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1.
Life Sci ; 241: 117144, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31830482

RESUMO

BACKGROUND: As an inflammation-related cytokine, interleukin (IL)-5 has been reported to be involved in the development of cardiovascular diseases, such as chronic heart failure and atherosclerosis. However, the role of IL-5 in acute aortic dissection (AAD) has barely been explored. METHODS: Aortic tissue samples from normal donors and patients with AAD were collected, and the expression and localization of IL-5 in aortic tissue were analyzed. In addition, a mouse AAD model was established by administering angiotensin II (Ang II) to ß-aminopropionitrile (BAPN)-treated mice. Morphological examinations and histopathologic analyses were performed to evaluate the effects of IL-5 overexpression on the occurrence of AAD. RESULTS: IL-5 expression was significantly decreased in aorta samples from AAD patients compared to those from donors, and macrophages were the main source of IL-5. In addition, IL-5 expression was decreased in plasma and aortic tissue samples from AAD mice. IL-5 overexpression markedly attenuated the occurrence of AAD in mice and produced corresponding decreases in the inflammatory response and cell apoptosis. In cocultures of macrophages and smooth muscle cells (SMCs), IL-5 overexpression in the macrophages significantly reduced Ang II-induced SMC apoptosis. CONCLUSION: IL-5 overexpression suppresses the development of AAD by reducing inflammation and SMC apoptosis. These results suggest that IL-5 is a potential therapeutic target in AAD.


Assuntos
Aneurisma Dissecante/prevenção & controle , Apoptose , Modelos Animais de Doenças , Inflamação/prevenção & controle , Interleucina-5/metabolismo , Macrófagos/patologia , Miócitos de Músculo Liso/patologia , Aminopropionitrilo/toxicidade , Aneurisma Dissecante/induzido quimicamente , Aneurisma Dissecante/complicações , Aneurisma Dissecante/metabolismo , Angiotensina II/toxicidade , Animais , Aorta/metabolismo , Aorta/patologia , Estudos de Casos e Controles , Feminino , Humanos , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Interleucina-5/genética , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Miócitos de Músculo Liso/metabolismo , Prognóstico
2.
Immunity ; 51(4): 696-708.e9, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31618654

RESUMO

Signaling abnormalities in immune responses in the small intestine can trigger chronic type 2 inflammation involving interaction of multiple immune cell types. To systematically characterize this response, we analyzed 58,067 immune cells from the mouse small intestine by single-cell RNA sequencing (scRNA-seq) at steady state and after induction of a type 2 inflammatory reaction to ovalbumin (OVA). Computational analysis revealed broad shifts in both cell-type composition and cell programs in response to the inflammation, especially in group 2 innate lymphoid cells (ILC2s). Inflammation induced the expression of exon 5 of Calca, which encodes the alpha-calcitonin gene-related peptide (α-CGRP), in intestinal KLRG1+ ILC2s. α-CGRP antagonized KLRG1+ ILC2s proliferation but promoted IL-5 expression. Genetic perturbation of α-CGRP increased the proportion of intestinal KLRG1+ ILC2s. Our work highlights a model where α-CGRP-mediated neuronal signaling is critical for suppressing ILC2 expansion and maintaining homeostasis of the type 2 immune machinery.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Inflamação/imunologia , Intestinos/imunologia , Linfócitos/imunologia , Neuropeptídeos/metabolismo , Animais , Peptídeo Relacionado com Gene de Calcitonina/genética , Células Cultivadas , Biologia Computacional , Imunidade Inata , Interleucina-5/genética , Interleucina-5/metabolismo , Lectinas Tipo C/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Neuropeptídeos/genética , Receptores Imunológicos/metabolismo , Análise de Sequência de RNA , Transdução de Sinais , Análise de Célula Única , Células Th2/imunologia , Transcriptoma , Regulação para Cima
3.
J Sci Food Agric ; 99(15): 7008-7015, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31435932

RESUMO

BACKGROUND: Silkworm droppings have long been used in traditional medicine to remedy allergic itching, palsy, blood circulation problems, and arthritis in Asian countries. To investigate the anti-allergic effect of silkworm dropping extract (SDE) and its mechanism, we used a mouse model of food allergy induced by ovalbumin (OVA). RESULTS: SDE ameliorated the symptoms of OVA-induced food allergies, and the levels of T helper 2 (Th2)-related cytokines [such as interleukin (IL)-4, IL-5, IL-10, and IL-13] were found to be significantly decreased in both the spleen and mesenteric lymph nodes by SDE. Furthermore, SDE treatment directly inhibited OVA permeation, IL-4 production, and degranulation of mast cells; in contrast, immunoglobulin E (IgE) production from B cells was not affected. CONCLUSION: These results suggest that SDE has potential anti-allergic activities, and SDE may be useful in the treatment/prevention of allergic disorders such as food allergies, serving as therapeutic agents. © 2019 Society of Chemical Industry.


Assuntos
Antialérgicos/administração & dosagem , Bombyx/química , Fezes/química , Hipersensibilidade Alimentar/tratamento farmacológico , Células Th2/efeitos dos fármacos , Animais , Antialérgicos/química , Feminino , Hipersensibilidade Alimentar/genética , Hipersensibilidade Alimentar/imunologia , Humanos , Imunoglobulina E/imunologia , Interleucina-13/genética , Interleucina-13/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Interleucina-5/genética , Interleucina-5/imunologia , Mastócitos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/efeitos adversos , Células Th2/imunologia
4.
BMC Pulm Med ; 19(1): 158, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31438916

RESUMO

BACKGROUND: Severe non-allergic eosinophilic asthma (SNEA) is a rare asthma phenotype associated with severe clinical course, frequent exacerbations, and resistance to therapy, including high steroid doses. The key feature is type 2 inflammation with predominant airway eosinophilia. Eosinophil maturation, activation, survivability, and recruitment are mainly induced by interleukin (IL)-3, IL-5 and granulocyte-macrophage colony-stimulating factor (GM-CSF) through their receptors on eosinophil surface and related with integrins activation states. The aim of the study was to estimate the expression of eosinophil ß chain-signaling cytokines receptors, outer-membrane integrins, and serum-derived type 2 inflammation biomarkers in SNEA. METHODS: We examined 8 stable SNEA patients with high inhaled steroid doses, 12 steroid-free patients with non-severe allergic asthma (AA), 12 healthy subjects (HS). Blood eosinophils were isolated using Ficol gradient centrifugation and magnetic separation. Eosinophils were lysed, and mRNA was isolated. Gene expressions of IL-5Rα, IL-3Rα, GM-CSFRα, and α4ß1, αMß2 integrins were analyzed using quantitative real-time reverse transcription polymerase chain reaction. Type 2 inflammation activity was evaluated measuring exhaled nitric oxide concentration (FeNO) collected with the electrochemical sensing device. Serum IL-5, IL-3, GM-CSF, periostin, chemokine ligand (CCL) 17 and eotaxin concentrations were assessed by enzyme-linked immunosorbent assay. RESULTS: Eosinophils from SNEA patients demonstrated significantly increased gene expression of IL-3Rα, IL-5Rα and GM-CSFRα as well as α4, ß1 and αM integrin subunits compared with the AA group. The highest IL-5 serum concentration was in the SNEA group; it significantly differed compared with AA and HS. GM-CSF serum levels were similar in the SNEA and AA groups and were significantly lower in the HS group. No differences in serum IL-3 concentration were found among all groups. Furthermore, serum levels of eotaxin, CCL17 and FeNO, but not periostin, differed in all groups, with the highest levels in SNEA patients. CONCLUSIONS: Eosinophil demonstrated higher expression of IL-3, IL-5, GM-CSF α-chain receptors and α4, ß1, αM integrins subunits in SNEA compared with the AA group. Additionally, SNEA patients had increased serum levels of IL-5, eotaxin and CCL-17. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03388359.


Assuntos
Asma/sangue , Eosinófilos/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/sangue , Integrinas/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Adulto , Asma/fisiopatologia , Biomarcadores/sangue , Quimiocina CCL17/sangue , Feminino , Expressão Gênica , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Humanos , Inflamação/metabolismo , Interleucina-3/sangue , Interleucina-3/genética , Interleucina-5/sangue , Interleucina-5/genética , Contagem de Leucócitos , Lituânia , Masculino , Pessoa de Meia-Idade , Testes de Função Respiratória , Adulto Jovem
5.
Am J Chin Med ; 47(5): 1099-1112, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31366207

RESUMO

Asthma is the most prevalent chronic respiratory disease worldwide. Garlic extracts have long been used as a food source and in traditional medicine. Crude extracts of garlic are used as an anti-inflammatory agent and have been reported to exhibit antiasthmatic properties. However, molecular mechanisms of garlic extracts in the context of antiasthmatic airway inflammation are still unclear. In this study, the antiasthmatic effect of garlic extracts on Th1, Th2, and Th3 cytokine profiles and immunoregulatory mechanism were explored using an animal model of allergic asthma. Garlic extracts significantly reduced total inflammatory cell counts and eosinophil infiltration and decreased the production of Dermatophagoides pteronyssinus IgE in serum and Th1/Th2/Th3 cytokine in bronchoalveolar fluid. Enzyme-linked immunosorbent assay analysis demonstrated that garlic extracts downregulated the levels of cytokines and chemokines, namely Th2-related IL-4, IL-5, and IL-13; but they simultaneously upregulated Th1-related IFN-γ, IL-12, and Th3-related IL-10 and TGF-ß expression in BALF. The mechanism may be ascribed to the modulation of Th1-, Th2-, and Th3-related cytokine imbalance.


Assuntos
Asma/prevenção & controle , Alho/química , Extratos Vegetais/administração & dosagem , Substâncias Protetoras/administração & dosagem , Alérgenos/efeitos adversos , Animais , Anti-Inflamatórios/administração & dosagem , Asma/induzido quimicamente , Asma/genética , Asma/imunologia , Feminino , Humanos , Imunoglobulina E/imunologia , Interleucina-12/genética , Interleucina-12/imunologia , Interleucina-5/genética , Interleucina-5/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th2/efeitos dos fármacos , Células Th2/imunologia
6.
Curr Med Sci ; 39(4): 560-567, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31346991

RESUMO

Positive bronchodilation (BD) tests can be noticed in some stable chronic obstructive pulmonary disease (COPD) patients. The characteristics of airway inflammation in this entity remain unclear. Our study aimed to identify the characteristics of airway inflammation in stable COPD patients with positive BD tests. The airway inflammation was assessed in 88 patients with stable COPD using the examination of induced sputum in the aftermath of lung function and BD tests. Cellular counts and the levels of molecular markers including eosinophil cationic protein (ECP), myeloperoxidase (MPO), interleukin-5 (IL-5), and IL-8 were assayed by Wright's stain, Immuno-CAP system, and ELISA, RT-PCR. Among the 88 patients with stable COPD, 20 (22.7%) showed positive BD tests. The values of eosinophils (4.7%±3.4%) and ECP (90.1±41.6 ng/mL) in induced sputum in stable COPD patients with positive BD tests were markedly elevated as compared with those in stable COPD patients with negative BD tests or in healthy controls (all P>0.05), but significantly lower than those in asthmatic patients (all P<0.01). The IL-5 in sputum supernatant was significantly decreased in stable COPD patients with positive BD tests as compared with the patients with asthma (12.5±7.8 vs. 48.2±26.0 ng/mL;.P<0.01). However, healthy controls exhibited similar concentrations of IL-5 in induced sputum with patients with stable COPD, whether with positive or negative BD tests (all P>0.05). Moreover, the values of neutrophils (61.8%±15.1%), MPO (574.0±111.8 ng/mL), and IL-8 (32.6±13.4 ng/mL) in induced sputum in stable COPD patients with positive BD tests were significantly higher than those in asthmatics or normal controls (all P<0.01). However, the values of the above inflammatory markers in induced sputum were similar among stable COPD patients with positive or negative BD tests (all P>0.05). The stable COPD patients with positive BD tests may present not only eosinophilic airway inflammation but also neutrophilic airway inflammation.


Assuntos
Asma/diagnóstico , Biomarcadores , Inflamação/diagnóstico , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Adolescente , Adulto , Idoso , Asma/genética , Asma/patologia , Broncodilatadores/administração & dosagem , Proteína Catiônica de Eosinófilo/genética , Eosinófilos/metabolismo , Eosinófilos/patologia , Feminino , Humanos , Inflamação/genética , Inflamação/patologia , Interleucina-5/genética , Masculino , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Neutrófilos/patologia , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/patologia , Testes de Função Respiratória , Escarro/metabolismo , Adulto Jovem
7.
Environ Toxicol ; 34(10): 1121-1128, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31240852

RESUMO

meta-Xylene (m-xylene) is one of three isomers of xylene, which is widely used as a solvent and detergent in various industries and medical technology. Exposure to volatile organic compounds, such as m-xylene, causes pulmonary inflammation and airway inflammation, thereby contributing to the onset of asthma. Exposure to m-xylene increases acute wheezing and intensity of asthma symptom. However, the mechanism of the onset of asthma by m-xylene has not been studied yet. C57BL/6 mice were sensitized and challenged by m-xylene at 100 or 300 mg/kg. The mice were then sacrificed after the last challenge. Exposure to m-xylene increased the total number of inflammatory cells and the production of interleukin (IL)-4, IL-5, IL-13, and immunoglobulin E related to the Th2 immune response. In contrast, the production of interferon-γ related to the Th1 immune response was decreased. In addition, the airway resistance increased according to the airway hyper-responsiveness measurements. Finally, a histological analysis revealed infiltration of inflammatory cells, mucus production, and lung fibrosis. These results suggest that m-xylene is a potential risk factor for asthma and the onset of asthma is caused by TH2 cytokines.


Assuntos
Asma/induzido quimicamente , Citocinas/imunologia , Células Th2/imunologia , Xilenos/efeitos adversos , Animais , Asma/genética , Asma/imunologia , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/genética , Feminino , Humanos , Imunoglobulina E/imunologia , Interleucina-13/genética , Interleucina-13/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Interleucina-5/genética , Interleucina-5/imunologia , Pulmão/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th2/efeitos dos fármacos
8.
J Biosci ; 44(2)2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31180054

RESUMO

This study was conducted to determine whether exposure to particulate matter 2.5 (PM2.5) affects the immune tolerance of neonatal mice via the regulation of PD-L1 expression. One-week-old BALB/c mice were exposed to PM2.5 for 8 days. From day 8 to day 18, the mice were treated with 5 µg house dust mite (HDM) (i. n.) every two days. Adenovirus-carried PD-L1 overexpression vectors were infected into mice via nasal inhalation 6 days after exposure to PM2.5. Airway hyperresponsiveness (AHR) was examined in mice 19 days after exposure to PM2.5, and the related parameters of airway inflammation were studied on day 22. Co-exposure to PM2.5 and HDM reduced PD-L1 expression but greatly increased infiltration of inflammatory cells, which was reversed by PD-L1 overexpression. Co-exposure to PM2.5 and HDM also elevated serum IL-4, IL-5 and IL-13 levels and reduced TGF-ß level. Exposure to PM2.5 alone slightly increased the numbers of dendritic cells (DCs) but reduced the numbers of antigen-presenting cells expressing PD-L1 and Treg cells. Therefore, early exposure to PM2.5 reduced PD-L1 expression in the lungs of neonatal mice, which interfered with immune tolerance establishment and subsequently resulted in allergic airway inflammation.


Assuntos
Antígeno B7-H1/imunologia , Células Dendríticas/efeitos dos fármacos , Tolerância Imunológica/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Material Particulado/administração & dosagem , Hipersensibilidade Respiratória/imunologia , Adenoviridae/genética , Adenoviridae/imunologia , Administração por Inalação , Animais , Animais Recém-Nascidos , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Células Dendríticas/imunologia , Células Dendríticas/patologia , Regulação da Expressão Gênica , Vetores Genéticos/administração & dosagem , Vetores Genéticos/química , Vetores Genéticos/imunologia , Interleucina-13/genética , Interleucina-13/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Interleucina-5/genética , Interleucina-5/imunologia , Pulmão/imunologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Pyroglyphidae/química , Pyroglyphidae/imunologia , Hipersensibilidade Respiratória/induzido quimicamente , Hipersensibilidade Respiratória/genética , Hipersensibilidade Respiratória/patologia , Transdução de Sinais , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/imunologia
9.
Int J Mol Sci ; 20(9)2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31072011

RESUMO

Group 2 innate lymphoid cells (ILC2) have emerged as a major component of type 2 inflammation in mice and humans. ILC2 secrete large amounts of interleukins 5 and 13, which are largely responsible for host protective immunity against helminth parasites because these cytokines induce profound changes in host physiology that include: goblet cell metaplasia, mucus accumulation, smooth muscle hypercontractility, eosinophil and mast cell recruitment, and alternative macrophage activation (M2). This review covers the initial recognition of ILC2 as a distinct cell lineage, the key studies that established their biological importance, particularly in helminth infection, and the new directions that are likely to be the focus of emerging work that further explores this unique cell population in the context of health and disease.


Assuntos
Helmintíase/imunologia , Helmintos/imunologia , Imunidade Inata/imunologia , Linfócitos/imunologia , Animais , Linhagem da Célula/imunologia , Helmintíase/parasitologia , Helmintos/patogenicidade , Humanos , Imunidade Inata/genética , Interleucina-13/genética , Interleucina-5/genética , Camundongos
10.
Parasit Vectors ; 12(1): 248, 2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-31109364

RESUMO

BACKGROUND: Mice are susceptible to infections with the rodent filarial nematode Litomosoides sigmodontis and develop immune responses that resemble those of human filarial infections. Thus, the L. sigmodontis model is used to study filarial immunomodulation, protective immune responses against filariae and to screen drug candidates for human filarial diseases. While previous studies showed that type 2 immune responses are protective against L. sigmodontis, the present study directly compared the impact of eosinophils, IL-5, and the IL-4R on the outcome of L. sigmodontis infection. METHODS: Susceptible wildtype (WT) BALB/c mice, BALB/c mice lacking eosinophils (dblGATA mice), IL-5-/- mice, IL-4R-/- mice and IL-4R-/-/IL-5-/- mice were infected with L. sigmodontis. Analyses were performed during the peak of microfilaremia in WT animals (71 dpi) as well as after IL-4R-/-/IL-5-/- mice showed a decline in microfilaremia (119 dpi) and included adult worm counts, peripheral blood microfilariae levels, cytokine production from thoracic cavity lavage, the site of adult worm residence, and quantification of major immune cell types within the thoracic cavity and spleen. RESULTS: Our study reveals that thoracic cavity eosinophil numbers correlated negatively with the adult worm burden, whereas correlations of alternatively activated macrophage (AAM) numbers with the adult worm burden (positive correlation) were likely attributed to the accompanied changes in eosinophil numbers. IL-4R-/-/IL-5-/- mice exhibited an enhanced embryogenesis achieving the highest microfilaremia with all animals becoming microfilariae positive and had an increased adult worm burden combined with a prolonged adult worm survival. CONCLUSIONS: These data indicate that mice deficient for IL-4R-/-/IL-5-/- have the highest susceptibility for L. sigmodontis infection, which resulted in an earlier onset of microfilaremia, development of microfilaremia in all animals with highest microfilariae loads, and an extended adult worm survival.


Assuntos
Suscetibilidade a Doenças/imunologia , Eosinófilos/imunologia , Filariose/imunologia , Interleucina-5/genética , Receptores de Superfície Celular/genética , Animais , Modelos Animais de Doenças , Filariose/sangue , Filarioidea/fisiologia , Técnicas de Inativação de Genes , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Microfilárias/imunologia , Ácaros/parasitologia , Transdução de Sinais , Baço/imunologia
11.
Vet Parasitol ; 268: 73-80, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30981309

RESUMO

The infection of ruminants by Fasciola spp. always induces a non-protective Th2-type immune response. However, little is known about changes in the local and systemic immune environment during F. gigantica migration in buffalo. In this study, native swamp buffaloes were each infected with 500 viable F. gigantica metacercariae. Mesenteric lymph node (MLN), hepatic lymph node (HLN), spleen, and serum samples were collected from control and infected buffaloes at 3, 10, 28, 42, 70, and 98 days post-infection (DPI). The mRNA expression levels of the Th1- and Th2-related cytokines IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p40, IFN-γ, TNF-α, and CD4 were measured during different infection stages in the MLNs, spleens, and HLNs using quantitative real-time PCR (qRT-PCR). Levels of the specific anti-ESP isotype antibodies IgG, IgG1, and IgG2 were used to reflect changes in humoral immunity. The results of this study indicated that swamp buffaloes were susceptible to F. gigantica infection, and that susceptibility to this infection was closely related to the cytokine environment associated with the Th2-type immune response. The MLNs showed a mixed Th1- and Th2-type immune response during the acute infection stages, after which the production of these cytokines returned to normal. Cytokine expression in the HLNs also expressed a mixed Th1- and Th2-type immune response during the early infection stages. When the infection became chronic, the typical Th2 immune response was induced in the HLNs. At the acute infection stages, the spleen exhibited a Th2 immune response. Nevertheless, cytokines associated with the Th1 and Th2 immune responses were upregulated at 98 DPI. In addition, the total IgG and IgG1 of the parasite-specific antibodies increased. This suggested that the Th2-related cytokines and IgG1 induced by F. gigantica infection might mediate successful F. gigantica infection in the natural host, swamp buffalo.


Assuntos
Búfalos/imunologia , Doenças dos Bovinos/imunologia , Citocinas/imunologia , Fasciolíase/veterinária , Evasão da Resposta Imune , Células Th2/imunologia , Animais , Anticorpos Anti-Helmínticos/imunologia , Búfalos/parasitologia , Bovinos , Doenças dos Bovinos/parasitologia , Citocinas/genética , Fasciola , Fasciolíase/imunologia , Imunidade Humoral , Imunoglobulina G/imunologia , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Interleucina-5/genética , Interleucina-5/imunologia , Linfonodos/imunologia , Linfonodos/parasitologia , Metacercárias/imunologia , Reação em Cadeia da Polimerase em Tempo Real , Baço/imunologia , Baço/parasitologia , Células Th1/imunologia
12.
Immunity ; 50(4): 796-811, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30995500

RESUMO

The ß common chain cytokines GM-CSF, IL-3, and IL-5 regulate varied inflammatory responses that promote the rapid clearance of pathogens but also contribute to pathology in chronic inflammation. Therapeutic interventions manipulating these cytokines are approved for use in some cancers as well as allergic and autoimmune disease, and others show promising early clinical activity. These approaches are based on our understanding of the inflammatory roles of these cytokines; however, GM-CSF also participates in the resolution of inflammation, and IL-3 and IL-5 may also have such properties. Here, we review the functions of the ß common cytokines in health and disease. We discuss preclinical and clinical data, highlighting the potential inherent in targeting these cytokine pathways, the limitations, and the important gaps in understanding of the basic biology of this cytokine family.


Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Inflamação/imunologia , Interleucina-3/imunologia , Interleucina-5/imunologia , Animais , Doenças Autoimunes/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/deficiência , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Hematopoese/imunologia , Humanos , Inflamação/terapia , Interleucina-3/antagonistas & inibidores , Interleucina-3/deficiência , Interleucina-3/genética , Interleucina-5/antagonistas & inibidores , Interleucina-5/deficiência , Interleucina-5/genética , Camundongos , Camundongos Knockout , Família Multigênica , Neoplasias/imunologia , Neoplasias/terapia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/imunologia , Receptores de Interleucina-3/genética , Receptores de Interleucina-3/imunologia , Receptores de Interleucina-5/genética , Receptores de Interleucina-5/imunologia , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/uso terapêutico , Transdução de Sinais , Relação Estrutura-Atividade , Vacinação , Cicatrização/imunologia
13.
Allergol. immunopatol ; 47(2): 172-178, mar.-abr. 2019. graf, tab
Artigo em Inglês | IBECS | ID: ibc-180806

RESUMO

Background: Common variable immunodeficiency (CVID) is the most common symptomatic form of primary immunodeficiency (PID). LPS-responsive beige-like anchor protein (LRBA) deficiency is an autosomal recessive disease characterized by a CVID-like phenotype. T cell abnormality was reported in patients with CVID and LRBA deficiency. The study's aim was to evaluate IL-4, IL-5, IL-10 and GATA3 expression in patients with LRBA deficiency and CVID with no known monogenic disease, and further evaluate its relevance with immunological futures and clinical complications of patients. Methods: The study population comprised patients with CVID, LRBA deficiency and age–sex matched healthy controls. Mutation analysis was done by whole exome sequencing in CVID patients to rule out monogenic PIDs. After CD4+ T cell stimulation with anti-CD3 and anti-CD28 monoclonal antibodies, gene expression of IL-4, IL-5, IL-10 and transcription factor GATA3 was evaluated by real-time polymerase chain reaction. The protein of mentioned cytokines was assessed by enzyme-linked immunosorbent assay. Results: The main clinical presentations of CVID patients were infections only and lymphoproliferations phenotypes, but in LRBA patients were autoimmune and enteropathy phenotype. The frequencies of CD4+ T cells were significantly reduced in LRBA and CVID patients. There were no statistically significant differences among GATA3, IL4, and IL5 gene expressions by CD4+ T cells of patients and controls, however, the IL10 expressions in CVID patients was significantly lower than in LRBA patients and HCs. As compared with HCs, CVID patients showed a prominent decrease in IL-4 and IL-10 production by CD4+ T cells. Conclusions: Our findings demonstrated that patients with CVID and LRBA deficiency (even with severe infectious and inflammatory complications) have not imbalance in Th2 response, which is in parallel with lower frequency of allergy and asthma in these patients


No disponible


Assuntos
Humanos , Masculino , Feminino , Criança , Adolescente , Adulto Jovem , Adulto , Proteínas Adaptadoras de Transdução de Sinal/genética , Linfócitos T CD4-Positivos/fisiologia , Imunodeficiência de Variável Comum/genética , Fator de Transcrição GATA3/genética , Interleucina-10/genética , Interleucina-4/genética , Interleucina-5/genética , Autoimunidade , Análise Mutacional de DNA , Células Cultivadas , Análise Mutacional de DNA , Progressão da Doença
14.
Kurume Med J ; 65(2): 37-46, 2019 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-30853691

RESUMO

BACKGROUND: The role of IL-38, a new member of the IL-1 family, in airway eosinophilic inflammatory conditions such as asthma is unclear. To investigate the role of IL-38 in airway eosinophilic inflammation, an IL-38-gene deficient (KO) murine asthma model was analyzed. METHODS: The numbers of eosinophils and neutrophils, and levels of IL-5, IL-13 and IL-17A protein and mRNA in bronchoalveolar lavage fluid (BALF) and lung tissue were compared between wild-type (WT) and IL-38-KO mice after OVA sensitization and challenge. The effects of additional purified recombinant mouse (rm) IL-38 protein were investigated in the IL-38-KO murine asthma model. RESULTS: The IL-38 and IL-5 mRNA in WT mice was significantly higher after OVA challenge than after saline challenge (p<0.05). The number of airway eosinophils in IL-38-KO mice was significantly lower than in WT mice after OVA challenge (p<0.01). BALF analysis confirmed the lower number of airway eosinophils in IL-38-KO mice and showed that this was significantly associated with lower IL-5 protein levels (r=0.92, p<0.0001). However, the additional rm IL-38 protein did not neutralize airway eosinophilia in IL-38-KO mice. CONCLUSION: IL-38 may enhance airway eosinophilic inflammation in asthma through IL-5 induction.


Assuntos
Asma/metabolismo , Eosinofilia/metabolismo , Inflamação/metabolismo , Interleucina-1/genética , Interleucina-5/genética , Animais , Asma/genética , Líquido da Lavagem Broncoalveolar , Cruzamentos Genéticos , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Eosinofilia/genética , Feminino , Inflamação/genética , Interleucina-1/metabolismo , Interleucina-13/metabolismo , Interleucina-17/metabolismo , Interleucina-5/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos/metabolismo , Ovalbumina , RNA Mensageiro/metabolismo , Proteínas Recombinantes/metabolismo
15.
Immunology ; 157(2): 110-121, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30779114

RESUMO

Baseline eosinophils reside in the gastrointestinal tract; however, in several allergic disorders, excessive eosinophils accumulate in the blood as well in the tissues. Recently, we showed in vitro that interleukin (IL)-18 matures and transforms IL-5-generated eosinophils into the pathogenic eosinophils that are detected in human allergic diseases. To examine the role of local induction of IL-18 in promoting eosinophil-associated intestinal disorders, we generated enterocyte IL-18-overexpressing mice using the rat intestinal fatty acid-binding promoter (Fabpi) and analysed tissue IL-18 overexpression and eosinophilia by performing real-time polymerase chain reaction, Enzyme-Linked Immunosorbent Assay and anti-major basic protein immunostaining. Herein we show that Fabpi-IL-18 mice display highly induced IL-18 mRNA and protein in the jejunum. IL-18 overexpression in enterocytes promotes marked increases of eosinophils in the blood and jejunum. Our analysis shows IL-18 overexpression in the jejunum induces a specific population of CD101+  CD274+ tissue eosinophils. Additionally, we observed comparable tissue eosinophilia in IL-13-deficient-Fabpi-IL-18 mice, and reduced numbers of tissue eosinophils in eotaxin-deficient-Fabpi-IL-18 and IL-5-deficient-Fabpi-IL-18 mice compared with Fabpi-IL-18 transgenic mice. Notably, jejunum eosinophilia in IL-5-deficient-Fabpi-IL-18 mice is significantly induced compared with wild-type mice, which indicates the direct role of induced IL-18 in the tissue accumulation of eosinophils and mast cells. Furthermore, we also found that overexpression of IL-18 in the intestine promotes eosinophil-associated peanut-induced allergic responses in mice. Taken together, we provide direct in vivo evidence that induced expression of IL-18 in the enterocytes promotes eotaxin-1, IL-5 and IL-13 independent intestinal eosinophilia, which signifies the clinical relevance of induced IL-18 in eosinophil-associated gastrointestinal disorders (EGIDs) to food allergens.


Assuntos
Enterócitos/imunologia , Eosinófilos/imunologia , Interleucina-18/imunologia , Jejuno/imunologia , Hipersensibilidade a Amendoim/imunologia , Animais , Antígenos CD/genética , Antígenos CD/imunologia , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Quimiocina CCL11/genética , Quimiocina CCL11/imunologia , Enterócitos/patologia , Eosinófilos/patologia , Humanos , Interleucina-13/genética , Interleucina-13/imunologia , Interleucina-18/genética , Interleucina-5/genética , Interleucina-5/imunologia , Jejuno/patologia , Mastócitos/imunologia , Mastócitos/patologia , Camundongos , Camundongos Transgênicos , Hipersensibilidade a Amendoim/genética , Hipersensibilidade a Amendoim/patologia , Ratos
16.
J Ethnopharmacol ; 230: 9-19, 2019 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-30359762

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Involucrum castaneae(IC)is used in Chinese folk medicine to treat various lung diseases, as well as for its reducing phlegm and anti-inflammatory properties. AIM OF THE STUDY: The purpose of this experiment is to verify the effect of IC on airway inflammation, responsiveness in ovalbumin (OVA)-induced asthmatic guinea pigs. The main chemical components of IC were also analyzed. MATERIALS AND METHODS: The potential of the ethanol extract of Involucrum castaneae (EEIC) to protect against OVA-induced allergic airway response in guinea pigs was investigated. The latency of asthma in guinea pigs were recorded after the allergic asthma induced. Enzyme-linked immunosorbent assay (ELISA) was used to measure the levels of immunoglobulin E (IgE), interleukin-5 (IL-5), nerve growth factor (NGF) and interferon-γ (IFN-γ) in asthma allergy. Reverse transcription-PCR (RT-PCR) was used to detect the expression of IL-5 mRNA in asthmatic guinea pig lungs. Paraffin sections of lung tissue were used to analyze pathological changes. The total flavonoid content was determined and the chemical components were analyzed by LC-MS/MS. RESULTS: It was found that EEIC was able to reduce the number of eosinophil (EOS) in bronchoalveolar lavage fluid (BALF) and peripheral blood (PB) in the guinea pig model of OVA -induced asthma. Meanwhile, it also significantly reduced the levels of inflammation-related factors IgE and IL-5, decreased the expression of IL-5 mRNA in lung tissue, and increased the level of IFN-γ. Pathological examination of paraffin section of lung tissue showed that EEIC can reduce the thickening of bronchial smooth muscle and reduce the infiltration damage of tissues by various inflammatory cells. The presence of flavonoids, terpenoids and phenolic compounds in EEIC might be responsible for these activities. CONCLUSION: IC alleviated airway inflammation and smooth muscle thickening in guinea pigs with OVA-sensitized allergic asthma. The paper explains the traditional efficacy and material basis of IC and lays a foundation for further development.


Assuntos
Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Fagaceae , Extratos Vegetais/uso terapêutico , Remodelação das Vias Aéreas/efeitos dos fármacos , Alérgenos , Animais , Antiasmáticos/farmacologia , Asma/induzido quimicamente , Asma/imunologia , Asma/patologia , Etanol/química , Cobaias , Imunoglobulina E/imunologia , Interferon gama/imunologia , Interleucina-5/genética , Interleucina-5/imunologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Músculo Liso/efeitos dos fármacos , Músculo Liso/patologia , Ovalbumina , Extratos Vegetais/farmacologia , Solventes/química
17.
Auris Nasus Larynx ; 46(4): 533-541, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30554982

RESUMO

OBJECTIVE: CD4+ T cells play an important role not only in the induction of allergy but also in allergic inflammation. Group 2 innate lymphoid cells (ILC2s) also mediate type 2 immune responses in allergic rhinitis (AR). However, the relationships between CD4+ T cells and ILC2s in allergic condition are currently not well defined. The study aimed to evaluate the potential influences of CD4+ T cells on ILC2s in the murine model of AR. METHODS: A murine model of AR was established using ovalbumin (OVA), and OVA-induced ILC2s were sorted and purified from the mouse nasal-associated lymphoid tissue (NALT), and cultured in vitro. Then, the expression of major histocompatibility complex class II (MHCII) on ILC2s was examined. CD4+ T cells were separated from AR mice peripheral blood mononuclear cells (PBMCs). After that, productions of IL-5 and IL-13 on ILC2s cultures were assessed when CD4+ T cells or plus anti-MHCII antibody or anti-CD4 antibody were administered into the cultures. Finally, we adoptively transferred ILC2s alone or ILC2s plus anti-MHCII antibody to the murine model of AR to investigate their roles in the nasal allergic inflammation. RESULTS: We showed that ILC2s could be induced by OVA in the mouse NALT. The number and percentage of ILC2s in AR mice were increased. MHCII was expressed on ILC2s, and its protein and mRNA were all enhanced in allergic condition. IL-5 and IL-13 proteins and mRNAs were elevated after CD4+ T cells administration, and were reduced after these cells plus anti-MHCII antibody or anti-CD4 antibody application. Numbers of sneezing and nasal rubbing as well as counts of eosinophils in nasal lavage fluid (NLF) were all enhanced after the adoptive transfer of ILC2s when compared to AR mice. IL-5 and IL-13 in the NLF of allergic mice were also increased in comparison with AR group. However, above parameters were all decreased after the transfer of ILC2s plus anti-MHCII antibody versus AR mice or ILC2s-treated ones. CONCLUSION: These findings show that CD4+ T cells induce productions of IL-5 and IL-13 through MHCII on ILC2s in AR mice models.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Interleucina-13/imunologia , Interleucina-5/imunologia , Linfócitos/imunologia , Rinite Alérgica/imunologia , Animais , Modelos Animais de Doenças , Imunidade Inata , Interleucina-13/genética , Interleucina-13/metabolismo , Interleucina-5/genética , Interleucina-5/metabolismo , Leucócitos Mononucleares/metabolismo , Linfócitos/metabolismo , Tecido Linfoide , Camundongos , Mucosa Nasal/imunologia , Ovalbumina , Rinite Alérgica/genética , Rinite Alérgica/metabolismo
18.
Allergol Immunopathol (Madr) ; 47(2): 172-178, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30193889

RESUMO

BACKGROUND: Common variable immunodeficiency (CVID) is the most common symptomatic form of primary immunodeficiency (PID). LPS-responsive beige-like anchor protein (LRBA) deficiency is an autosomal recessive disease characterized by a CVID-like phenotype. T cell abnormality was reported in patients with CVID and LRBA deficiency. The study's aim was to evaluate IL-4, IL-5, IL-10 and GATA3 expression in patients with LRBA deficiency and CVID with no known monogenic disease, and further evaluate its relevance with immunological futures and clinical complications of patients. METHODS: The study population comprised patients with CVID, LRBA deficiency and age-sex matched healthy controls. Mutation analysis was done by whole exome sequencing in CVID patients to rule out monogenic PIDs. After CD4+ T cell stimulation with anti-CD3 and anti-CD28 monoclonal antibodies, gene expression of IL-4, IL-5, IL-10 and transcription factor GATA3 was evaluated by real-time polymerase chain reaction. The protein of mentioned cytokines was assessed by enzyme-linked immunosorbent assay. RESULTS: The main clinical presentations of CVID patients were infections only and lymphoproliferations phenotypes, but in LRBA patients were autoimmune and enteropathy phenotype. The frequencies of CD4+ T cells were significantly reduced in LRBA and CVID patients. There were no statistically significant differences among GATA3, IL4, and IL5 gene expressions by CD4+ T cells of patients and controls, however, the IL10 expressions in CVID patients was significantly lower than in LRBA patients and HCs. As compared with HCs, CVID patients showed a prominent decrease in IL-4 and IL-10 production by CD4+ T cells. CONCLUSIONS: Our findings demonstrated that patients with CVID and LRBA deficiency (even with severe infectious and inflammatory complications) have not imbalance in Th2 response, which is in parallel with lower frequency of allergy and asthma in these patients.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Linfócitos T CD4-Positivos/fisiologia , Imunodeficiência de Variável Comum/genética , Fator de Transcrição GATA3/genética , Interleucina-10/genética , Interleucina-4/genética , Interleucina-5/genética , Adolescente , Adulto , Autoimunidade , Células Cultivadas , Criança , Análise Mutacional de DNA , Progressão da Doença , Feminino , Humanos , Masculino , Sequenciamento Completo do Exoma , Adulto Jovem
19.
J Exp Med ; 215(12): 3180-3193, 2018 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-30463876

RESUMO

Metabolic pathways such as glycolysis or oxidative phosphorylation play a key role in regulating macrophage function during inflammation and tissue repair. However, how exactly the VHL-HIF-glycolysis axis is involved in the function of tissue-resident macrophages remains unclear. Here we demonstrate that loss of VHL in myeloid cells resulted in attenuated pulmonary type 2 and fibrotic responses, accompanied by reduced eosinophil infiltration, decreased IL-5 and IL-13 concentrations, and ameliorated fiber deposition upon challenge. VHL deficiency uplifted glycolytic metabolism, decreased respiratory capacity, and reduced osteopontin expression in alveolar macrophages, which impaired the function of type 2 innate lymphoid cells but was significantly reversed by HIF1α inhibition or ablation. The up-regulated glycolysis altered the epigenetic modification of osteopontin gene, with the metabolic intermediate 3-phosphoglyceric acid as a key checkpoint controller. Thus, our results indicate that VHL acts as a crucial regulatory factor in lung inflammation and fibrosis by regulating alveolar macrophages.


Assuntos
Epigênese Genética/imunologia , Pulmão/imunologia , Macrófagos Alveolares/imunologia , Fibrose Pulmonar/imunologia , Proteína Supressora de Tumor Von Hippel-Lindau/imunologia , Animais , Glicólise/genética , Glicólise/imunologia , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Interleucina-13/genética , Interleucina-13/imunologia , Interleucina-5/genética , Interleucina-5/imunologia , Pulmão/patologia , Macrófagos Alveolares/patologia , Camundongos , Camundongos Knockout , Fibrose Pulmonar/genética , Fibrose Pulmonar/patologia , Proteína Supressora de Tumor Von Hippel-Lindau/genética
20.
Front Immunol ; 9: 2119, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30319608

RESUMO

Our previous in vitro studies revealed that histamine via histamine the H4-receptors (H4R), as compared to other stimuli, such as eotaxin or formylpeptides, rather partially activates eosinophilic granulocytes (eosinophils). In order to evaluate the H4R-mediated activation of eosinophils in vivo, we employed dextran sodium sulfate (DSS)-induced colitis in mice, closely resembling human ulcerative colitis (UC), which is largely characterized by a local eosinophilic infiltration of the colon. IL-5-deficient BALB/c mice served as a model with reduced endogenous numbers of eosinophils, in which wild-type (H4R+/+) or H4R-deficient (H4R-/-) eosinophils were adoptively transferred during the course of DSS-induced colitis. During the 1-week observation period, transfer of eosinophils transiently reversed the acute clinical colitis-like phenotype (body weight loss, perianal bleeding, soft stool consistency) resulting from IL-5-deficiency. This reversion was significantly more pronounced upon transfer of eosinophils from H4R+/+ mice as compared to those from H4R-/- mice. Already at the end of the observation period, the clinical effects of the transfer of H4R+/+ and H4R-/- eosinophils became similar, as were the results of the histological examination of the cola and the analyses of cytokine production in cola and in re-stimulated lymph node cells performed at this time. Thus, analyzing clinical and pathological parameters representative of colitis in this model, we demonstrate that as well as in vitro, also in vivo histamine via the H4R only partially activates eosinophils.


Assuntos
Colite Ulcerativa/imunologia , Eosinófilos/imunologia , Histamina/imunologia , Receptores Histamínicos H4/imunologia , Transferência Adotiva , Animais , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/patologia , Colo/citologia , Colo/imunologia , Colo/patologia , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Eosinófilos/transplante , Histamina/metabolismo , Humanos , Interleucina-5/deficiência , Interleucina-5/genética , Interleucina-5/imunologia , Mucosa Intestinal/citologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Histamínicos H4/genética , Receptores Histamínicos H4/metabolismo , Células Th2/imunologia
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