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1.
Expert Opin Drug Saf ; 19(1): 69-82, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31847608

RESUMO

Introduction: Psoriatic arthritis (PsA) is characterized by chronic inflammation mediated by pro-inflammatory cytokines, with clinical features resulting from dysfunctional integrated signaling pathways affecting different constituents of the immune system. Increased understanding of the processes responsible for enthesitis, synovial inflammation, joint erosion, and new bone formation during PsA has led to development of biologic therapies targeting these cytokines. There is an increased risk of opportunistic infections in patients with PsA, and this risk is increased further with targeted biologic therapy.Areas covered: This paper reviews the role of the interleukin (IL)-12, IL-23 and IL-17 axis in the pathogenesis of PsA. The data suggest that ustekinumab is associated with a low risk of infections in patients with PsA, including tuberculosis or hepatitis reactivation. No live vaccines can be safely administered; ustekinumab is contraindicated/cannot be given with live vaccines. However, long-term treatment with ustekinumab does not impair the immune response to these vaccines when administered after an appropriate interval.Expert opinion: Ustekinumab is associated with a low risk of serious and opportunistic infections. More research is needed to confirm these findings specifically in patients with PsA, and comparative studies are needed to investigate the relative risk of infection with different biologics.


Assuntos
Artrite Psoriásica/tratamento farmacológico , Infecções Oportunistas/etiologia , Ustekinumab/efeitos adversos , Animais , Artrite Psoriásica/complicações , Fármacos Dermatológicos/administração & dosagem , Fármacos Dermatológicos/efeitos adversos , Humanos , Interleucina-12/imunologia , Interleucina-17/imunologia , Interleucina-23/imunologia , Infecções Oportunistas/epidemiologia , Ustekinumab/administração & dosagem
2.
Pol J Microbiol ; 68(4): 439-447, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31880888

RESUMO

Salmonella infection is most common in patients with infected aortic aneurysm, especially in Asia. When the aortic wall is heavily atherosclerotic, the intima is vulnerable to invasion by Salmonella, leading to the development of infected aortic aneurysm. By using THP-1 macrophage-derived foam cells to mimic atherosclerosis, we investigated the role of three Salmonella enterica serotypes - Typhimurium, Enteritidis, and Choleraesuis - in foam cell autophagy and inflammasome formation. Herein, we provide possible pathogenesis of Salmonella-associated infected aortic aneurysms. Three S. enterica serotypes with or without virulence plasmid were studied. Through Western blotting, we investigated cell autophagy induction and inflammasome formation in Salmonella-infected THP-1 macrophage-derived foam cells, detected CD36 expression after Salmonella infection through flow cytometry, and measured interleukin (IL)-1ß, IL-12, and interferon (IFN)-α levels through enzyme-linked immunosorbent assay. At 0.5 h after infection, plasmid-bearing S. Enteritidis OU7130 induced the highest foam cell autophagy - significantly higher than that induced by plasmid-less OU7067. However, plasmid-bearing S. Choleraesuis induced less foam cell autophagy than did its plasmid-less strain. In foam cells, plasmid-less Salmonella infection (particularly S. Choleraesuis OU7266 infection) led to higher CD36 expression than did plasmid-bearing strains infection. OU7130 and OU7266 infection induced the highest IL-1ß secretion. OU7067-infected foam cells secreted the highest IL-12p35 level. Plasmid-bearing S. Typhimurium OU5045 induced a higher IFN-α level than did other Salmonella serotypes. Salmonella serotypes are correlated with foam cell autophagy and IL-1ß secretion. Salmonella may affect the course of foam cells formation, or even aortic aneurysm, through autophagy.Salmonella infection is most common in patients with infected aortic aneurysm, especially in Asia. When the aortic wall is heavily atherosclerotic, the intima is vulnerable to invasion by Salmonella, leading to the development of infected aortic aneurysm. By using THP-1 macrophage-derived foam cells to mimic atherosclerosis, we investigated the role of three Salmonella enterica serotypes ­ Typhimurium, Enteritidis, and Choleraesuis ­ in foam cell autophagy and inflammasome formation. Herein, we provide possible pathogenesis of Salmonella-associated infected aortic aneurysms. Three S. enterica serotypes with or without virulence plasmid were studied. Through Western blotting, we investigated cell autophagy induction and inflammasome formation in Salmonella-infected THP-1 macrophage-derived foam cells, detected CD36 expression after Salmonella infection through flow cytometry, and measured interleukin (IL)-1ß, IL-12, and interferon (IFN)-α levels through enzyme-linked immunosorbent assay. At 0.5 h after infection, plasmid-bearing S. Enteritidis OU7130 induced the highest foam cell autophagy ­ significantly higher than that induced by plasmid-less OU7067. However, plasmid-bearing S. Choleraesuis induced less foam cell autophagy than did its plasmid-less strain. In foam cells, plasmid-less Salmonella infection (particularly S. Choleraesuis OU7266 infection) led to higher CD36 expression than did plasmid-bearing strains infection. OU7130 and OU7266 infection induced the highest IL-1ß secretion. OU7067-infected foam cells secreted the highest IL-12p35 level. Plasmid-bearing S. Typhimurium OU5045 induced a higher IFN-α level than did other Salmonella serotypes. Salmonella serotypes are correlated with foam cell autophagy and IL-1ß secretion. Salmonella may affect the course of foam cells formation, or even aortic aneurysm, through autophagy.


Assuntos
Aneurisma Aórtico/microbiologia , Infecções por Salmonella/microbiologia , Salmonella typhimurium/patogenicidade , Animais , Aneurisma Aórtico/genética , Aneurisma Aórtico/imunologia , Linhagem Celular , Humanos , Interferon-alfa/genética , Interferon-alfa/imunologia , Interleucina-12/genética , Interleucina-12/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Antígeno Ki-1/genética , Antígeno Ki-1/imunologia , Macrófagos/imunologia , Macrófagos/microbiologia , Monócitos/imunologia , Monócitos/microbiologia , Plasmídeos/genética , Plasmídeos/metabolismo , Infecções por Salmonella/genética , Infecções por Salmonella/imunologia , Salmonella typhimurium/genética , Salmonella typhimurium/fisiologia , Sorogrupo , Virulência
3.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(11): 979-985, 2019 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-31878993

RESUMO

Objective To investigate the role of mitogen activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway in the salidroside (SAL)-regulated antitumor immunity of dendritic cells (DCs). Methods Lewis lung cancer-bearing mouse model was established and treated with normal saline (NS) (0.2 mL/d), SAL [500 mg/(kg.d)] and cyclophosphamide (CTX) [10 mg/(kg.d)] in corresponding groups. Then their survival and tumor quality were recorded. Meanwhile, the bone marrow-derived DCs from the Lewis lung cancer-bearing mice were isolated in vitro and cultured for 7 days before collection. After sorted with magnetic beads, cells were co-cultured with PBS, SAL (0.05 mg/mL), LPS (200 ng/mL) or SAL combined with ERK inhibitor U0126 separately for 48 hours, followed by detection of the expression of phosphorylated ERK (p-ERK) by flow cytometry. In addition, after the stimulation of DCs by SAL, the expression of p38 MAPK and phosphorylated c-jun N-terminal kinase (p-JNK) was detected by flow cytometry. Moreover, after sorted with magneticbeads, DCs were co-cultured with PBS, SAL (0.05 mg/mL), LPS (200 ng/mL) or SAL combined with U0126. Then, the supernatant was collected, and IL-12p70 secretion ability of DCs was detected by ELISA. Finally, sensitized bone marrow-derived DCs from Lewis lung cancer-bearing mice were stimulated with SAL and co-cultured with spleen T lymphocytes purified by nylon fiber column from C57BL/6 mice as effector cells. 3LL target cells were then added at the target ratio of 10:1, 25:1, 50:1, followed by the detection of cell viability of cytotoxic T lymphocytes (CTLs) using CCK-8 assay. Results SAL could significantly inhibit tumor growth and improve the survival rate. Compared with PBS group, the phosphorylation of ERK protein on DC was enhanced significantly, and then reduced significantly after U0126 treatment. The phosphorylation of p38MAPK and c-jun N-terminal kinase (JNK) protein was not statistically affected by SAL. The level of IL-12p70 significantly increased in SAL group, and became remarkably higher after U0126 treatment. Finally, the killing ability of CTL was significantly enhanced by SAL. Conclusion SAL can inhibit the tumor growth of Lewis lung cancer-bearing mice and activate the ERK signaling pathway, thereby promoting IL-12p70 secretion in DCs and enhancing the cytotoxicity of CTL.


Assuntos
Carcinoma Pulmonar de Lewis/imunologia , Células Dendríticas/efeitos dos fármacos , Glucosídeos/farmacologia , Sistema de Sinalização das MAP Quinases , Fenóis/farmacologia , Animais , Células Cultivadas , Células Dendríticas/imunologia , Interleucina-12/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T Citotóxicos/imunologia
4.
Expert Opin Drug Saf ; 18(11): 1031-1041, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31479282

RESUMO

Introduction: Psoriasis is a chronic inflammatory disease and affects about 10% of the world's population. Psoriasis is associated with a number of comorbidities. Biologic therapies for the treatment of moderate-severe plaque psoriasis include tumor necrosis factor α inhibitors (TNFi), and newer molecules targeting IL-12 and 23, blocking p40 subunit, or targeting subunit p19 of IL-23 and other molecules blocking IL-17A, or directed against the IL-17 receptor. Areas covered: Anti-interleukin drugs show great improvement in disease control and on the other hand are not affected by important adverse reactions of older compounds. Approach to chronic disease affected patients, in particular, and to patients with multiple comorbidities is revolutionized by novel molecules that are safer and more manageable. Expert opinion: A recent work suggests that pro-fibrogenic cytokines, IL-17, might be important player of liver damage and even in regulation of obesity, diabetes, and non-alcoholic fatty liver disease (NAFLD) pathogenesis. Choosing to interfere with IL-23/Il-17 axis, definitely, is like acting against psoriatic march and in a parallel way against its comorbidities.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Fármacos Dermatológicos/administração & dosagem , Psoríase/tratamento farmacológico , Animais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/imunologia , Produtos Biológicos/administração & dosagem , Produtos Biológicos/efeitos adversos , Produtos Biológicos/imunologia , Fármacos Dermatológicos/efeitos adversos , Fármacos Dermatológicos/imunologia , Humanos , Interleucina-12/imunologia , Interleucina-17/imunologia , Interleucina-23/imunologia , Psoríase/imunologia , Psoríase/patologia , Índice de Gravidade de Doença
5.
J Sci Food Agric ; 99(13): 5870-5880, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31206687

RESUMO

BACKGROUND: Sepsis is a set of serious organic manifestations caused by an infection, whose progression culminates in exacerbated inflammation and oxidative stress, poor prognosis, and high hospital costs. Antioxidants used against sepsis have been evaluated, including essential oils such as ß-caryophyllene (BCP), and polyunsaturated fatty acids, such as docosahexaenoic acid (DHA). The aim of this study was to evaluate the anti-inflammatory activity of the association of these two compounds. RESULTS: Treatment with BCP-DHA, at a dose of 200 µL/animal, significantly inhibited the migration of neutrophils in a Cg-induced peritonitis model. After Staphylococcus aureus infection, in the groups treated with BCP-DHA there was a significant decrease in the total and differential count of leukocytes, increased expression of cytokines TNF-α and IFN-γ in treated groups, an increase of IL-4 and IL-5 in B/D and B/D + SA groups, and an augmentation of IL-6 and IL-12 groups in B/D + SA groups. Histological and bacterial analysis revealed lower neutrophil migration and lower bacterial load in the infected and treated groups. CONCLUSION: In general, the BCP-DHA association presented anti-inflammatory activity against two different models of acute inflammation and infection, showing promising potential as a therapeutic adjuvant in sepsis. © 2019 Society of Chemical Industry.


Assuntos
Anti-Inflamatórios/administração & dosagem , Ácidos Docosa-Hexaenoicos/administração & dosagem , Peritonite/tratamento farmacológico , Sepse/tratamento farmacológico , Sesquiterpenos/administração & dosagem , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Animais , Citocinas/genética , Citocinas/imunologia , Modelos Animais de Doenças , Quimioterapia Combinada , Humanos , Interleucina-12/genética , Interleucina-12/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Peritonite/genética , Peritonite/imunologia , Peritonite/microbiologia , Sepse/genética , Sepse/imunologia , Sepse/microbiologia , Infecções Estafilocócicas/genética , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/fisiologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
6.
PLoS Pathog ; 15(6): e1007871, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31226171

RESUMO

Infection of host cells by Toxoplasma gondii is an active process, which is regulated by secretion of microneme (MICs) and rhoptry proteins (ROPs and RONs) from specialized organelles in the apical pole of the parasite. MIC1, MIC4 and MIC6 assemble into an adhesin complex secreted on the parasite surface that functions to promote infection competency. MIC1 and MIC4 are known to bind terminal sialic acid residues and galactose residues, respectively and to induce IL-12 production from splenocytes. Here we show that rMIC1- and rMIC4-stimulated dendritic cells and macrophages produce proinflammatory cytokines, and they do so by engaging TLR2 and TLR4. This process depends on sugar recognition, since point mutations in the carbohydrate-recognition domains (CRD) of rMIC1 and rMIC4 inhibit innate immune cells activation. HEK cells transfected with TLR2 glycomutants were selectively unresponsive to MICs. Following in vitro infection, parasites lacking MIC1 or MIC4, as well as expressing MIC proteins with point mutations in their CRD, failed to induce wild-type (WT) levels of IL-12 secretion by innate immune cells. However, only MIC1 was shown to impact systemic levels of IL-12 and IFN-γ in vivo. Together, our data show that MIC1 and MIC4 interact physically with TLR2 and TLR4 N-glycans to trigger IL-12 responses, and MIC1 is playing a significant role in vivo by altering T. gondii infection competency and murine pathogenesis.


Assuntos
Moléculas de Adesão Celular/imunologia , Células Dendríticas/imunologia , Imunidade Inata , Macrófagos/imunologia , Proteínas de Protozoários/imunologia , Ácidos Siálicos/imunologia , Receptor 2 Toll-Like/imunologia , Receptor 4 Toll-Like/imunologia , Toxoplasma/imunologia , Toxoplasmose Animal/imunologia , Animais , Interleucina-12/imunologia , Camundongos , Camundongos Knockout , Receptor 2 Toll-Like/genética , Receptor 4 Toll-Like/genética , Toxoplasmose Animal/genética
7.
Immunopharmacol Immunotoxicol ; 41(2): 327-336, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31039648

RESUMO

Objective: Hecogenin is a sapogenin found in Agave sisalana species that is used extensively for the treatment of anti-inflammatory, antifungal, hypotensive, anti-nociceptive activity and cancer. We have studied the anti-inflammatory effect of Hecogenin and its combination with Fluticasone on atopic dermatitis and airway hyper-responsiveness in Balb/c mice. Material and methods: Dermatitis was induced by repeated application of 2, 4-dinitrofluorobenzene in Balb/c mice. After a topical application of Hecogenin, Fluticasone and their combination on the skin lesions, the ear thickness, ear weight and erythema score were evaluated. Asthma was induced by sensitization and challenge of ovalbumin in Balb/c mice. Results: The topical application of Hecogenin and its combination with Fluticasone in mice effectively suppressed the ear swelling and weight. As well as the levels of pro-inflammatory cytokines were decreased by Hecogenin and its combination in-vivo. Whereas, intra-nasal administration of Hecogenin and its combination in ovalbumin induced airway hyper-responsiveness reveals a significant decrement in total cell count, differential cell count and cytokines levels. Similar observations were obtained for myeloperoxidase level in ear and lung tissue. The results were supported by histological studies of ear and lung tissue. Conclusion: These data indicate that Hecogenin has been proved as a potential therapy for allergic skin diseases and bronchial asthma treatments in combination with Fluticasone by reducing its dose from 50 to 25 µg/mice in combination to circumvent the long term side effects of Fluticasone. The beneficial effect of Hecogenin may be related to the diminution of TNF-α and IL-12 cytokines production in Balb/c mice.


Assuntos
Anti-Inflamatórios/farmacologia , Asma/tratamento farmacológico , Dermatite Atópica/tratamento farmacológico , Interleucina-12/imunologia , Sapogeninas/farmacologia , Fator de Necrose Tumoral alfa/imunologia , Animais , Asma/induzido quimicamente , Asma/imunologia , Asma/patologia , Dermatite Atópica/induzido quimicamente , Dermatite Atópica/imunologia , Dermatite Atópica/patologia , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Fluticasona/farmacologia , Camundongos
8.
Microb Pathog ; 132: 20-25, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31004722

RESUMO

BACKGROUND: Various promising procedures have been used to improve the potency of DNA vaccines for the treatment of human papillomavirus type 16 (HPV16) infections. Interleukin-12 (IL12) is a powerful adjuvant that can contribute to T cell-mediated protection against many pathogens, specifically viruses. Considering the important role of T cell-mediated immunity in tumor clearance, the induction of these responses can help control the progression of tumors in animal models. We have demonstrated that the co-administration of codon-optimized E7 (uE7) gene of HPV16 with interleukin-12 is effective in the development of antitumor responses. OBJECTIVES: The present study examined the co-administration of codon-optimized HPV16 E7 gene with murine interleukin-12 gene (mIL-12) as a vaccine adjuvant in tumor mice model. MATERIALS AND METHODS: C57BL/6 mice were studied for tumor progression after injection of recombinant DNA vaccines. Lactate dehydrogenase (LDH) and IFN-γ were measured to evaluate the activity of cytotoxic T lymphocytes (CTLs). Measurements of tumor volume and MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay were used for assessment of therapeutic antitumor effects of the vaccines. RESULTS: Results showed that DNA vaccines, specifically codon-optimized E7/murine interleukin-12 (mIL-12), elicited significant differences in levels of IFN-γ and cytotoxic T lymphocyte (CTLs) responses compared to control groups. Furthermore, higher antitumor response and lower tumor size in the vaccine group was significantly evident compared to control group. CONCLUSION: The co-administration of codon-optimized HPV16 E7 gene with IL12 significantly enhances the DNA vaccine potency against HPV16-associated cervical cancer.


Assuntos
Códon , Papillomavirus Humano 16/genética , Imunização , Interleucina-12/imunologia , Proteínas E7 de Papillomavirus/imunologia , Infecções por Papillomavirus/prevenção & controle , Neoplasias do Colo do Útero/prevenção & controle , Vacinas Virais/imunologia , Adjuvantes Imunológicos , Animais , Sequência de Bases , Linhagem Celular Tumoral , Proliferação de Células , Citotoxicidade Imunológica , Feminino , Papillomavirus Humano 16/patogenicidade , Interferon gama , Interleucina-12/genética , Camundongos , Camundongos Endogâmicos C57BL , Proteínas E7 de Papillomavirus/genética , Proteínas Recombinantes de Fusão/genética , Linfócitos T Citotóxicos , Neoplasias do Colo do Útero/virologia , Vacinação , Vacinas de DNA/genética , Vacinas de DNA/imunologia , Vacinas Virais/genética
9.
Nat Commun ; 10(1): 1898, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015515

RESUMO

N6-methyladenosine (m6A) modification plays important roles in various cellular responses by regulating mRNA biology. However, how m6A modification is involved in innate immunity via affecting the translation of immune transcripts remains to be further investigated. Here we report that RNA methyltransferase Mettl3-mediated mRNA m6A methylation promotes dendritic cell (DC) activation and function. Specific depletion of Mettl3 in DC resulted in impaired phenotypic and functional maturation of DC, with decreased expression of co-stimulatory molecules CD40, CD80 and cytokine IL-12, and reduced ability to stimulate T cell responses both in vitro and in vivo. Mechanistically, Mettl3-mediated m6A of CD40, CD80 and TLR4 signaling adaptor Tirap transcripts enhanced their translation in DC for stimulating T cell activation, and strengthening TLR4/NF-κB signaling-induced cytokine production. Our findings identify a new role for Mettl3-mediated m6A modification in increasing translation of certain immune transcripts for physiological promotion of DC activation and DC-based T cell response.


Assuntos
Adenosina/análogos & derivados , Células Dendríticas/imunologia , Epigênese Genética , Metiltransferases/genética , RNA Mensageiro/genética , Linfócitos T/imunologia , Adenosina/imunologia , Adenosina/metabolismo , Sequência de Aminoácidos , Animais , Antígenos/imunologia , Antígenos/farmacologia , Antígeno B7-1/genética , Antígeno B7-1/imunologia , Células da Medula Óssea/citologia , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/imunologia , Antígenos CD40/genética , Antígenos CD40/imunologia , Células Dendríticas/citologia , Células Dendríticas/efeitos dos fármacos , Interleucina-12/genética , Interleucina-12/imunologia , Ativação Linfocitária , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/imunologia , Metilação , Metiltransferases/imunologia , Camundongos , Camundongos Transgênicos , NF-kappa B/genética , NF-kappa B/imunologia , Peptídeos/imunologia , Peptídeos/farmacologia , Cultura Primária de Células , Biossíntese de Proteínas , RNA Mensageiro/imunologia , Receptores de Interleucina-1/genética , Receptores de Interleucina-1/imunologia , Transdução de Sinais , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/imunologia
10.
Immunity ; 50(4): 851-870, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30995503

RESUMO

The discovery of interleukin (IL)-6 and its receptor subunits provided a foundation to understand the biology of a group of related cytokines: IL-12, IL-23, and IL-27. These family members utilize shared receptors and cytokine subunits and influence the outcome of cancer, infection, and inflammatory diseases. Consequently, many facets of their biology are being therapeutically targeted. Here, we review the landmark discoveries in this field, the combinatorial biology inherent to this family, and how patient datasets have underscored the critical role of these pathways in human disease. We present significant knowledge gaps, including how similar signals from these cytokines can mediate distinct outcomes, and discuss how a better understanding of the biology of the IL-12 family provides new therapeutic opportunities.


Assuntos
Citocinas/imunologia , Interleucina-12/imunologia , Família Multigênica/imunologia , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/terapia , Citocinas/antagonistas & inibidores , Citocinas/genética , Humanos , Imunidade Celular , Inflamação/imunologia , Interleucina-12/antagonistas & inibidores , Interleucina-12/genética , Interleucina-27/uso terapêutico , Subpopulações de Linfócitos/imunologia , Linfopoese , Camundongos , Camundongos Knockout , Família Multigênica/genética , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/terapia , Subunidades Proteicas , Relação Estrutura-Atividade
11.
Muscle Nerve ; 59(6): 694-698, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30847948

RESUMO

INTRODUCTION: Polyneuropathy with immunoglobulin M monoclonal gammopathy (IgM-PNP) is associated with the presence of IgM antibodies against nerve constituents such as myelin associated glycoprotein (MAG) and gangliosides. METHODS: To test whether B-cell-stimulating cytokines are increased in IgM-PNP, we measured serum concentrations of 11 cytokines in 81 patients with IgM-PNP and 113 controls. RESULTS: Median interleukin (IL)-6 concentrations were higher in patients with IgM-PNP, and median IL-10 concentrations were higher in the subgroup with anti-MAG IgM antibodies. These serum concentrations were not increased in 110 patients with multifocal motor neuropathy. DISCUSSION: Median IL-6 and IL-10 serum concentrations differ between patients with anti-MAG neuropathy and other patients with IgM-PNP compared with healthy and neuropathy controls. These differences may indicate differences in immune-mediated disease mechanisms. Muscle Nerve 59:694-698, 2019.


Assuntos
Citocinas/imunologia , Imunoglobulina M/imunologia , Paraproteinemias/imunologia , Polineuropatias/imunologia , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/imunologia , Linfócitos B/imunologia , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Humanos , Interferon gama/imunologia , Interleucina-10/imunologia , Interleucina-12/imunologia , Interleucina-2/imunologia , Interleucina-4/imunologia , Interleucina-6/imunologia , Interleucina-8/imunologia , Masculino , Pessoa de Meia-Idade , Glicoproteína Associada a Mielina/imunologia , Fator de Necrose Tumoral alfa/imunologia
12.
J Med Food ; 22(5): 451-459, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30897013

RESUMO

To examine the anti-metastatic activities of polysaccharides in broccoli, purified polysaccharides (BCE-I, -II, and -III) were isolated by fractionation of broccoli enzyme extracts and subsequent ethanol precipitation. BCE-I mainly consisted of galactose and arabinose, whereas BCE-II mainly consisted of galacturonic acid and rhamnose, and BCE-III mainly consisted of rhamnose and galactose. Of the three fractions, stimulation of murine peritoneal macrophages by BCE-I showed the greatest enhancement of tumor necrosis factor-α, interleukin (IL)-12, and IL-6 secretion. In addition, intravenous (i.v.) administration of BCE-I enhanced the lethal activity of natural killer (NK) cells on YAC-1 tumor cells significantly and dose-dependently in an ex vivo experiment of NK cell activity. In an experimental model using lung metastasis of Colon26-M3.1 carcinoma cells, prophylactic i.v. and oral administration of BCE-I significantly and dose-dependently inhibited lung metastatic activity. Furthermore, the inhibitory activity of BCE-1 on lung metastasis partially disappeared when NK cell function was removed through treatment of rabbit anti-asialo GM1. These results indicated that BCE-I has potent antitumor metastatic activity, and that its anti-metastatic activity has relevance to the stimulation of NK and other immune cells.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Brassica/química , Neoplasias do Colo/imunologia , Imunidade Inata/efeitos dos fármacos , Neoplasias Pulmonares/prevenção & controle , Pectinas/farmacologia , Extratos Vegetais/farmacologia , Polissacarídeos/farmacologia , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Neoplasias do Colo/patologia , Feminino , Humanos , Interleucina-12/genética , Interleucina-12/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/secundário , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Metástase Neoplásica/imunologia , Metástase Neoplásica/prevenção & controle , Pectinas/química , Pectinas/isolamento & purificação , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Polissacarídeos/química , Polissacarídeos/isolamento & purificação
13.
Methods Enzymol ; 618: 211-227, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30850053

RESUMO

ISG15 is a ubiquitin-like protein (Ubl) that is expressed in response to Type 1 Interferon (IFN-α/ß) signaling. Remarkably, ISG15 has three distinct biochemical activities involved in innate immune responses to viral and/or microbial infections. The canonical function of ISG15 is as a posttranslational modifier, and protein ISGylation has been demonstrated to be antiviral. A second intracellular function, independent of conjugation activity, is attenuation of IFN-α/ß signaling at the interferon receptor, which appears to be important for terminating IFN responses. The third function of ISG15, and the focus of this chapter, is as an extracellular signaling molecule that promotes the secretion of Type 2 Interferon (IFN-γ) by Natural Killer (NK) cells. This function is important for control of microbial infections, including mycobacterial infections. Here, we describe methods for purification of ISG15, preparation, and culture of primary peripheral blood mononuclear cells (PBMCs) and NK-92 cells, assays for IL-12- and ISG15-dependent cytokine (IFN-γ and IL-10) secretion, and assays for initial intracellular signaling events triggered by extracellular ISG15.


Assuntos
Citocinas/imunologia , Células Matadoras Naturais/imunologia , Leucócitos Mononucleares/imunologia , Ubiquitinas/imunologia , Técnicas de Cultura de Células , Linhagem Celular , Células Cultivadas , Citocinas/isolamento & purificação , Humanos , Interferon gama/imunologia , Interleucina-10/imunologia , Interleucina-12/imunologia , Transdução de Sinais , Ubiquitinas/isolamento & purificação
14.
J Sci Food Agric ; 99(8): 4174-4181, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30779132

RESUMO

BACKGROUND: Astragalus membranaceus is a traditional Chinese medicine that has a long history of medical applications. It is of interest to investigate the functional components of A. membranaceus waste with regard to its development and utilization and increasing resource utilization. RESULTS: The protein AMWP was isolated from the A. membranaceus waste. This protein was further purified by DEAE-cellulose-52 chromatography and Sephadex G-200 size-exclusion chromatography to obtain three fractions, named AMWPDG2, AMWPDG4 and AMWPDG6. Then, their immunomodulatory activities were evaluated by using cell model experiments. The results indicated that the protein fractions could significantly increase the proliferation of splenic lymphocytes, peritoneal macrophages and bone-marrow-derived cells (BMDCs). AMWPDG2 showed the highest immunocompetence. AMWPDG2, AMWPDG4 and AMWPDG6 not only significantly improved the phagocytosis and immunomodulatory factors (interleukin (IL)-6, tumor necrosis factor-α, nitric oxide, hydrogen peroxide) secretion of peritoneal macrophages, but also promoted the expression of inflammatory cytokines (IL-6, IL-12 p40, IL-1ß, IL-1α) and chemokines (CXCL1, CCL3) in BMDCs. CONCLUSION: Taken together, these results indicated that three protein fractions from the A. membranaceus waste might be a potential natural immunomodulator. Moreover, it also provided the theoretical basis for further researching the mechanism of AMWPDG2, AMWPDG4 and AMWPDG6 on improving the immune response. © 2019 Society of Chemical Industry.


Assuntos
Astragalus propinquus/química , Medicamentos de Ervas Chinesas/farmacologia , Fatores Imunológicos/farmacologia , Resíduos/análise , Animais , Células Cultivadas , Quimiocinas/genética , Quimiocinas/imunologia , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/isolamento & purificação , Fatores Imunológicos/química , Fatores Imunológicos/isolamento & purificação , Interleucina-12/genética , Interleucina-12/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos ICR , Fagocitose/efeitos dos fármacos
15.
J Immunol ; 202(5): 1406-1416, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30674576

RESUMO

Mice deficient for ADP-ribosyltransferase diphteria toxin-like 1 (ARTD1) are protected against microbially induced inflammation. To address the contribution of ARTD1 to inflammation specifically in myeloid cells, we generated an Artd1ΔMyel mouse strain with conditional ARTD1 deficiency in myeloid lineages and examined the strain in three disease models. We found that ARTD1, but not its enzymatic activity, enhanced the transcriptional activation of distinct LPS-induced genes that included IL-12, TNF-α, and IL-6 in primary bone marrow-derived macrophages and LPS-induced IL-12/18-IFN-γ signaling in Artd1ΔMyel mice. The loss of Artd1 in myeloid cells also reduced the TH1 response to Helicobacter pylori and impaired immune control of the bacteria. Furthermore, Artd1ΔMyel mice failed to control tumor growth in a s.c. MC-38 model of colon cancer, which could be attributed to reduced TH1 and CD8 responses. Together, these data provide strong evidence for a cell-intrinsic role of ARTD1 in myeloid cells that is independent of its enzymatic activity and promotes type I immunity by promoting IL-12/18 expression.


Assuntos
Infecções por Helicobacter/imunologia , Modelos Imunológicos , Células Mieloides/imunologia , Neoplasias/imunologia , Poli(ADP-Ribose) Polimerase-1/imunologia , Sepse/imunologia , Animais , Células Cultivadas , Biologia Computacional , Interferon gama/imunologia , Interleucina-12/genética , Interleucina-12/imunologia , Interleucina-18/genética , Interleucina-18/imunologia , Camundongos
17.
Gynecol Oncol ; 153(1): 149-157, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30658847

RESUMO

OBJECTIVE: Natural killer (NK) cells are lymphocytes well suited for adoptive immunotherapy. Attempts with adoptive NK cell immunotherapy against ovarian cancer have proven unsuccessful, with the main limitations including failure to expand and diminished effector function. We investigated if incubation of NK cells with interleukin (IL)-12, IL-15, and IL-18 for 16h could produce cytokine-induced memory-like (CIML) NK cells capable of enhanced function against ovarian cancer. METHODS: NK cells were preactivated briefly with IL-12, IL-15, and IL-18, rested, then placed against ovarian cancer targets to assess phenotype and function via flow cytometry. Real-time NK-cell-mediated tumor-killing was evaluated. Using ascites cells and cell-free ascites fluid, NK cell proliferation and function within the immunosuppressive microenvironment was evaluated in vitro. Finally, CIML NK cells were injected intraperitoneal (IP) into an in vivo xenogeneic mouse model of ovarian cancer. RESULTS: CIML NK cells demonstrate enhanced cytokine (IFN-γ) production and NK-cell-mediated killing of ovarian cancer. NK cells treated overnight with cytokines led to robust activation characterized by temporal shedding of CD16, induction of CD25, and enhanced proliferation. CIML NK cells proliferate more with enhanced effector function compared to controls in an immunosuppressive microenvironment. Finally, human CIML NK cells exhibited potent antitumor effects within a xenogeneic mouse model of ovarian cancer. CONCLUSIONS: CIML NK cells have enhanced functionality and persistence against ovarian cancer in vitro and in vivo, even when exposed to ascites fluid. These findings provide a strategy for NK cell-based immunotherapy to circumvent the immunosuppressive nature of ovarian cancer.


Assuntos
Carcinoma Epitelial do Ovário/terapia , Células Matadoras Induzidas por Citocinas/imunologia , Células Matadoras Induzidas por Citocinas/transplante , Imunoterapia Adotiva/métodos , Interleucinas/farmacologia , Animais , Carcinoma Epitelial do Ovário/imunologia , Carcinoma Epitelial do Ovário/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Memória Imunológica/imunologia , Interferon gama/biossíntese , Interferon gama/imunologia , Interleucina-12/imunologia , Interleucina-12/farmacologia , Interleucina-15/imunologia , Interleucina-15/farmacologia , Interleucina-18/imunologia , Interleucina-18/farmacologia , Interleucinas/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Camundongos , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/farmacologia , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Cancer Sci ; 110(3): 888-902, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30629318

RESUMO

Dendritic cells (DC) play a key role in the initiation of both antitumor immunity and immunological tolerance. It has been demonstrated that exposure to soluble factors produced by tumor cells modulates DC functions and induces tolerogenic DC differentiation. In this study, we investigated the effects of neuroblastoma cell line-derived soluble factors on DC differentiation. Monocytes isolated from healthy volunteers were incubated with interleukin (IL)-4 and granulocyte-macrophage colony-stimulating factor in the presence of culture supernatants from neuroblastoma cell lines. The culture supernatants from neuroblastoma cell lines, such as NLF and GOTO, partially blocked both downregulation of CD14 and upregulation of CD1a, and dramatically decreased IL-12 and tumor necrosis factor (TNF)-α production from mature DC, while no effect of SH-SY5Y cell supernatant was noted. In addition, IL-6 and IL-10 production from monocytes was increased by the supernatants of NLF and GOTO cells at 24 hours after incubation. Furthermore, we evaluated DC functions through stimulation of invariant natural killer T (iNKT) cells. α-Galactosylceramide-pulsed DC co-cultured with supernatants of NLF cells were unable to sufficiently stimulate iNKT cells. The decreased ability of iNKT cells to produce interferon (IFN)-γ after stimulation with neuroblastoma cell line supernatant-cultured DC was reversed by addition of IL-12. CD40 expression and IL-12 production in NLF-sup-treated DC were increased by addition of exogenous IFN-γ. These results indicate that tolerogenic DC are induced in the neuroblastoma tumor microenvironment and attenuate the antitumor effects of iNKT cells. Interactions between iNKT cells and αGalCer-pulsed DC have the potential to restore the immunosuppression of tolerogenic DC through IFN-γ production.


Assuntos
Diferenciação Celular/imunologia , Células Dendríticas/imunologia , Ativação Linfocitária/imunologia , Neuroblastoma/imunologia , Antígenos CD1/imunologia , Linhagem Celular , Linhagem Celular Tumoral , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Humanos , Interferon gama/imunologia , Interleucina-10/imunologia , Interleucina-12/imunologia , Interleucina-4/imunologia , Receptores de Lipopolissacarídeos/imunologia , Monócitos/imunologia , Monócitos/metabolismo
19.
Parasitol Res ; 118(1): 369-376, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30519883

RESUMO

The treatment of cutaneous leishmaniasis in associated with several adverse effects and therapeutic failure, resulting in patients' abandonment of treatment. Research on new drugs with leishmanicidal potential from medicinal plants is essential. The anti-Leishmania activity of Tetradenia riparia essential oil (TrEO) and its derivatives, such as the diterpene 6,7-dehydroroyleanone (TrROY), and the immunomodulatory effects of TrEO have been reported. However, few studies have investigated the effects of TrROY. The present study evaluated the modulation of cytokine production by murine macrophages that were infected with Leishmania amazonensis (6 parasites/macrophage) and treated with TrROY (0.1, 1, and 100 µg/ml). Cytokine levels were measured by flow cytometry. The results were analyzed using Student's t test at a 95% confidence interval. Microscopic counting was performed to evaluate the inhibitory effects of TrROY on intracellular infection. TrROY modulated the production of cytokines that are essential for the immune defense response to Leishmania, with a decrease in interleukin-4 (IL-4) levels and an increase in IL-12 levels. A TrROY concentration of 0.1 µg/ml was chosen for the subsequent experiments. This dose was chosen because it modulated IL-4/IL-12 release by murine macrophages that were infected with Leishmania and because it presented no cytotoxic effects. TrROY (0.1 µg/ml) induced a 31% reduction of the rate of infection in murine macrophages compared with untreated cells. TrROY may be a promising leishmanicidal agent. Further in vitro and in vivo studies should be conducted to evaluate the anti-Leishmania and immunomodulatory activity of TrROY.


Assuntos
/farmacologia , Antiprotozoários/farmacologia , Lamiaceae/química , Leishmania/efeitos dos fármacos , Leishmaniose Cutânea/imunologia , Macrófagos/imunologia , Óleos Voláteis/farmacologia , /química , Animais , Antiprotozoários/química , Humanos , Interleucina-12/imunologia , Interleucina-4/imunologia , Leishmania/fisiologia , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/parasitologia , Macrófagos/parasitologia , Camundongos , Óleos Voláteis/química , Células RAW 264.7
20.
Int J Biol Macromol ; 124: 1213-1219, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30529203

RESUMO

A wide number of Lactic Acid Bacteria (LAB) species produce α-glucans with their ability to synthesize glucansucrases (GS) which use sucrose as substrate for the glucan production. Recently another group of enzymes in LAB gained special interest for their ability to produce α-glucans targeting the substrates containing α1-4-linkages and synthesizing new (α1-6) or (α1-3)-linkages as α­glucanotransferases. In this study, a putative 4,6­α­glucanotransferase (GTFB) from sourdough isolate Lactobacillus reuteri E81 was identified and expressed in Escherichia coli. The biochemical characterization of the GTFB-E81 confirmed its function as it cleaved the α1-4-linkages in different substrates and produced new gluco-oligomers/polymers containing α1-6 linkages together with the α1-4-linkages detected by NMR analysis. GTFB-E81 produced malto-oligosaccharides targeting maltose and maltoheptaose as substrates with up to DP 8 detected by TLC and ESI-MS/MS analysis. The functional roles of these malto-oligosaccharides were determined by testing their immune-modulatory functions in HT29 cells and they triggered the production of anti-inflammatory 1L-4 and pro-inflammatory IL-12 cytokines.


Assuntos
Proteínas de Bactérias/genética , Expressão Gênica/efeitos dos fármacos , Sistema da Enzima Desramificadora do Glicogênio/genética , Fatores Imunológicos/isolamento & purificação , Lactobacillus reuteri/química , Oligossacarídeos/isolamento & purificação , Proteínas de Bactérias/metabolismo , Clonagem Molecular , Escherichia coli/genética , Escherichia coli/metabolismo , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Glucanos/metabolismo , Sistema da Enzima Desramificadora do Glicogênio/metabolismo , Células HT29 , Humanos , Fatores Imunológicos/biossíntese , Fatores Imunológicos/farmacologia , Interleucina-12/genética , Interleucina-12/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Lactobacillus reuteri/enzimologia , Lactobacillus reuteri/genética , Maltose/metabolismo , Oligossacarídeos/biossíntese , Oligossacarídeos/farmacologia , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Especificidade por Substrato
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