de Crescimento Transformador beta1/metabolismo
5.
Medicine (Baltimore) ; 99(13): e19430, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32221067

RESUMO

INTRODUCTION: Loss of a dental element can generate several repercussions in the stomatognathic system. According to the latest survey by the Ministry of Health, in 2010, Brazilian adults had, on average, 7 missing teeth. This loss may lead to movement of the adjacent teeth and the antagonist, which would make prosthetic rehabilitation harder to do. Anchoring systems, such as mini-implants, have been increasingly used as a treatment option because they act with heavy but controlled forces and without side effects. Recent studies have shown that photobiomodulation (PBM) can accelerate orthodontic movement in molar intrusion. The objective of this study will be to evaluate the effect of PBM on the acceleration of the orthodontic movement of molar verticalization and its effect on pain and inflammation of the periodontal tissues. PATIENT CONCERNS:: the concerns assessments will be done over the study using anamnesis interviews and specific questionnaire. DIAGNOSIS: verticalization will be evaluated by clinical and radiographic analysis. INTERVENTIONS: Thirty four healthy patients aged 30 to 60 years, who need to recover the prosthetic space for oral rehabilitation after loss of the posterior inferior dental elements and inclination of the adjacent element, will be randomly divided into 2 groups: G1 (control group) - verticalization by mini-implant + PBM simulation (placebo); G2 (experimental group) - verticalization by mini-implant + PBM. The movements will occur with the aid of mini-implants and elastomeric chains ligatures. The PBM will occur with diode laser application, 808 nm, 100 mW, receiving 1J per point, 10 seconds, 10 points (5 per buccal and 5 per lingual) and radiant exposure of 25 J/cm. The orthodontic forces of verticalization (corresponding to any exchange of elastomeric ligation) will be applied every 30 days and the PBM will be applied immediately, 3 and 7 days of each month, for a period of 3 months. The crevicular gingival fluid (CGF) will be collected on the 1st, 3rd, and 7th days after the first activation, and then on the 3rd day of the following 2 months. OUTCOMES: Interleukins IL1ß, IL-6, IL-8, IL-10, and TNF-α will be analyzed by ELISA. Panoramic radiography will be performed at baseline and 90 afterwards to ascertain the amount (in degrees) of verticalization. To evaluate the pain, the Visual Analog Scale (VAS) will be used in all the consultations, and to evaluate the quality of life, the Oral Health Impact Profile (OHIP-14) questionnaire will be applied. Analgesics will be given and the quantity of drugs will be counted. If the data are normal, they will be submitted to Student t test. The data will be presented as means ± SD and the value of p will be defined as <0.05. DISCUSSION: This protocol will determine the effectiveness of photobiomoduation regarding the orthodontic movement of molar verticalization. ETHICS AND DISSEMINATION: This protocol received approval from the Human Research Ethics Committee of Universidade Nove de Julho (certificate number: 3 533 219). The data will be published in a peer-reviewed periodical.


Assuntos
Interleucinas/biossíntese , Terapia com Luz de Baixa Intensidade/métodos , Dente Molar/efeitos da radiação , Técnicas de Movimentação Dentária/métodos , Adulto , Brasil , Método Duplo-Cego , Feminino , Líquido do Sulco Gengival , Humanos , Lasers Semicondutores , Masculino , Pessoa de Meia-Idade , Dor/etiologia , Medição da Dor , Qualidade de Vida , Técnicas de Movimentação Dentária/efeitos adversos , Fator de Necrose Tumoral alfa/biossíntese
6.
Nature ; 579(7800): 575-580, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32050257

RESUMO

The intestinal mucosa serves both as a conduit for the uptake of food-derived nutrients and microbiome-derived metabolites, and as a barrier that prevents tissue invasion by microorganisms and tempers inflammatory responses to the myriad contents of the lumen. How the intestine coordinates physiological and immune responses to food consumption to optimize nutrient uptake while maintaining barrier functions remains unclear. Here we show in mice how a gut neuronal signal triggered by food intake is integrated with intestinal antimicrobial and metabolic responses that are controlled by type-3 innate lymphoid cells (ILC3)1-3. Food consumption rapidly activates a population of enteric neurons that express vasoactive intestinal peptide (VIP)4. Projections of VIP-producing neurons (VIPergic neurons) in the lamina propria are in close proximity to clusters of ILC3 that selectively express VIP receptor type 2 (VIPR2; also known as VPAC2). Production of interleukin (IL)-22 by ILC3, which is upregulated by the presence of commensal microorganisms such as segmented filamentous bacteria5-7, is inhibited upon engagement of VIPR2. As a consequence, levels of antimicrobial peptide derived from epithelial cells are reduced but the expression of lipid-binding proteins and transporters is increased8. During food consumption, the activation of VIPergic neurons thus enhances the growth of segmented filamentous bacteria associated with the epithelium, and increases lipid absorption. Our results reveal a feeding- and circadian-regulated dynamic neuroimmune circuit in the intestine that promotes a trade-off between innate immune protection mediated by IL-22 and the efficiency of nutrient absorption. Modulation of this pathway may therefore be effective for enhancing resistance to enteropathogens2,3,9 and for the treatment of metabolic diseases.


Assuntos
Ingestão de Alimentos/fisiologia , Imunidade Inata/imunologia , Absorção Intestinal/fisiologia , Intestinos/imunologia , Intestinos/fisiologia , Linfócitos/imunologia , Neurônios/metabolismo , Peptídeo Intestinal Vasoativo/metabolismo , Animais , Ritmo Circadiano/fisiologia , Ingestão de Alimentos/imunologia , Feminino , Interleucinas/biossíntese , Interleucinas/imunologia , Absorção Intestinal/imunologia , Intestinos/citologia , Intestinos/microbiologia , Linfócitos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Período Pós-Prandial/fisiologia , Receptores CCR6/metabolismo , Receptores Tipo II de Peptídeo Intestinal Vasoativo/metabolismo , Simbiose
7.
Cancer Immunol Res ; 8(3): 309-320, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31953246

RESUMO

Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death in the world, and curative systemic therapies are lacking. Chimeric antigen receptor (CAR)-expressing T cells induce robust antitumor responses in patients with hematologic malignancies but have limited efficacy in patients with solid tumors, including HCC. IL15 and IL21 promote T-cell expansion, survival, and function and can improve the antitumor properties of T cells. We explored whether transgenic expression of IL15 and/or IL21 enhanced glypican-3-CAR (GPC3-CAR) T cells' antitumor properties against HCC. We previously optimized the costimulation in GPC3-CARs and selected a second-generation GPC3-CAR incorporating a 4-1BB costimulatory endodomain (GBBz) for development. Here, we generated constructs encoding IL15, IL21, or both with GBBz (15.GBBz, 21.GBBz, and 21.15.GBBz, respectively) and examined the ability of transduced T cells to kill, produce effector cytokines, and expand in an antigen-dependent manner. We performed gene-expression and phenotypic analyses of GPC3-CAR T cells and CRISPR-Cas9 knockout of the TCF7 gene. Finally, we measured GPC3-CAR T-cell antitumor activity in murine xenograft models of GPC3+ tumors. The increased proliferation of 21.15.GBBz T cells was at least in part dependent on the upregulation and maintenance of TCF-1 (encoded by TCF7) and associated with a higher percentage of stem cell memory and central memory populations after manufacturing. T cells expressing 21.15.GBBz had superior in vitro and in vivo expansion and persistence, and the most robust antitumor activity in vivo These results provided preclinical evidence to support the clinical evaluation of 21.15.GPC3-CAR T cells in patients with HCC.


Assuntos
Carcinoma Hepatocelular/terapia , Glipicanas/imunologia , Imunoterapia Adotiva/métodos , Interleucina-15/imunologia , Interleucinas/imunologia , Neoplasias Hepáticas/terapia , Animais , Apoptose/imunologia , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proliferação de Células/fisiologia , Feminino , Glipicanas/genética , Humanos , Interleucina-15/biossíntese , Interleucina-15/genética , Interleucinas/biossíntese , Interleucinas/genética , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Am J Respir Cell Mol Biol ; 62(6): 760-766, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31991091

RESUMO

Invasive pulmonary aspergillosis is a life-threatening disease, particularly in immunocompromised patients, despite currently available therapy. IL-27 is an important regulatory cytokine in infection and immunity. However, its role in the pathogenesis of invasive pulmonary aspergillosis remains unknown. Here we found that Aspergillus fumigatus pulmonary infection induced an elevated production of IL-27 in the lung. As compared with wild-type (WT) mice, IL-27R (IL-27 receptor)-deficient mice developed less severe infection when challenged with A. fumigatus conidia, as evidenced by the decreased fungal colonization and pathology of lungs and the increased survival. IL-27R deficiency led to significantly higher production of IFN-γ in the lung after A. fumigatus infection, and the increased resistance to invasive pulmonary A. fumigatus infection in IL-27R-deficient mice was ablated by neutralizing IFN-γ. Importantly, neutralization of IL-27 could protect WT mice against invasive pulmonary A. fumigatus infection. Our data therefore suggest an important role of IL-27 in impairing anti-A. fumigatus host immunity, which may have translational implications in treating clinical cases of invasive pulmonary aspergillosis.


Assuntos
Aspergillus fumigatus/imunologia , Interações Hospedeiro-Patógeno/imunologia , Interleucinas/fisiologia , Aspergilose Pulmonar Invasiva/imunologia , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Ciclofosfamida/toxicidade , Resistência à Doença , Feminino , Hospedeiro Imunocomprometido , Imunossupressores/toxicidade , Interferon gama/antagonistas & inibidores , Interferon gama/imunologia , Interferon gama/fisiologia , Interleucinas/biossíntese , Interleucinas/genética , Aspergilose Pulmonar Invasiva/microbiologia , Pulmão/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Animais , Receptores de Interleucina/deficiência , Receptores de Interleucina/genética , Receptores de Interleucina/fisiologia , Regulação para Cima
9.
Sci Adv ; 6(3): eaay8230, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31998845

RESUMO

Aryl hydrocarbon receptor (AHR) is an essential regulator of gut immunity and a promising therapeutic target for inflammatory bowel disease (IBD). Current AHR agonists are inadequate for clinical translation due to low activity, inadequate pharmacokinetics, or toxicity. We synthesized a structurally diverse library and used integrated computational and experimental studies to discover mechanisms governing ligand-receptor interaction and to design potent drug leads PY109 and PY108, which display physiochemical drug-likeness properties, desirable pharmacokinetic profiles, and low toxicity. In a murine model of dextran sulfate sodium-induced colitis, orally administered compounds increase interleukin-22 (IL-22) production and accelerate mucosal healing by modulating mucosal adaptive and innate lymphoid cells. AHR and IL-22 pathway induction was confirmed using RNA sequencing and characterization of the lymphocyte protein-protein interaction network. Significant induction of IL-22 was also observed using human T cells from patients with IBD. Our findings support rationally designed AHR agonists for IBD therapy.


Assuntos
Desenho de Fármacos , Imunomodulação/efeitos dos fármacos , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Receptores de Hidrocarboneto Arílico/agonistas , Cicatrização/efeitos dos fármacos , Cicatrização/imunologia , Animais , Peptídeos Catiônicos Antimicrobianos/genética , Peptídeos Catiônicos Antimicrobianos/farmacologia , Colite/etiologia , Colite/metabolismo , Colite/patologia , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Estabilidade de Medicamentos , Expressão Gênica , Humanos , Interleucinas/biossíntese , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Ligantes , Linfócitos/imunologia , Camundongos , Modelos Moleculares , Conformação Molecular , Receptores de Hidrocarboneto Arílico/química , Regeneração , Relação Estrutura-Atividade , Linfócitos T/imunologia , Linfócitos T/metabolismo , Cicatrização/genética
10.
Int Immunol ; 32(3): 175-186, 2020 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-31868884

RESUMO

Ovarian cancer is the second-most lethal gynecological malignancy and the seventh-commonest cause of cancer-related death in women around the world. Most of the ovarian cancer patients are diagnosed at advanced stages and suffer from recurrence after primary cytoreductive surgery and standard first-line chemotherapy. Thus, the successful management of ovarian cancer patients requires the identification of factors that contribute to progression and relapse. Interleukin-34 (IL-34) is a novel cytokine that acts as a tissue-specific ligand of colony-stimulating factor-1 receptor (CSF-1R). In cancer, IL-34 exerts pro-tumorigenic functions that promote tumor growth, metastasis, angiogenesis, immune suppression and therapeutic resistance. In this study, we evaluate the impact of IL-34 on progression and survival of ovarian cancer patients. First, IL-34 was found to be expressed in several human ovarian cancer cell lines and cancer tissues from patients. The expression of IL-34 was enhanced by cytotoxic chemotherapy in ovarian cancer cell lines and cancer tissues from chemotherapy-treated ovarian cancer patients. Importantly, high IL-34 expression correlated with worse progression-free survival (PFS) and overall survival in different cohorts. The assessment of PFS based on a combination between IL34 expression and other related genes such as CSF1R and CD163 helped further to reach more statistical significance compared with IL34 alone. Furthermore, in the murine ovarian cancer cell HM-1 in vivo model, it was suggested that IL-34-derived tumor cells was correlated with tumor progression and survival by modulating the immune environment. Collectively, these findings indicate a possible correlation between IL-34 expression and disease progression in ovarian cancer patients and the mouse model.


Assuntos
Progressão da Doença , Interleucinas/biossíntese , Interleucinas/genética , Neoplasias Ovarianas/metabolismo , Células A549 , Animais , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/farmacologia , Relação Dose-Resposta a Droga , Doxorrubicina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Interleucinas/imunologia , Camundongos , Camundongos Endogâmicos , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Células Tumorais Cultivadas
11.
J Invest Dermatol ; 140(4): 850-859.e3, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31626785

RESUMO

Stasis dermatitis (SD) is a common disease in the elderly population, with pruritus being one of the troublesome symptoms. However, there are few therapeutic modalities available for SD-associated itch because little is known about its pathophysiological mechanism. Therefore, we sought to investigate the mediators of itch in SD using an immunofluorescence study on patient lesions focusing on IL-31. Ex vivo stimulation studies using murine peritoneal macrophages were also used to elucidate the pathological mechanisms of the generation of IL-31. In SD lesions, dermal infiltrating IL-31(+) cells were increased in number compared with the healthy controls, and the majority of IL-31(+) cells were CD68(+) macrophages. The presence of itch in SD was significantly associated with the amount of CD68(+)/IL-31(+) macrophages and CD68(+)/CD163(+) M2 macrophages. The number of CD68(+)/IL-31(+) macrophages was correlated with the number of dermal C-C chemokine receptor type 4(+) T helper type 2 cells, IL-17(+) cells, basophils, substance P(+) cells, and dermal deposition of periostin and hemosiderin. Furthermore, murine peritoneal macrophages expressed an M2 marker arginase-1 and generated IL-31 when stimulated with a combination of substance P, periostin, and red blood cell lysate (representing hemosiderin). IL-31 from macrophages may play a role in itch in SD.


Assuntos
Dermatite/metabolismo , Imunidade Celular , Interleucinas/biossíntese , Macrófagos/metabolismo , Prurido/metabolismo , Células Th2/imunologia , Dermatite/imunologia , Dermatite/patologia , Humanos , Macrófagos/imunologia , Macrófagos/patologia , Prurido/imunologia , Prurido/patologia , Células Th2/metabolismo , Células Th2/patologia
13.
Mutat Res ; 846: 403073, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31585635

RESUMO

The use of anesthetics during surgical interventions may contribute to disorders in the perioperative period. Desflurane is the newest volatile halogenated anesthetic to be introduced in clinical practice. Considering that inflammation and genotoxicity are linked events, and that little is known regarding possible genetic and inflammatory effects of desflurane in surgical patients, this study evaluated DNA damage, systemic inflammatory cytokines and related gene expression in adult patients without comorbidities who underwent minor otorhinological surgeries under general anesthesia maintained with the inhalational anesthetic desflurane. This study involved a self-controlled design in which venous blood samples were collected from subjects before anesthesia administration and after the surgical procedure. The comet assay was applied to assess DNA lesions, while the cytokines IL-1ß, IL-6, IL-8, IL-10, IL-17A and TNF-α were evaluated by flow cytometry. A genotoxic effect was observed (p = 0.027), and pro-inflammatory IL-6 and IL-8 levels were significantly increased after surgery (p = 0.001 and p = 0.02, respectively), whereas the levels of the other cytokines did not significantly change. Considering that serum IL-6 and IL-8 were increased, we further evaluated IL-6 and IL-8 gene expression by quantitative real-time polymerase chain reaction (qPCR). However, IL-6 and IL-8 gene expression was unaltered (p >  0.05). In conclusion, anesthetic maintenance with the modern agent desflurane during minor surgeries led to genotoxic and inflammatory effects without altering the expression of inflammation related-genes the day after surgery in patients without comorbidities.


Assuntos
Anestésicos Inalatórios/toxicidade , Dano ao DNA , Desflurano/toxicidade , Inflamação/induzido quimicamente , Interleucinas/biossíntese , Fator de Necrose Tumoral alfa/biossíntese , Adulto , Ensaio Cometa , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/sangue , Interleucinas/sangue , Interleucinas/genética , Masculino , Reação em Cadeia da Polimerase em Tempo Real , Procedimentos Cirúrgicos Operatórios , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/genética , Adulto Jovem
14.
Indian J Ophthalmol ; 67(11): 1821-1828, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31638041

RESUMO

Purpose: The purpose of this study was to investigate the production of IL-27 p28 and EBI3 in the ocular inflammatory sites, and the role of IL-27 signaling in a model of HSV-1 induced herpetic stromal keratitis (HSK). Methods: The BALB/c mice were injected intraperitoneally (24 h before infection) with anti-IL-27 antibody or IgG antibody as control, infected with HSV-1 via corneal scarification, and then injected intraperitoneally with anti-IL-27 antibody or IgG antibody at 1, 3, and 5 days postinfection. Slit lamp and histopathology were used to assess disease outcome. The levels of IL-27 p28 and EBI3 in corneas were determined by western blotting and immunofluorescence. Furthermore, viral titers were determined, and immune cell infiltrates were collected and analyzed by flow cytometry. Results: We found that the levels of IL-27 p28 and EBI3 in corneas were elevated significantly at the peak of HSK, and both of them were expressed simultaneously in the epithelium, stroma, and endothelium of corneas. In the group of anti-IL-27 treatment, the severity of the corneal lesion and CD4+ T cells infiltration were significantly decreased, and the percentage of CD4+ Foxp3+ Tregs was upregulated markedly in the spleen, DLNs and cornea of HSK mice compared to IgG treatment. Conclusion: These results provided evidence that IL-27 as a pathogenic pro-inflammatory cytokine controlled CD4+ Foxp3+ Tregs production in HSK, which ultimately resulted in promoting the progression of HSK and poor prognosis.


Assuntos
Anticorpos/uso terapêutico , Linfócitos T CD4-Positivos/metabolismo , Infecções Oculares Virais/tratamento farmacológico , Fatores de Transcrição Forkhead/biossíntese , Herpesvirus Humano 1 , Interleucinas/antagonistas & inibidores , Ceratite Herpética/tratamento farmacológico , Animais , Linfócitos T CD4-Positivos/patologia , Substância Própria/metabolismo , Substância Própria/patologia , Substância Própria/virologia , Modelos Animais de Doenças , Infecções Oculares Virais/metabolismo , Infecções Oculares Virais/patologia , Feminino , Citometria de Fluxo , Interleucinas/biossíntese , Interleucinas/imunologia , Ceratite Herpética/metabolismo , Ceratite Herpética/patologia , Camundongos , Camundongos Endogâmicos BALB C , Regulação para Cima
15.
Nat Commun ; 10(1): 4246, 2019 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-31534137

RESUMO

Allergic asthma is an inflammatory disorder of the airway without satisfactory traditional therapies capable of controlling the underlying pathology. New approaches that can overcome the detrimental effects of immune dysregulation are thus desirable. Here we adoptively transfer ovalbumin (OVA) peptide-primed CD4-CD8- double negative T (DNT) cells intravenously into a mouse model of OVA-induced allergic asthma to find that OVA-induced airway hyperresponsiveness, lung inflammation, mucus production and OVA-specific IgG/IgE production are significantly suppressed. The immunosuppressive function of the OVA-specific DNT cells is dependent on the inhibition of CD11b+ dendritic cell function, T follicular helper cell proliferation, and IL-21 production. Mechanistically, Lag3 contributes to MHC-II antigen recognition and trogocytosis, thereby modulating the antigen-specific immune regulation by DNT cells. The effectiveness of ex vivo-generated allergen-specific DNT cells in alleviating airway inflammation thus supports the potential utilization of DNT cell-based therapy for the treatment of allergic asthma.


Assuntos
Antígenos CD/metabolismo , Asma/fisiopatologia , Asma/terapia , Hiper-Reatividade Brônquica/imunologia , Linfócitos T Reguladores/transplante , Células Th2/imunologia , Transferência Adotiva , Alérgenos/imunologia , Animais , Asma/induzido quimicamente , Asma/imunologia , Hiper-Reatividade Brônquica/induzido quimicamente , Hiper-Reatividade Brônquica/terapia , Células Dendríticas/imunologia , Modelos Animais de Doenças , Antígenos de Histocompatibilidade Classe II , Imunoglobulina E/biossíntese , Imunoglobulina G/biossíntese , Interleucinas/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ovalbumina , Linfócitos T Reguladores/imunologia
16.
Presse Med ; 48(9): 919-930, 2019 Sep.
Artigo em Francês | MEDLINE | ID: mdl-31543394

RESUMO

Giant cell arteritis (GCA) is a large-vessel vasculitis involving the aorta and its main branches, especially supra aortic branches. Although much progress has been made, the pathophysiology remains incompletely understood. An initial trigger, suspected of infectious origin, lead to the maturation and recruitment of dendritic cells (DC). The lack of migration of these DC allows the local recruitment of T-lymphocytes (LT). These LT- CD4+ polarize in Type 1 helper (Th1), Th17 but also Th9. A qualitative and quantitative deficit in regulatory T cells (Treg) is observed under the influence of IL-21 overproduction. In addition, an imbalance in the Th17/Treg balance is favored by IL-6. The secretion of IFN-γ, IL-17, IL-6, IL-33 is responsible for a sustained local inflammatory reaction that is organized around tertiary lymphoid follicles. Locally recruited macrophages secrete reactive forms of oxygen together with VEGF and PDGF. These growth factors, together with neurotrophins and endothelin contribute to increase the proliferation of vascular smooth muscle cells (VSMCs). The imbalance between matrix metalloproteases (MMP)-2, MMP-9 and MMP-14 and tissue inhibitors of metalloproteases (TIMP)-1 and TIMP-2 also contribute to the remodeling process occurring in the vessel wall. Finally, arterial neovascularization contribute to the perpetuation of lymphocyte recruitment. This persistent remodeling is sometimes complicated by ischemic events responsible for the initial severity of the disease.


Assuntos
Arterite de Células Gigantes/fisiopatologia , Remodelação Vascular/fisiologia , Animais , Linfócitos B/fisiologia , Linfócitos T CD4-Positivos/fisiologia , Movimento Celular , Proliferação de Células , Células Dendríticas/fisiologia , Modelos Animais de Doenças , Predisposição Genética para Doença , Arterite de Células Gigantes/tratamento farmacológico , Arterite de Células Gigantes/etiologia , Arterite de Células Gigantes/patologia , Humanos , Interferon gama/metabolismo , Interleucina-17/metabolismo , Interleucina-33/metabolismo , Interleucina-6/fisiologia , Interleucinas/biossíntese , Ativação Linfocitária/fisiologia , Macrófagos/metabolismo , Metaloproteinases da Matriz/metabolismo , Músculo Liso Vascular/patologia , Neovascularização Patológica/fisiopatologia , Linfócitos T Reguladores/fisiologia , Células Th17/fisiologia
17.
J Virol ; 93(20)2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31375585

RESUMO

Early interactions of influenza A virus (IAV) with respiratory epithelium might determine the outcome of infection. The study of global cellular innate immune responses often masks multiple aspects of the mechanisms by which populations of cells work as organized and heterogeneous systems to defeat virus infection, and how the virus counteracts these systems. In this study, we experimentally dissected the dynamics of IAV and human epithelial respiratory cell interaction during early infection at the single-cell level. We found that the number of viruses infecting a cell (multiplicity of infection [MOI]) influences the magnitude of virus antagonism of the host innate antiviral response. Infections performed at high MOIs resulted in increased viral gene expression per cell and stronger antagonist effect than infections at low MOIs. In addition, single-cell patterns of expression of interferons (IFN) and IFN-stimulated genes (ISGs) provided important insights into the contributions of the infected and bystander cells to the innate immune responses during infection. Specifically, the expression of multiple ISGs was lower in infected than in bystander cells. In contrast with other IFNs, IFN lambda 1 (IFNL1) showed a widespread pattern of expression, suggesting a different cell-to-cell propagation mechanism more reliant on paracrine signaling. Finally, we measured the dynamics of the antiviral response in primary human epithelial cells, which highlighted the importance of early innate immune responses at inhibiting virus spread.IMPORTANCE Influenza A virus (IAV) is a respiratory pathogen of high importance to public health. Annual epidemics of seasonal IAV infections in humans are a significant public health and economic burden. IAV also causes sporadic pandemics, which can have devastating effects. The main target cells for IAV replication are epithelial cells in the respiratory epithelium. The cellular innate immune responses induced in these cells upon infection are critical for defense against the virus, and therefore, it is important to understand the complex interactions between the virus and the host cells. In this study, we investigated the innate immune response to IAV in the respiratory epithelium at the single-cell level, providing a better understanding on how a population of epithelial cells functions as a complex system to orchestrate the response to virus infection and how the virus counteracts this system.


Assuntos
Células Epiteliais/metabolismo , Células Epiteliais/virologia , Interações Hospedeiro-Patógeno/imunologia , Imunidade Inata , Vírus da Influenza A/imunologia , Influenza Humana/imunologia , Influenza Humana/metabolismo , Interferons/biossíntese , Interleucinas/biossíntese , Perfilação da Expressão Gênica , Regulação Viral da Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Humanos , Imunidade Inata/genética , Vírus da Influenza A/genética , Influenza Humana/genética , Influenza Humana/virologia , Interferons/genética , Interleucinas/genética , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo , Mucosa Respiratória/virologia , Análise de Célula Única , Proteínas não Estruturais Virais/genética
18.
Biosci Biotechnol Biochem ; 83(12): 2298-2306, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31448678

RESUMO

Lactic acid bacteria are known to have various health-promoting effects and are highly expected to find applications in anti-allergic food materials. In this study, we focused on Lactobacillus helveticus SBT2171 (LH2171), which reportedly modifies some unique immune responses and ameliorated symptoms of patients allergic to mites and house dust in the previous studies. We examined the effect of LH2171 on cytokine production by antigen-stimulated murine naïve splenocytes in vitro and demonstrated that it inhibited IL-4 and IL-13 production while enhancing IFN-γ and IL-10 production. Then, we examined the anti-allergic effect of LH2171 in vivo using a murine model of pollen allergy and found that LH2171 reduced the sneezing frequency when orally administered to mice. We successfully confirmed the immune modulatory activity of LH2171 and its anti-allergic activity against inhaled antigens. These evidences would contribute to identifying the anti-allergic mechanism of LH2171.Abbreviations: ALDH: aldehyde dehydrogenase; EGCG: epigallocatechin gallate; LAB: lactic acid bacteria; LH2171: Lactobacillus helveticus SBT2171; NALT: nasal-associated lymphoid tissue; OVA: ovalbumin.


Assuntos
Lactobacillus helveticus , Rinite Alérgica Sazonal/prevenção & controle , Administração Oral , Animais , Células Cultivadas , Modelos Animais de Doenças , Feminino , Imunoglobulina E/biossíntese , Imunoglobulina E/imunologia , Interferon gama/biossíntese , Interleucinas/antagonistas & inibidores , Interleucinas/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Rinite Alérgica Sazonal/imunologia , Rinite Alérgica Sazonal/metabolismo
19.
Viruses ; 11(9)2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31443406

RESUMO

Members of the interleukin 12 (IL-12) family have been known to be inflammatory factors since their discovery. The IL-12 family consists of IL-12, IL-23, IL-27, IL-35, and a new member, IL-39, which has recently been identified and has not yet been studied extensively. Current literature has described the mechanisms of immunity of these cytokines and potential uses for therapy and medical cures. IL-12 was found first and is effective in combatting a wide range of naturally occurring viral infections through the upregulation of various cytokines to clear the infected cells. IL-23 has an essential function in immune networks, can induce IL-17 production, and can antagonize inhibition from IL-12 in the presence of T helper (Th) 17 cells, resulting in type II IFN (IFN-γ) regulation. IL-27 has a competitive relationship to IL-35 because they both include the same subunit, the Epstein-Barr virus-induced gene3 (EBi3). This review provides a simple introduction to the IL-12 family and focuses on their functions relevant to their actions to counteract viral infections.


Assuntos
Citocinas , Interleucina-12 , Viroses/imunologia , Imunidade Adaptativa , Animais , Antivirais , Citocinas/biossíntese , Citocinas/imunologia , Citocinas/uso terapêutico , Humanos , Imunidade Inata , Interferon gama/metabolismo , Interleucina-12/biossíntese , Interleucina-12/imunologia , Interleucina-17/biossíntese , Interleucina-17/metabolismo , Interleucina-23/biossíntese , Interleucina-23/imunologia , Interleucina-27/biossíntese , Interleucina-27/imunologia , Interleucinas/biossíntese , Interleucinas/imunologia , Células Th1/imunologia , Células Th1/metabolismo , Células Th17/metabolismo , Viroses/tratamento farmacológico
20.
Eur Respir J ; 54(5)2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31439682

RESUMO

Information on the clinical traits associated with bronchial neutrophilia in asthma is scant, preventing its recognition and adequate treatment. We aimed to assess the clinical, functional and biological features of neutrophilic asthma and identify possible predictors of bronchial neutrophilia.The inflammatory phenotype of 70 mild-to-severe asthma patients was studied cross-sectionally based on the eosinophilic/neutrophilic counts in their bronchial lamina propria. Patients were classified as neutrophilic or non-neutrophilic. Neutrophilic asthma patients (neutrophil count cut-off: 47.17 neutrophils·mm-2; range: 47.17-198.11 neutrophils·mm-2; median: 94.34 neutrophils·mm-2) were further classified as high (≥94.34 neutrophils·mm-2) or intermediate (47.17- <94.34 neutrophils·mm-2). The effect of smoking ≥10 pack-years was also assessed.Neutrophilic asthma patients (n=38; 36 mixed eosinophilic/neutrophilic) had greater disease severity, functional residual capacity, inhaled corticosteroid (ICS) dose and exacerbations, and lower forced vital capacity (FVC) % pred and forced expiratory volume in 1 s (FEV1) reversibility than non-neutrophilic asthma patients (n=32; 28 eosinophilic and four paucigranulocytic). Neutrophilic asthma patients had similar eosinophil counts, increased bronchial CD8+, interleukin (IL)-17-F+ and IL-22+ cells, and decreased mast cells compared with non-neutrophilic asthma patients. FEV1 and FVC reversibility were independent predictors of bronchial neutrophilia in our cohort. High neutrophilic patients (n=21) had increased serum IgE levels, sensitivity to perennial allergens, exacerbation rate, oral corticosteroid dependence, and CD4+ and IL-17F+ cells in their bronchial mucosa. Excluding smokers revealed increased IL-17A+ and IL-22+ cells in highly neutrophilic patients.We provide new evidence linking the presence of high bronchial neutrophilia in asthma to an adaptive immune response associated with allergy (IgE) and IL-17/22 cytokine expression. High bronchial neutrophilia may discriminate a new endotype of asthma. Further research is warranted on the relationship between bronchoreversibility and bronchial neutrophilia.


Assuntos
Corticosteroides/administração & dosagem , Asma/sangue , Asma/tratamento farmacológico , Imunoglobulina E/sangue , Interleucina-17/imunologia , Interleucinas/imunologia , Neutrófilos , Administração Oral , Adulto , Asma/imunologia , Asma/metabolismo , Estudos Transversais , Feminino , Humanos , Interleucina-17/biossíntese , Interleucinas/biossíntese , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade
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