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1.
Molecules ; 26(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34361744

RESUMO

Korean red pine (Pinus densiflora) belongs to the Genus Pinus, and its bark contains a great amount of naturally occurring phenolic compounds. Until now, few studies have been conducted to assess the neuroprotective effects of Pinus densiflora bark extract against brain ischemic injury. The aim of this study was to investigate the neuroprotective effects of pre-treatment with the extract in the hippocampus following 5-min transient forebrain ischemia in gerbils. Furthermore, this study examined the anti-inflammatory effect as a neuroprotective mechanism of the extract. Pinus densiflora bark was extracted by pure water (100 °C), and this extract was quantitatively analyzed and contained abundant polyphenols, flavonoids, and proanthocyanidins. The extract (25, 50, and 100 mg/kg) was orally administered once a day for seven days before the ischemia. In the gerbil hippocampus, death of the pyramidal neurons was found in the subfield cornu ammonis 1 (CA1) five days after the ischemia. This death was significantly attenuated by pre-treatment with 100 mg/kg, not 25 or 50 mg/kg, of the extract. The treatment with 100 mg/kg of the extract markedly inhibited the activation of microglia (microgliosis) and significantly decreased the expression of pro-inflammatory cytokines (interleukin 1ß and tumor necrosis factor α). In addition, the treatment significantly increased anti-inflammatory cytokines (interleukin 4 and interleukin 13). Taken together, this study clearly indicates that pre-treatment with 100 mg/kg of Pinus densiflora bark extract in gerbils can exert neuroprotection against brain ischemic injury by the attenuation of neuroinflammatory responses.


Assuntos
Anti-Inflamatórios/farmacologia , Isquemia Encefálica/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Pinus/química , Prosencéfalo/efeitos dos fármacos , Animais , Anti-Inflamatórios/química , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Flavonoides/química , Flavonoides/farmacologia , Expressão Gênica/efeitos dos fármacos , Gerbillinae , Hipocampo/metabolismo , Hipocampo/patologia , Inflamação , Interleucina-13/agonistas , Interleucina-13/genética , Interleucina-13/metabolismo , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-4/agonistas , Interleucina-4/genética , Interleucina-4/metabolismo , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Fármacos Neuroprotetores/química , Casca de Planta/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Polifenóis/química , Polifenóis/farmacologia , Proantocianidinas/química , Proantocianidinas/farmacologia , Prosencéfalo/metabolismo , Prosencéfalo/patologia , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Células Piramidais/patologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
2.
Clin Immunol ; 229: 108784, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34126239

RESUMO

OBJECTIVE: Osteoarthritis (OA), the leading cause of joint failure, is characterized by breakdown of articular cartilage and remodeling of subchondral bone in synovial joints. Despite the high prevalence and debilitating effects of OA, no disease-modifying drugs exist. Increasing evidence, including genetic variants of the interleukin 4 (IL-4) and IL-4 receptor genes, implicates a role for IL-4 in OA, however, the mechanism underlying IL-4 function in OA remains unknown. Here, we investigated the role of IL-4 in OA pathogenesis. METHODS: Il4-, myeloid-specific-Il4ra-, and Stat6-deficient and control mice were subjected to destabilization of the medial meniscus to induce OA. Macrophages, osteoclasts, and synovial explants were stimulated with IL-4 in vitro, and their function and expression profiles characterized. RESULTS: Mice lacking IL-4, IL-4Ra in myeloid cells, or STAT6 developed exacerbated cartilage damage and osteophyte formation relative to WT controls. In vitro analyses revealed that IL-4 downregulates osteoarthritis-associated genes, enhances macrophage phagocytosis of cartilage debris, and inhibits osteoclast differentiation and activation via the type I receptor. CONCLUSION: Our findings demonstrate that IL-4 protects against osteoarthritis in a myeloid and STAT6-dependent manner. Further, IL-4 can promote an immunomodulatory microenvironment in which joint-resident macrophages polarize towards an M2 phenotype and efficiently clear pro-inflammatory debris, and osteoclasts maintain a homeostatic level of activity in subchondral bone. These findings support a role for IL-4 modulation of myeloid cell types in maintenance of joint health and identify a pathway that could provide therapeutic benefit for osteoarthritis.


Assuntos
Interleucina-4/imunologia , Macrófagos/imunologia , Osteoartrite/prevenção & controle , Osteoclastos/imunologia , Animais , Cartilagem Articular/imunologia , Cartilagem Articular/patologia , Modelos Animais de Doenças , Humanos , Inflamação/imunologia , Inflamação/patologia , Inflamação/prevenção & controle , Interleucina-4/deficiência , Interleucina-4/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteoartrite/imunologia , Osteoartrite/patologia , Osteoclastos/patologia , Fagocitose , Receptores de Superfície Celular/deficiência , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/imunologia , Fator de Transcrição STAT6/deficiência , Fator de Transcrição STAT6/genética , Fator de Transcrição STAT6/imunologia , Transdução de Sinais/imunologia
3.
Clin Immunol ; 229: 108783, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34129931

RESUMO

INTRODUCTION: IL4 pathway is known to upregulate IgE mediated immune responses and responsible for the manifestation of Atopic disorders. The current study was aimed to elucidate the genetic variations of Interleukin 4 (IL4) and Interleukin 4 receptor alpha (IL4R) genes and their possible association with atopic subjects. METHODS: The well-designed questionnaire was used to collect the subject demographic and clinical details. Biochemical parameters were analysed using Chemiluminescent Immunoassay (CLIA) technique. The genotyping was performed using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP). RESULTS: We observed a statistically significant difference of serum Immunoglobulin-E (IgE) levels among cases and controls (P<0.05). Subjects harbouring the variant genotypes of I50V and Q576R single nucleotide polymorphisms (SNPs) in IL4R gene showed statistically differential risk towards atopic disorders. However, the variants genotype of 70 bp VNTR polymorphism in IL4 gene showed a protective role towards in predisposition to Atopy. On stratification, the above genetic variants had a significant impact on modifiable and non-modifiable factors associated with the disease. CONCLUSION: Our study demonstrates that increased IgE levels and IL4 gene variants (I50V and Q576R) are significantly associated towards predisposition to allergic disorders in this study population.


Assuntos
Hipersensibilidade Imediata/genética , Hipersensibilidade Imediata/imunologia , Subunidade alfa de Receptor de Interleucina-4/genética , Interleucina-4/genética , Adulto , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Variação Genética , Humanos , Índia , Masculino , Repetições Minissatélites , Polimorfismo de Nucleotídeo Único
4.
J Med Food ; 24(6): 569-576, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34161163

RESUMO

Ginseng (the root of Panax ginseng Meyer) has been reported to have many biologic therapeutic effects, including anti-inflammatory properties, and ginsenosides are considered as one of the factors responsible for these therapeutic effects. To improve their therapeutic action, probiotic bacteria are used to ferment and chemically transform ginsenosides in red ginseng (RG). In this study, we aimed to investigate the beneficial effects of RG fermented by probiotic bacteria (FRG) against ovalbumin (OVA)-induced allergic rhinitis in a mouse model. We induced the mouse model via OVA inhalation; experimental results revealed increased immunoglobulin E (IgE) and interleukin (IL)-4 levels, leading to Th2-type cytokine response. The mice with induced allergy were then orally administered RG and FRG over 2 weeks, as a result of which, IL-4 and IgE levels in bronchoalveolar lavage fluid, nasal fluid, and serum were found to be ameliorated more effectively by FRG than by RG, suggesting that FRG has better immune regulatory effects than RG. FRG also downregulated immune cell levels, such as those of eosinophils and basophils, and significantly decreased the thickness of OVA-induced respiratory epithelium compared to RG. Collectively, the results showed that FRG treatment alleviates inflammation, thereby extending a protective effect to mice with OVA-induced inflammatory allergic rhinitis.


Assuntos
Alimentos e Bebidas Fermentados , Imunoglobulina E , Interleucina-4 , Rinite Alérgica , Animais , Citocinas/genética , Modelos Animais de Doenças , Inflamação , Interleucina-4/genética , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina , Panax , Rinite Alérgica/tratamento farmacológico
5.
Arch Biochem Biophys ; 706: 108918, 2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-33992596

RESUMO

Tripartite motif-containing 21 (TRIM21) has been confirmed to mediate the production of inflammatory mediators via NF-κB signaling. However, the function of TRIM21 in microglia-mediated neuroinflammation remains unclear. This study aimed to explore the effect of TRIM21 on LPS-activated BV2 microglia and its underlying mechanism. BV2 cells exposed to lipopolysaccharide (LPS) were used to simulated neuroinflammation in vitro. Loss-of-function and gain-of-function of TRIM21 in BV2 cells were used to assess the effect of TRIM21 on LPS-induced neuroinflammation. BV2 microglia and HT22 cells co-culture system were used to investigate whether TRIM21 regulated neuronal inflammation-mediated neuronal death. TRIM21 knockdown triggered the polarization of BV2 cells from M1 to M2 phenotype. Knockdown of TRIM21 reduced the secretion of TNF-α, IL-6, and IL-1ß, while increased the content of IL-4 in LPS-treated cells. Knockdown of TRIM21 inhibited the expression of p65 and the binding activity of NF-κB-DNA. Additionally, TRIM21 siRNA eliminated the increase in NLRP3 and cleaved caspase-1 proteins expression and caspase-1 activity induced by LPS. TRIM21 knockdown could resist cytotoxicity induced by activated microglia, including increasing the viability of co-cultured HT22 cells and reducing the emancipation of LDH. Moreover, the increased apoptosis and caspase-3 activity of HT22 neurons induced by activated BV2 cells were blocked by TRIM21 siRNA. Blocking of NF-κB abolished the effect of TRIM21 in promoting the expression of M1 phenotype marker genes. Similarly, the blockade of NF-κB pathway eliminated the promotion of TRIM21 on neurotoxicity induced by neuroinflammation. TRIM21 knockdown suppressed the M1 phenotype polarization of microglia and neuroinflammation-mediated neuronal damage via NF-κB/NLRP3 inflammasome pathway, which suggested that TRIM21 might be a potential therapeutic target for the therapy of central nervous system diseases.


Assuntos
Inflamassomos/efeitos dos fármacos , Lipopolissacarídeos/toxicidade , Microglia/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Neurônios/efeitos dos fármacos , Ribonucleoproteínas/genética , Fator de Transcrição RelA/genética , Animais , Caspase 1/genética , Caspase 1/metabolismo , Diferenciação Celular , Linhagem Celular , Técnicas de Cocultura , Cultura em Câmaras de Difusão , Regulação da Expressão Gênica , Hipocampo/citologia , Hipocampo/metabolismo , Inflamassomos/genética , Inflamassomos/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-4/genética , Interleucina-4/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Camundongos , Microglia/citologia , Microglia/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neurônios/citologia , Neurônios/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ribonucleoproteínas/antagonistas & inibidores , Ribonucleoproteínas/metabolismo , Transdução de Sinais , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
6.
Nat Commun ; 12(1): 2574, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976140

RESUMO

Allergic asthma is characterized by elevated levels of IgE antibodies, type 2 cytokines such as interleukin-4 (IL-4) and IL-13, airway hyperresponsiveness (AHR), mucus hypersecretion and eosinophilia. Approved therapeutic monoclonal antibodies targeting IgE or IL-4/IL-13 reduce asthma symptoms but require costly lifelong administrations. Here, we develop conjugate vaccines against mouse IL-4 and IL-13, and demonstrate their prophylactic and therapeutic efficacy in reducing IgE levels, AHR, eosinophilia and mucus production in mouse models of asthma analyzed up to 15 weeks after initial vaccination. More importantly, we also test similar vaccines specific for human IL-4/IL-13 in mice expressing human IL-4/IL-13 and the related receptor, IL-4Rα, to find efficient neutralization of both cytokines and reduced IgE levels for at least 11 weeks post-vaccination. Our results imply that dual IL-4/IL-13 vaccination may represent a cost-effective, long-term therapeutic strategy for the treatment of allergic asthma as demonstrated in mouse models, although additional studies are warranted to assess its safety and feasibility.


Assuntos
Asma/terapia , Interleucina-13/antagonistas & inibidores , Interleucina-4/antagonistas & inibidores , Vacinação/métodos , Animais , Asma/imunologia , Proteínas de Bactérias/administração & dosagem , Proteínas de Bactérias/imunologia , Doença Crônica/terapia , Modelos Animais de Doenças , Feminino , Humanos , Injeções Intramusculares , Interleucina-13/genética , Interleucina-13/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Camundongos , Camundongos Transgênicos , Vacinas Conjugadas/administração & dosagem , Vacinas Conjugadas/imunologia
7.
Microb Pathog ; 158: 104959, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34022353

RESUMO

BACKGROUND: Interleukin-4 (lL-4) is a critical negative cytokine in tuberculosis (TB) immune process, acting through modulating macrophages activation and Th1/Th2 balance. rs2243250 has been demonstrated to be associated with enhanced promoter strength in IL-4 expression. We performed a meta-analysis to assess the association between IL-4 rs2243250 polymorphism and TB risk. METHODS: We identified relevant studies by a comprehensive search of PubMed, Web of Science, and Embase databases, published up to February 10, 2021. The pooled odds ratios (ORs) and its 95% confidential intervals (95%CIs) were used to evaluate the associations under five genetic models. All statistical analyses were conducted with STATA 12.0 software. RESULTS: Totally 11 qualified studies involving 3097 TB cases and 3697 controls were enrolled in this meta-analysis. Overall, we didn't detect any significant association between IL-4 rs2243250 polymorphism and TB risk (T vs. C: OR = 1.05, 95% CI = 0.85-1.30, p = 0; 65; TT + TC vs. CC: OR = 1.05, 95% CI = 0.73-1.50, p = 0.81; TT vs. TC + CC: OR = 1.10, 95% CI = 0.81-1.50, p = 0.54; TT vs. CC: OR = 1.17, 95% CI = 0.71-1.94, p = 0.54; TC vs. CC: OR = 1.03, 95% CI = 0.73-1.45, p = 0.88). Significant heterogeneity was identified in analyses under all genetic models. However, in the subgroup of European population, the recessive model provided an OR of 2.54 (1.30-4.96), with no significant between-study heterogeneity. CONCLUSION: In conclusion, our meta-analysis indicated that IL-4 rs2243250 may increase TB risk in European population in recessive genetic model. Further research is needed to clarify the cause of ethnic difference in genetic association study.


Assuntos
Interleucina-4 , Tuberculose , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Interleucina-4/genética , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , Tuberculose/genética
8.
Clin Biochem ; 93: 66-72, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33861987

RESUMO

BACKGROUND: Interleukin 4 (IL4) is a key cytokine that regulates the inflammatory cascade in bronchial asthma. We investigated the association between the IL4 and IL4R polymorphisms and the susceptibility for bronchial asthma among Egyptian children. METHODS: IL4 VNTR and IL4R c.1902 A>G p.(Q576R) polymorphisms were investigated among 100 children with bronchial asthma and 100 healthy controls using PCR method. Serum levels of IL4 and immunoglobulin E (IgE) were assessed by ELISA. RESULTS: The frequencies of (A1A2 + A2A2) genotypes and A2-allele of the IL4 VNTR variant were significantly higher among asthmatic patients than controls (p = 0.01, OR = 2.34, 95% CI = 1.24-4.44; p = 0.01, OR = 2.27, 95% CI = 1.29-3.99, respectively). The frequencies of (AG + GG) genotypes and G-allele of the IL4R (A1902G) variant were significantly higher among asthmatic patients than controls (p = 0.003, OR = 2.52, 95% CI = 1.39-4.58; p = 0.002, OR = 2.25, 95% CI = 1.35-3.76, respectively). There was a significant association between (A1A2 + A2A2) genotypes of the IL4 VNTR variant and high serum IL4 level among asthmatic patients (p < 0.001). The (AG + GG) genotypes of the IL4R (A1902G) variant were significantly associated with exposure to triggers, atopic dermatitis and higher serum IgE level in asthmatic patients (p = 0.02, 0.04 and 0.01, respectively). CONCLUSION: IL4 VNTR and IL4R (A1902G) polymorphisms could be associated with higher risks of bronchial asthma among Egyptian children.


Assuntos
Asma/genética , Subunidade alfa de Receptor de Interleucina-4/genética , Interleucina-4/genética , Polimorfismo de Nucleotídeo Único/genética , Alelos , Asma/sangue , Asma/complicações , Asma/imunologia , Estudos de Casos e Controles , Criança , Dermatite Atópica/sangue , Dermatite Atópica/etiologia , Dermatite Atópica/genética , Dermatite Atópica/imunologia , Feminino , Predisposição Genética para Doença , Genótipo , Voluntários Saudáveis , Humanos , Imunoglobulina E/sangue , Interleucina-4/sangue , Masculino , Análise de Componente Principal
9.
J Biol Chem ; 296: 100615, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33798555

RESUMO

Persistent high levels of proinflammatory and Th1 responses contribute to cerebral malaria (CM). Suppression of inflammatory responses and promotion of Th2 responses prevent pathogenesis. IL-4 commonly promotes Th2 responses and inhibits inflammatory and Th1 responses. Therefore, IL-4 is widely considered as a beneficial cytokine via its Th2-promoting role that is predicted to provide protection against severe malaria by inhibiting inflammatory responses. However, IL-4 may also induce inflammatory responses, as the result of IL-4 action depends on the timing and levels of its production and the tissue environment in which it is produced. Recently, we showed that dendritic cells (DCs) produce IL-4 early during malaria infection in response to a parasite protein and that this IL-4 response may contribute to severe malaria. However, the mechanism by which IL-4 produced by DCs contributing to lethal malaria is unknown. Using Plasmodium berghei ANKA-infected C57BL/6 mice, a CM model, we show here that mice lacking IL-4Rα only in CD8α+ DCs are protected against CM pathogenesis and survive, whereas WT mice develop CM and die. Compared with WT mice, mice lacking IL-4Rα in CD11c+ or CD8α+ DCs showed reduced inflammatory responses leading to decreased Th1 and cytotoxic CD8+ T cell responses, lower infiltration of CD8+ T cells to the brain, and negligible brain pathology. The novel results presented here reveal a paradoxical role of IL-4Rα signaling in CM pathogenesis that promotes CD8α+ DC-mediated inflammatory responses that generate damaging Th1 and cytotoxic CD8+ T cell responses.


Assuntos
Antígenos CD8/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Malária Cerebral/imunologia , Plasmodium berghei/imunologia , Receptores de Superfície Celular/imunologia , Transdução de Sinais/imunologia , Células Th1/imunologia , Animais , Antígenos CD8/genética , Linfócitos T CD8-Positivos/patologia , Células Dendríticas/patologia , Interleucina-4/genética , Interleucina-4/imunologia , Malária Cerebral/genética , Malária Cerebral/patologia , Camundongos , Camundongos Knockout , Plasmodium berghei/genética , Receptores de Superfície Celular/genética , Transdução de Sinais/genética , Células Th1/patologia , Células Th2/imunologia , Células Th2/patologia
10.
Mol Ther ; 29(6): 1970-1983, 2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-33823303

RESUMO

A self-transcribing and replicating RNA (STARR)-based vaccine (LUNAR-COV19) has been developed to prevent SARS-CoV-2 infection. The vaccine encodes an alphavirus-based replicon and the SARS-CoV-2 full-length spike glycoprotein. Translation of the replicon produces a replicase complex that amplifies and prolongs SARS-CoV-2 spike glycoprotein expression. A single prime vaccination in mice led to robust antibody responses, with neutralizing antibody titers increasing up to day 60. Activation of cell-mediated immunity produced a strong viral antigen-specific CD8+ T lymphocyte response. Assaying for intracellular cytokine staining for interferon (IFN)γ and interleukin-4 (IL-4)-positive CD4+ T helper (Th) lymphocytes as well as anti-spike glycoprotein immunoglobulin G (IgG)2a/IgG1 ratios supported a strong Th1-dominant immune response. Finally, single LUNAR-COV19 vaccination at both 2 µg and 10 µg doses completely protected human ACE2 transgenic mice from both mortality and even measurable infection following wild-type SARS-CoV-2 challenge. Our findings collectively suggest the potential of LUNAR-COV19 as a single-dose vaccine.


Assuntos
Anticorpos Neutralizantes/biossíntese , Anticorpos Antivirais/biossíntese , Vacinas contra COVID-19/administração & dosagem , COVID-19/prevenção & controle , SARS-CoV-2/efeitos dos fármacos , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinas Sintéticas/administração & dosagem , Alphavirus/genética , Alphavirus/imunologia , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/imunologia , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , COVID-19/imunologia , COVID-19/patologia , COVID-19/virologia , Vacinas contra COVID-19/biossíntese , Vacinas contra COVID-19/genética , Vacinas contra COVID-19/imunologia , Feminino , Expressão Gênica , Humanos , Imunidade Celular/efeitos dos fármacos , Imunidade Humoral/efeitos dos fármacos , Interferon gama/genética , Interferon gama/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Camundongos , Camundongos Transgênicos , Replicon/imunologia , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th1/virologia , Transgenes , Resultado do Tratamento , Vacinação/métodos , Vacinas Sintéticas/biossíntese , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia
11.
Int J Mol Sci ; 22(6)2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33804263

RESUMO

Interleukin (IL)-4 and IL-13 are known as pleiotropic Th2 cytokines with a wide range of biological properties and functions especially in immune responses. In addition, increasing activities have also been determined in oncogenesis and tumor progression of several malignancies. It is now generally accepted that IL-4 and IL-13 can exert effects on epithelial tumor cells through corresponding receptors. Type II IL-4 receptor (IL-4Rα/IL-13Rα1), predominantly expressed in non-hematopoietic cells, is identified to be the main target for both IL-4 and IL-13 in tumors. Moreover, IL-13 can also signal by binding to the IL-13Rα2 receptor. Structural similarity due to the use of the same receptor complex generated in response to IL-4/IL-13 results in overlapping but also distinct signaling pathways and functions. The aim of this review was to summarize knowledge about IL-4 and IL-13 and their receptors in pancreatic cancer in order understand the implication of IL-4 and IL-13 and their receptors for pancreatic tumorigenesis and progression and for developing possible new diagnostic and therapeutic targets.


Assuntos
Subunidade alfa1 de Receptor de Interleucina-13/genética , Subunidade alfa2 de Receptor de Interleucina-13/genética , Interleucina-13/genética , Interleucina-4/genética , Neoplasias Pancreáticas/genética , Carcinogênese/genética , Humanos , Subunidade alfa de Receptor de Interleucina-4/genética , Neoplasias Pancreáticas/patologia , Receptores de Interleucina/genética , Transdução de Sinais/genética
12.
Emerg Microbes Infect ; 10(1): 763-773, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33739899

RESUMO

Coxsackievirus A6 (CV-A6) has been emerging as a major pathogen of hand, foot and mouth disease (HFMD). Study on the pathogenesis of CV-A6 infection and development of vaccines is hindered by a lack of appropriate animal models. Here, we report an actively immunized-challenged mouse model to evaluate the efficacy of a Vero-cell-based, inactivated CV-A6 vaccine candidate. The neonatal Kunming mice were inoculated with a purified, formaldehyde-inactivated CV-A6 vaccine on days 3 and 9, followed by challenging on day 14 with a naturally selected virulent strain at a lethal dose. Within 14 days postchallenge, all mice in the immunized groups survived, while 100% of the Alum-only inoculated mice died. Neutralizing antibodies (NtAbs) were detected in the serum of immunized suckling mice, and the NtAb levels correlated with the survival rate of the challenged mice. The virus loads in organs were reduced, and pathological changes and viral protein expression were weak in the immunized mice compared with those in Alum-only inoculated control mice. Elevated levels of interleukin-4, 6, interferon γ and tumour necrosis factor α were also observed in Alum-only control mice compared with immunized mice. Importantly, the virulent CV-A6 challenge strain was selected quickly and conveniently from a RD cell virus stock characterized with the natural multi-genotypes. The virulent determinants were mapped to V124M and I242 V at VP1. Together, our results indicated that this actively immunized mouse model is invaluable for future studies to develop multivalent vaccines containing the major component of CV-A6 against HFMD.


Assuntos
Enterovirus Humano A/imunologia , Doença de Mão, Pé e Boca/virologia , Vacinas Virais/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Chlorocebus aethiops , Modelos Animais de Doenças , Enterovirus Humano A/genética , Doença de Mão, Pé e Boca/genética , Doença de Mão, Pé e Boca/imunologia , Humanos , Imunização , Interleucina-4/genética , Interleucina-4/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Camundongos , Vacinas de Produtos Inativados/administração & dosagem , Vacinas de Produtos Inativados/imunologia , Células Vero , Vacinas Virais/administração & dosagem
13.
Free Radic Biol Med ; 168: 168-179, 2021 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-33736980

RESUMO

NADPH oxidase (Nox) mediates ROS production and contributes to cardiac remodeling. However, macrophage p47phox, a Nox subunit regulating cardiac remodeling, is unclear. We aimed to investigate the role of macrophage p47phox in hypertensive cardiac remodeling. Pressure-overload induced by Angiotensin II (AngII) for two weeks in young adult male p47phox deficient (KO) mice showed aggravated cardiac dysfunction and hypertrophy as indicated from echocardiographic and histological studies in comparison with wild-type littermates (WT). Additionally, LV of AngII-infused KO mice showed augmented interstitial fibrosis, collagen deposition and, myofibroblasts compared to AngII-infused WT mice. Moreover, these changes in AngII-infused KO mice correlated well with the gene analysis of hypertrophic and fibrotic markers. Similar results were also found in the transverse aortic constriction model. Further, AngII-infused KO mice showed elevated circulating immunokines and increased LV leukocytes infiltration and CD206+ macrophages compared to AngII-infused WT mice. Likewise, LV of AngII-infused KO mice showed upregulated mRNA expression of anti-inflammatory/pro-fibrotic M2 macrophage markers (Ym1, Arg-1) compared to AngII-infused WT mice. AngII and IL-4 treated bone marrow-derived macrophages (BMDMs) from KO mice showed upregulated M2 macrophage markers and STAT6 phosphorylation (Y641) compared to AngII and IL-4 treated WT BMDMs. These alterations were at least partly mediated by macrophage as bone marrow transplantation from KO mice into WT mice aggravated cardiac remodeling. Mechanistically, AngII-infused KO mice showed hyperactivated IL-4/STAT6/PPARγ signaling and downregulated SOCS3 expression compared to AngII-infused WT mice. Our studies show that macrophage p47phox limits anti-inflammatory signaling and extracellular matrix remodeling in response to pressure-overload.


Assuntos
PPAR gama , Remodelação Ventricular , Angiotensina II , Animais , Interleucina-4/genética , Macrófagos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oxazóis , PPAR gama/genética , Fator de Transcrição STAT6/genética
14.
Aging (Albany NY) ; 13(4): 5087-5103, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33535180

RESUMO

This study aimed to investigate the therapeutic mechanism of Huankuile suspension (HKL), a typical traditional Chinese medicine, on ulcerative colitis (UC) in a rat model. UC model was established by 2,4,6-trinitrobenzene sulfonic acid (TNBS) enema. Then, the rats were randomly divided into three groups: water treated group, HKL treated group and 5- amino salicylic acid (5-ASA) treated group. After 7 days treatment, the histological score in the HKL treated group was comparable with those in the control group. qRT-PCR and western blot demonstrated that HKL could significantly decreased pro-inflammatory cytokines, including TNF-α, IL-1ß and IL-6, while having less effect on anti-inflammatory cytokines, including IL-4 and IL-10. Transcriptomic analysis identified 670 differentially expressed genes (DEGs) between HKL treated UC rats and water treated UC rats. These DEGs were mostly related with immune response. Besides, metabonomic profile revealed 136 differential metabolites which were significantly enriched in "pyrimidine metabolism", "glutathione metabolism", "purine metabolism" and "citrate cycle". Finally, integrated analysis revealed that metabonomic pathways including "steroid hormone biosynthesis", "pyrimidine metabolism", "purine metabolism", and "glutathione metabolism" were altered by HKL at both transcriptomic and metabonomic levels. HKL could inhibit inflammation and regulate bile metabolism, pyrimidine metabolism, purine metabolism, glutathione metabolism and citrate cycle.


Assuntos
Colite Ulcerativa/genética , Citocinas/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Mucosa Intestinal/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/patologia , Colite Ulcerativa/fisiopatologia , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Interleucina-10/genética , Interleucina-10/metabolismo , Interleucina-1beta/efeitos dos fármacos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-4/genética , Interleucina-4/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Mesalamina/farmacologia , Metabolômica , Ratos , Ácido Trinitrobenzenossulfônico , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
15.
Arch Microbiol ; 203(5): 2719-2725, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33606039

RESUMO

Heat shock proteins are molecular chaperones that are immunogens as well as potent inducers of an antigen-specific immunological response. In this study, we aimed to evaluate if co-immunization of Brucella rOmp22 and rDnaK proteins had boosted immunogenic activity as compared to rOmp22 immunization alone in mice. For this, gene-encoding DnaK of B. abortus was cloned, expressed in E. coli and purified using Ni-NTA agarose. Immuno-modulatory effect of rDnaK protein was evaluated in mice when co-immunized with Brucella rOmp22. Four groups of mice (n = 6 per group) were used in the study. The control group was immunized with rOmp22 alone, while rOmp22 emulsified with conventional adjuvants (Freund's complete and incomplete adjuvants) and rOmp22 mixed with rDnaK were injected to group I and group II in mice, respectively. Group III mice were immunized with rDnaK alone. IgG class switching (IgG1 and IgG2a) response to immunization was assessed by enzyme-linked immunosorbent assay and expression of IL-4 and IL-12 mRNA was assessed by real-time PCR to evaluate the immune response in mice. The ratio of IgG1-IgG2a was less than 1 in mice co-immunized with rOmp22 and rDnaK, indicating that the immune response was directed towards CMI arm in this group of mice. Moreover, IL-12 mRNA expression was also up-regulated to a greater extent in mice co-immunized with rOmp22 and rDnaK as compared to those immunized with rOmp22 along with the conventional adjuvants, or rOmp22 alone. Our data suggest that rDnaK could be responsible for modulating the immune response, specifically the CMI response.


Assuntos
Anticorpos Antibacterianos/imunologia , Proteínas da Membrana Bacteriana Externa/imunologia , Brucella abortus/imunologia , Proteínas de Choque Térmico HSP70/imunologia , Switching de Imunoglobulina/imunologia , Animais , Anticorpos Antibacterianos/biossíntese , Brucella abortus/genética , Ensaio de Imunoadsorção Enzimática , Escherichia coli/genética , Imunização , Imunoglobulina G/imunologia , Subunidade p35 da Interleucina-12/genética , Interleucina-4/genética , Masculino , Camundongos , Proteínas Recombinantes/genética
16.
Vet Immunol Immunopathol ; 234: 110196, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33582406

RESUMO

The pathogenesis of Canine leishmaniosis (CanL) is associated with altered cytokine expression and parasitic tissue shows a lot of inflammation. The aim of this study was to assess the renal inflammation and cytokine expression in eight symptomatic and eight asymptomatic Leishmania- infected dogs, and seven uninfected control dogs. Kidney fragments were stained with hematoxylin and eosin for morphometric evaluation. mRNA expression levels of interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), interleukin (IL)-2, IL-4, IL-10, and IL-12 were assessed in the kidney fragments using quantitative real time-polymerase chain reaction. Inflammation, quantified by the average area of the infiltrated immune cells, was greater in symptomatic dogs than in those asymptomatic, whereas asymptomatic dogs exhibited higher inflammation than the control dogs (p > 0.05, Tukey's test). Expression levels of IFN-γ, TNF-α, IL-4, IL-10, and IL-12 were upregulated in symptomatic dogs and downregulated in asymptomatic dogs compared with those of the uninfected group. Furthermore, IL-4 showed higher expression in symptomatic dogs than in asymptomatic ones (p < 0.05, Mann-Whitney test), which was directly associated with clinical manifestations (p < 0.05, Chi-square test). However, IL-12 was predominantly expressed in symptomatic dogs, shifting the balance from IL-12/IL-4 to IL-12, which elicits a change in the inflammatory response. Leishmania was not found in the renal tissues in any one of the studied groups. Our data suggests that the balance between IL-12 and IL-4 plays an important role in the regulation of inflammation in renal tissue and clinical presentations in CanL.


Assuntos
Doenças do Cão/imunologia , Inflamação/veterinária , Interleucina-12/genética , Interleucina-4/genética , Rim/imunologia , Leishmaniose/imunologia , Leishmaniose/veterinária , Animais , Doenças do Cão/parasitologia , Cães , Feminino , Regulação da Expressão Gênica/imunologia , Inflamação/parasitologia , Interleucina-12/imunologia , Interleucina-4/imunologia , Leishmania infantum/imunologia , Masculino
17.
Stem Cell Res Ther ; 12(1): 40, 2021 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-33413614

RESUMO

BACKGROUND: Mesenchymal stem cell (MSC)-based therapy has the potential for immunomodulation and enhancement of tissue regeneration. Genetically modified MSCs that over-express specific cytokines, growth factors, or chemokines have shown great promise in pre-clinical studies. In this regard, the anti-inflammatory cytokine interleukin (IL)-4 converts pro-inflammatory M1 macrophages into an anti-inflammatory M2 phenotype; M2 macrophages mitigate chronic inflammation and enhance osteogenesis by MSC lineage cells. However, exposure to IL-4 prematurely inhibits osteogenesis of MSCs in vitro; furthermore, IL-4 overexpressing MSCs inhibit osteogenesis in vivo during the acute inflammatory period. Platelet-derived growth factor (PDGF)-BB has been shown to enhance osteogenesis of MSCs with a dose-dependent effect. METHODS: In this study, we generated a lentiviral vector that produces PDGF-BB under a weak promoter (phosphoglycerate kinase, PGK) and lentiviral vector producing IL-4 under a strong promoter (cytomegalovirus, CMV). We infected MSCs with PDGF-BB and IL-4-producing lentiviral vectors separately or in combination to investigate cell proliferation and viability, protein expression, and the capability for osteogenesis. RESULTS: PDGF-BB and IL-4 co-overexpression was observed in the co-infected MSCs and shown to enhance cell proliferation and viability, and osteogenesis compared to IL-4 overexpressing MSCs alone. CONCLUSIONS: Overexpression of PDGF-BB together with IL-4 mitigates the inhibitory effect of IL-4 on osteogenesis by IL-4 overexpressing MSCS. PDGF-BB and IL-4 overexpressing MSCs may be a potential strategy to facilitate osteogenesis in scenarios of both acute and chronic inflammation.


Assuntos
Células-Tronco Mesenquimais , Becaplermina , Regeneração Óssea , Interleucina-4/genética , Osteogênese
18.
BMC Infect Dis ; 21(1): 28, 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33413198

RESUMO

BACKGROUND: Pneumocystis pneumonia (PCP) is a fatal infectious disease caused by Pneumocystis jirovecii (PJP). The major factor relevant to morbidity and mortality seems to be the host inflammatory reaction. The objective of this study was to evaluate the role of IL-2, IL-4, IL-10, and IL-13 cytokine mRNA expression among suspected P. jirovecii infection. METHODS: This was a cross-sectional analytical study undertaken in Aseer region, Saudi Arabia. One hundred suspected PCP cases and 100 healthy controls were included in the study. Basic clinical manifestations, radiological findings, microbiological and immunological findings were extracted from the hospital records from January 2019 to August 2019, Pneumocystis detection was done by immune-fluorescent staining (IFAT, Gomorimethanamine silver staining (GMSS), Giemsa staining, Toluidine blue O (TBO), and Pneumocystis RT-PCR. RESULTS: Increased more than 5 fold, 3 fold, 4 fold, and 7 fold of IL-2, IL-4, IL-10, and IL-13 mRNA expression were observed in PCP cases compared to controls. Higher expression of IL-2 mRNA was connected with crept, wheezing and chest X-ray findings like central perihilar infiltrate, patchy infiltrate, consolidation, hilar lymphadenopathy, pneumothorax, pleural effusion which showed higher expression compared to counterpart (p< 0.0001). Higher expression of IL-4 mRNA was found to be significantly associated with weight loss (p=0.002), dyspnea (p=0.003), crept (p=0.01), and chest X-ray findings (p< 0.0001). Significantly increased expression of IL-10 mRNA was observed to be associated with weight loss, dyspnea, night sweats, wheezing, and different findings of chest X-ray compared to their counterparts, whereas, IL-13 mRNA was observed in cases with fever. Suspected cases of PCP confirmed positive by IFTA with higher IL-2, IL-4, and IL-10 mRNA expression compared to negative cases. RT-PCR confirmed PCP cases had significantly higher expression of IL-2, IL-4, and IL-10 as well as IL-13 mRNA compared to negative cases. Positive detected cases by GMSS showed higher IL-2, IL-10 mRNA expression, while Giemsa showed only higher IL-4 mRNA expression compared to negative cases. CONCLUSION: Confirmed cases of P. jirovecii showed higher IL-2, IL-4, IL-10, and IL-13 mRNA expression comparatively to negative cases. Increased expression of cytokines may be indicative of infection severity and could help in patients' management.


Assuntos
Citocinas/genética , Pneumonia por Pneumocystis/genética , Adulto , Corantes Azur , Estudos de Casos e Controles , Estudos Transversais , Citocinas/sangue , Feminino , Imunofluorescência , Expressão Gênica , Humanos , Interleucina-10/genética , Interleucina-13/genética , Interleucina-2/genética , Interleucina-4/genética , Masculino , Pessoa de Meia-Idade , Pneumocystis carinii/genética , Pneumocystis carinii/patogenicidade , Pneumonia por Pneumocystis/diagnóstico por imagem , Pneumonia por Pneumocystis/microbiologia , Reação em Cadeia da Polimerase , RNA Mensageiro/sangue , Arábia Saudita , Cloreto de Tolônio
19.
Int J Mol Sci ; 22(2)2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33450900

RESUMO

Interleukin (IL)-4 and -13 are structurally and functionally related cytokines sharing common receptor subunits. They regulate immune responses and, moreover, are involved in the pathogenesis of a variety of human neoplasms. Three different receptors have been described for IL-4, but only IL-4 receptor type II (IL-4Rα/IL-13Rα1) is expressed in solid tumors. While IL-13 can also bind to three different receptors, IL-13 receptor type I (IL-4Rα/IL-13Rα1/IL-13Rα2) and type II (IL-4Rα/IL-13Rα1) are expressed in solid tumors. After receptor binding, IL-4 and IL-13 can mediate tumor cell proliferation, survival, and metastasis in gastric or colon cancer. This review summarizes the results about the role of IL-4/IL-13 and their receptors in gastric and colon cancer.


Assuntos
Neoplasias do Colo/metabolismo , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Receptores de Interleucina-13/metabolismo , Receptores de Interleucina-4/metabolismo , Neoplasias Gástricas/metabolismo , Animais , Neoplasias do Colo/etiologia , Neoplasias do Colo/patologia , Citocinas/metabolismo , Suscetibilidade a Doenças , Humanos , Interleucina-13/genética , Interleucina-4/genética , Polimorfismo de Nucleotídeo Único , Ligação Proteica , Receptores de Interleucina-13/genética , Receptores de Interleucina-4/genética , Transdução de Sinais , Neoplasias Gástricas/etiologia , Neoplasias Gástricas/patologia
20.
Exp Parasitol ; 222: 108063, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33412170

RESUMO

Leishmaniasis is one of the most neglected tropical infectious diseases in the world. The emergence of drug resistance and toxicity and the high cost of the available drugs with a lack of new anti-leishmanial drugs highlight the need to search for newer therapies with anti-leishmanial activities. Due to the mesenchymal stem cell (MSC) immunomodulatory capacity, they have been applied in a wide variety of disorders. In this study, the potential effects of adipose-derived MSC (AD-MSCs) therapy and its combination with glucantime were evaluated in a murine model of cutaneous leishmaniasis induced by L. major. The results showed that AD-MSCs improved wound healing and decreased parasite burden. The real-time PCR results obtained from mice treated with AD-MSCs showed that IL-12 and TNF-α genes were upregulated. IL-10, arginase, and FOXP3 genes were downregulated whereas no differences in expression of the IL-4 gene were found. Overall, it seems that AD-MSCs therapy enhances Th1 immune response in L. major infected BALB/c mice. Unexpectedly, our results showed that the association of glucantime to AD-MSCs treatments did not lead to an increment in the anti-leishmanial activity.


Assuntos
Leishmania major , Leishmaniose Cutânea/terapia , Células-Tronco Mesenquimais/imunologia , Análise de Variância , Animais , Arginase/genética , Arginase/metabolismo , Regulação para Baixo , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Expressão Gênica , Interleucina-10/genética , Interleucina-10/metabolismo , Interleucina-12/genética , Interleucina-12/metabolismo , Interleucina-4/genética , Interleucina-4/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Células Th1/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima
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