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1.
J Agric Food Chem ; 67(47): 13082-13092, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31671940

RESUMO

Elevated circulating level of the intestinal microbiota-derived l-carnitine metabolite trimethylamine-N-oxide (TMAO) has recently been linked to many chronic diseases. The purpose of our study was to investigate the effects of omega-7-enriched Decaisnea insignis seed oil (DISO) on reducing TMAO formation to prevent the l-carnitine-induced hepatic damage in mice. Feeding of mice with 3% l-carnitine in drinking water clearly increased the serum and urinary levels of TMAO (p < 0.05 vs Normal), whereas the serum and urinary TMAO formation was sharply reduced by DISO administration (p < 0.05). Meanwhile, DISO resulted in strong inhibition against the elevation of hepatic injury marker (AST, ALT, and ALP) activities and dyslipidemia (TC, TG, LDL-C, and HDL-C), as well as liver inflammatory cytokine (IL-1, IL-6, TNF-α, and TNF-ß) release in l-carnitine-fed mice (p < 0.05). As revealed by 16S rDNA gene sequencing, DISO significantly inhibited the l-carnitine-induced elevations in the abundance of Firmicutes, Proteobacteria, and Erysipelotrichaceae and the increases in the proportion of Lactobacillus and Akkermansia, revealing that DISO attenuated the l-carnitine-caused gut dysbiosis. These findings suggested that DISO could alleviate liver dysfunction in l-carnitine-fed mice, which might be due to the protection against TMAO formation by modulating the gut microbiota.


Assuntos
Carnitina/efeitos adversos , Microbioma Gastrointestinal/efeitos dos fármacos , Hepatopatias/tratamento farmacológico , Magnoliopsida/química , Óleos Vegetais/farmacologia , Animais , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Humanos , Interleucina-1/genética , Interleucina-1/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Hepatopatias/metabolismo , Hepatopatias/microbiologia , Masculino , Metilaminas/efeitos adversos , Camundongos , Sementes/química
2.
Cell Biochem Funct ; 37(8): 618-624, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31710117

RESUMO

The aim of this study was to investigate the effect of vaccinia virus expressing IL-37 (VV-IL-37) on cell proliferation, migration and invasion of hepatocellular carcinoma (HCC) and its possible underlying molecular mechanisms. In this study, we constructed a cancer-targeted vaccinia virus carrying the IL-37 gene knocked in the region of the viral thymidine kinase (TK) gene. Human HCC cell lines were assayed in vitro for cell proliferation, migration and invasion. Serum level, relative mRNA level and protein level of IL-37 in HCC cell lines SMMC7721 and Bel7402 were tested by ELISA assay, qRT-PCR and western blot, respectively. The levels of IL-2, IFN-γ and TNF-α in HCC tumor tissues were also analyzed by ELISA. STAT3 and p-STAT3 expression in tumor tissues were determined by western blot. Our results showed that VV-IL-37 efficiently infected and inhibited HCC cells proliferation, migration and invasion via decreasing STAT3 phosphorylation. In vivo, VV-IL-37 expressed IL-37 at a high level in the transplanted tumor, reduced STAT3 activity, and eventually inhibited tumor growth. In conclusion, we demonstrate that VV-IL-37 promotes antitumor immune responses in HCC.


Assuntos
Carcinoma Hepatocelular/patologia , Interleucina-1/metabolismo , Neoplasias Hepáticas/patologia , Vírus Vaccinia/fisiologia , Animais , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Humanos , Interferon gama/metabolismo , Interleucina-1/genética , Interleucina-2/metabolismo , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Fator de Transcrição STAT3/metabolismo , Transplante Heterólogo , Vírus Vaccinia/genética
3.
Nat Commun ; 10(1): 4700, 2019 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-31619669

RESUMO

The functions of the IL-36 cytokines remain poorly understood. We report a previously unrecognized mechanism whereby IL-36 promotes innate antiviral immunity in mouse and human models of herpes simplex virus-1 (HSV-1) infections. HSV-1 actively suppresses production of type I interferon (IFN); our data reveal that IL-36 overcomes this immune evasion strategy by increasing cellular sensitivity to IFN. IL-36ß deficient mice display impaired IFN responses and poorly restrict viral replication in skin keratinocytes. In mouse and human keratinocytes IL-36 elicits an antiviral state driven by STAT1 and STAT2 via enhanced expression of IFNAR1 and IFNAR2 subunits of the type I IFN receptor. The degree of IFN regulatory factor 1 (IRF1) involvement is species dependent, with IRF1 playing a more prominent role in human cells. Similar mechanisms are activated by IL-1. Overall, IL-36 acts as an antiviral cytokine by potentiating type I IFN signaling and thereby upholds immune responses to viruses that limit the production of IFNs.


Assuntos
Herpes Simples/imunologia , Interferon Tipo I/imunologia , Interleucina-1/imunologia , Receptor de Interferon alfa e beta/genética , Animais , Modelos Animais de Doenças , Herpesvirus Humano 1 , Humanos , Evasão da Resposta Imune , Fator Regulador 1 de Interferon/imunologia , Interleucina-1/genética , Queratinócitos , Camundongos , Camundongos Knockout , Receptor de Interferon alfa e beta/metabolismo , Fator de Transcrição STAT1/imunologia , Fator de Transcrição STAT2/imunologia , Regulação para Cima
4.
Histochem Cell Biol ; 152(6): 467-473, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31584126

RESUMO

IL-37, the anti-inflammatory cytokine of the IL-1 family, plays several key roles in the regulation of autoimmune diseases. Yet, its role in Hashimoto's thyroiditis (HT) is not clear. In the present study, we found that, in tissues from HT patients, most of the follicular epithelial cells were positive for both IL-37 and single Ig IL-1-related receptor (SIGIRR) by immunohistochemical staining, while the infiltrating lymphocytes and other inflammatory cells hardly expressed any. Meanwhile, mRNA expression levels of IL-37 in peripheral blood mononuclear cells (PBMC) of HT patients were significantly higher than those in normal controls measured by quantitative real-time PCR. Finally, we studied the possible role of IL-37 in IFN-γ-stimulated rat FRTL-5 cells. The results showed that IL-1ß, TNF-α, and MCP-1 mRNA levels were significantly decreased, while the expression of IL-4 mRNA was dramatically up-regulated in IFN-γ-stimulated rat thyroid cell line FRTL-5 pre-treated with IL-37. The current study, for the first time, demonstrated that the IL-37 network is involved in Hashimoto's thyroiditis, and IL-37 signaling pathway may ameliorate the excessive autoimmune responses in this chronic lymphocytic thyroiditis.


Assuntos
Doença de Hashimoto/metabolismo , Interleucina-1/metabolismo , Transdução de Sinais , Adulto , Animais , Células Cultivadas , Retroalimentação Fisiológica , Feminino , Humanos , Interleucina-1/análise , Interleucina-1/genética , Pessoa de Meia-Idade , RNA Mensageiro/análise , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Transdução de Sinais/genética , Adulto Jovem
5.
Nat Commun ; 10(1): 4003, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31488830

RESUMO

Members of the interleukin-1 (IL-1) family are important mediators of obesity and metabolic disease and have been described to often play opposing roles. Here we report that the interleukin-36 (IL-36) subfamily can play a protective role against the development of disease. Elevated IL-36 cytokine expression is found in the serum of obese patients and negatively correlates with blood glucose levels among those presenting with type 2 diabetes. Mice lacking IL-36Ra, an IL-36 family signalling antagonist, develop less diet-induced weight gain, hyperglycemia and insulin resistance. These protective effects correlate with increased abundance of the metabolically protective bacteria Akkermansia muciniphila in the intestinal microbiome. IL-36 cytokines promote its outgrowth as well as increased colonic mucus secretion. These findings identify a protective role for IL-36 cytokines in obesity and metabolic disease, adding to the current understanding of the role the broader IL-1 family plays in regulating disease pathogenesis.


Assuntos
Citocinas/metabolismo , Microbioma Gastrointestinal/fisiologia , Interleucina-1/metabolismo , Doenças Metabólicas/metabolismo , Obesidade/metabolismo , Animais , Colo/imunologia , Colo/microbiologia , Colo/patologia , Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal/imunologia , Expressão Gênica , Teste de Tolerância a Glucose , Interações entre Hospedeiro e Microrganismos/imunologia , Interações entre Hospedeiro e Microrganismos/fisiologia , Humanos , Mediadores da Inflamação/metabolismo , Resistência à Insulina , Interleucina-1/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mucina-2/metabolismo , Obesidade/imunologia , Receptores de Interleucina-1/genética , Receptores de Interleucina-1/metabolismo , Transcriptoma , Verrucomicrobia
6.
J Immunol Res ; 2019: 3575803, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31396542

RESUMO

Overactivation of the innate immune system together with the impaired downstream pathway of type I interferon-responding genes is a hallmark of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic sclerosis (SSc). To date, limited data on the cross-disease innate gene signature exists among those diseases. We compared therefore an innate gene signature of Toll-like receptors (TLRs), seven key members of the interleukin (IL)1/IL1R family, and CXCL8/IL8 in peripheral blood mononuclear cells from well-defined patients with active stages of RA (n = 36, DAS28 ≥ 3.2), SLE (n = 28, SLEDAI > 6), and SSc (n = 22, revised EUSTAR index > 2.25). Emerging diversity and abundance of the innate signature in RA patients were detected: RA was characterized by the upregulation of TLR3, TLR5, IL1RAP/IL1R3, IL18R1, and SIGIRR/IL1R8 when compared to SSc (P corr < 0.02) and of TLR2, TLR5, and SIGIRR/IL1R8 when compared to SLE (P corr < 0.02). Applying the association rule analysis, six rules (combinations and expression of genes describing disease) were identified for RA (most frequently included high TLR3 and/or IL1RAP/IL1R3) and three rules for SLE (low IL1RN and IL18R1) and SSc (low TLR5 and IL18R1). This first cross-disease study identified emerging heterogeneity in the innate signature of RA patients with many upregulated innate genes compared to that of SLE and SSc.


Assuntos
Artrite Reumatoide/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Escleroderma Sistêmico/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/sangue , Artrite Reumatoide/genética , Feminino , Humanos , Imunidade Inata/genética , Interleucina-1/genética , Interleucina-1/metabolismo , Interleucina-8/genética , Interleucina-8/metabolismo , Leucócitos Mononucleares/metabolismo , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/genética , Masculino , Pessoa de Meia-Idade , Receptores Tipo I de Interleucina-1/genética , Receptores Tipo I de Interleucina-1/metabolismo , Escleroderma Sistêmico/sangue , Escleroderma Sistêmico/genética , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismo , Transcriptoma
7.
BMC Complement Altern Med ; 19(1): 195, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31366385

RESUMO

BACKGROUND: Probiotics have been reported to be the active component used in the treatment of many functional gastrointestinal symptoms and syndromes. Lactobacillus and yeast culture are extensively used in probiotic supplements and traditional treatments for irritable bowel syndrome (IBS). The aim of this study was to investigate the effects of probiotic treatments (Lactobacillus acidophilus LA5, Bifidobacterium animalis subsp. lactis BB12 and Saccharomyces cerevisiae var. boulardii) on the behavioral response, targeted gene expression and pro-inflammatory cytokine levels of Pi (Post infectious)-IBS -induced mice. METHODS: Pathogen-free male C57L/B6 mice and the Trichinella-infected mice were used to measure the score of abdominal withdrawal reflex (AWR). To compare molecular, biological and biochemical evidences of given probiotics with normal and positive control groups in mice, we conducted quantitative reverse transcription polymerase chain reaction (RT-qPCR), western blotting, and cytokine analysis. RESULTS: Pi-IBS-induced immune response was confirmed that PAR-2 mRNA level was significantly increased by Trichinella infection (P < 0.05). The reduction of Pi-IBS symptoms through Trichinella infection and the effects of given probiotics were confirmed by a change in the protein levels of cytokines (P < 0.05). In addition, the administration of DW (Daewon) probiotics significantly decreased serum levels of IL-1 and IL-6 (P < 0.05). CONCLUSIONS: We have demonstrated that the given probiotics decreased pro-inflammatory cytokine levels in both the control and Pi-IBS induced mice. Taken all the results together, the results support that DW probiotics has a potential as a probiotic medication for patient with IBS via regulating TNF-α and IL-6 protein levels and serum IL-1 and IL-6 levels.


Assuntos
Síndrome do Intestino Irritável/tratamento farmacológico , Probióticos/administração & dosagem , Triquinelose/complicações , Animais , Humanos , Interleucina-1/genética , Interleucina-1/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Síndrome do Intestino Irritável/etiologia , Síndrome do Intestino Irritável/genética , Síndrome do Intestino Irritável/metabolismo , Lactobacillus/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptor PAR-2/genética , Receptor PAR-2/metabolismo , Trichinella/fisiologia , Triquinelose/parasitologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
8.
Korean J Parasitol ; 57(3): 217-223, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31284343

RESUMO

Acanthamoeba castellanii has ubiquitous distribution and causes primary acanthamoebic keratitis (AK). AK is a common disease in contact lens wearers and results in permanent visual impairment or blindness. In this study, we observed the cytopathic effect, in vitro cytotoxicity, and secretion pattern of cytokines in human corneal epithelial cells (HCECs) induced by A. castellanii trophozoites and/or cysts. Morphological observation revealed that panked dendritic HCECs co-cultured with amoeba cysts had changed into round shape and gradually died. Such changes were more severe in co-culture with cyst than those of co-cultivation with trophozoites. In vitro cytotoxicity assay revealed the highest cytotoxicity to HCECs in the co-culture system with amoeba cysts. A. castellanii induced the expression of IL-1α, IL-6, IL-8, and CXCL1 in HCECs. Secreted levels of IL-1α, IL-6, and IL-8 in HCECs co-cultured with both trophozoites and cysts were increased at an early incubation time (3 and 6 hr). These results suggested that cytopathic changes and pro-inflammatory cytokines release of HCECs in response to A. castellanii, especially amoebic cysts, are an important mechanism for AK development.


Assuntos
Ceratite por Acanthamoeba/imunologia , Acanthamoeba castellanii/fisiologia , Córnea/citologia , Células Epiteliais/imunologia , Trofozoítos/fisiologia , Ceratite por Acanthamoeba/parasitologia , Acanthamoeba castellanii/crescimento & desenvolvimento , Células Cultivadas , Córnea/imunologia , Córnea/parasitologia , Células Epiteliais/parasitologia , Humanos , Interleucina-1/genética , Interleucina-1/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Interleucina-8/genética , Interleucina-8/imunologia , Trofozoítos/crescimento & desenvolvimento
9.
Biofactors ; 45(4): 517-535, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31206893

RESUMO

Traumatic brain injury (TBI) is the most prevalent health problem affecting all age groups, and leads to many secondary problems in other organs especially kidneys, gastrointestinal tract, and heart function. In this review, the search terms were TBI, fluid percussion injury, cold injury, weight drop impact acceleration injury, lateral fluid percussion, cortical impact injury, and blast injury. Studies with Actaea racemosa, Artemisia annua, Aframomum melegueta, Carthamus tinctorius, Cinnamomum zeylanicum, Crocus sativus, Cnidium monnieri, Curcuma longa, Gastrodia elata, Malva sylvestris, Da Chuanxiong Formula, Erigeron breviscapus, Panax ginseng, Salvia tomentosa, Satureja khuzistanica, Nigella sativa, Drynaria fortune, Dracaena cochinchinensis, Polygonum cuspidatum, Rosmarinus officinalis, Rheum tanguticum, Centella asiatica, and Curcuma zedoaria show a significant decrease in neuronal injury by different mechanisms such as increasing superoxide dismutase and catalase activities, suppressing nuclear factor kappa B (NF-κB), interleukin 1 (IL-1), glial fibrillary acidic protein, and IL-6 expression. The aim of this study was to evaluate the neuroprotective effects of medicinal plants in central nervous system pathologies by reviewing the available literature.


Assuntos
Traumatismos por Explosões/prevenção & controle , Lesões Encefálicas Traumáticas/prevenção & controle , Lesão por Frio/prevenção & controle , Regulação da Expressão Gênica/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Plantas Medicinais/química , Animais , Traumatismos por Explosões/genética , Traumatismos por Explosões/metabolismo , Traumatismos por Explosões/patologia , Lesões Encefálicas Traumáticas/genética , Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/patologia , Catalase/genética , Catalase/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/lesões , Córtex Cerebral/metabolismo , Lesão por Frio/genética , Lesão por Frio/metabolismo , Lesão por Frio/patologia , Modelos Animais de Doenças , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Interleucina-1/genética , Interleucina-1/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Camundongos , NF-kappa B/genética , NF-kappa B/metabolismo , Fármacos Neuroprotetores/isolamento & purificação , Ratos , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo
10.
Iran J Allergy Asthma Immunol ; 18(2): 218-224, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31066258

RESUMO

The mustard lung is a late consequence of exposure to sulfur mustard (SM) in veterans who had participated in the Iraq-Iran war. Three mechanisms are contributed in the pathogenesis of mustard lung including oxidative stress, protease-antiprotease imbalance, and dysregulated immune response. In the context of the immune response, the role of the inflammasome complex and their inflammatory cytokines are important. This study aims to investigate the inflammasome pathway and their inflammatory cytokine (i.e IL-1 and IL-18) in the peripheral blood of mustard lung patients as well as chronic obstructive pulmonary disease (COPD) patients. This research was conducted as a cross-sectional analytical study on 15 SM patients and was compared with 15 COPD patients and 15 healthy controls. The real-time polymerase chain reaction was used to assess gene expression levels of inflammasome components (NLRP1, NLRP3, NLRC4, and ASC), inflammatory cytokines (IL-1ß, IL-18, and IL-1ßR), and IL-37 as an anti-inflammatory cytokine. Finally, the data were analyzed by SPSS version 21 software. The gene expression level of molecules involved in inflammasome pathway showed a slight increase in the peripheral blood of SM and COPD patients compared to the control group. However, this difference was not statistically significant. Only IL-37 and NLRP1 had a significant increase in mustard lung and COPD patients; compared to healthy controls (p<0.05). Due to the normal expression of genes involved in the inflammasome pathway, it can be stated that the inflammasome pathway is not active in the blood of mustard lung patients.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Substâncias para a Guerra Química/efeitos adversos , Inflamassomos/metabolismo , Interleucina-1/metabolismo , Pneumopatias/imunologia , Gás de Mostarda/efeitos adversos , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Reguladoras de Apoptose/genética , Estudos Transversais , Exposição Ambiental/efeitos adversos , Feminino , Humanos , Mediadores da Inflamação/sangue , Interleucina-1/sangue , Interleucina-1/genética , Interleucina-18/sangue , Guerra do Iraque 2003-2011 , Pneumopatias/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/imunologia , Veteranos
11.
J Immunol ; 202(10): 3020-3032, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30988118

RESUMO

The inflammatory response to infection or injury dramatically increases the hematopoietic demand on the bone marrow to replace effector leukocytes consumed in the inflammatory response. In the setting of infection, pathogen-associated molecular patterns induce emergency hematopoiesis, activating hematopoietic stem and progenitor cells to proliferate and produce progeny for accelerated myelopoiesis. Sterile tissue injury due to trauma also increases leukocyte demand; however, the effect of sterile tissue injury on hematopoiesis is not well described. We find that tissue injury alone induces emergency hematopoiesis in mice subjected to polytrauma. This process is driven by IL-1/MyD88-dependent production of G-CSF. G-CSF induces the expansion of hematopoietic progenitors, including hematopoietic stem cells and multipotent progenitors, and increases the frequency of myeloid-skewed progenitors. To our knowledge, these data provide the first comprehensive description of injury-induced emergency hematopoiesis and identify an IL-1/MyD88/G-CSF-dependent pathway as the key regulator of emergency hematopoiesis after injury.


Assuntos
Fator Estimulador de Colônias de Granulócitos/imunologia , Hematopoese/imunologia , Interleucina-1/imunologia , Fator 88 de Diferenciação Mieloide/imunologia , Ferimentos e Lesões/imunologia , Animais , Fator Estimulador de Colônias de Granulócitos/genética , Hematopoese/genética , Interleucina-1/genética , Camundongos , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/genética , Ferimentos e Lesões/genética , Ferimentos e Lesões/patologia
12.
Glycoconj J ; 36(3): 185-197, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31016559

RESUMO

In this study, we assessed the potential of liposomes coated with a neoglycolipid containing α1-3,α1-6-mannotriose residues (Man3-DPPE; Manα1-6(Manα1-3)Manitol-DPPE) for in vitro activation and maturation of human mononuclear phagocytes. In response to treatment with Man3-DPPE-coated liposomes (Man3-OMLs), PMA-stimulated human THP-1 cells showed enhanced expression of CD40, CD80 and HLA-DR and secreted significant levels of IL-12p40. Among various linkages of Man2-DPPE-coated liposomes, only liposomes coated with Manα1-6Manitol-DPPE (α1-6Man2-DPPE) induced these cellular responses similarly to Man3-OML treatment. Liposomes coated with Manα1-6(Manα1-3)Manα1-6(Manα1-3)Manitol-DPPE (Man5-DPPE) failed to activate the cells. These results suggest that an unsubstituted α1-6Man branch bound to a mannitol unit at the reducing end in Man3-DPPE is required for in vitro activation of human mononuclear phagocytes. Man3-OML-induced IL-12p40 production was not inhibited by BAY11-7082, an inhibitor of the MyD88-dependent signaling network, suggesting that TLRs are not involved in activation of human mononuclear phagocytes by Man3-OMLs. Stimulation of inflammatory monocytes or monocyte-derived dendritic cells (moDCs) with Man3-OMLs also induced enhanced expression of co-stimulatory molecules, HLA-DR, and CCR7, and IL-12p40 production from both types of cells. In response to Man3-OML treatment, moDCs but not inflammatory monocytes produced bioactive IL-12p70, which was enhanced by CD40 ligation. Thus, Man3-OMLs can activate naïve human mononuclear phagocytes and lead human moDCs to a fully matured status in vitro to elicit CTLs and a Th1 response without addition of inflammatory cytokines or TLR agonists.


Assuntos
Glicolipídeos/farmacologia , Lipossomos/farmacologia , Monócitos/efeitos dos fármacos , Trissacarídeos/farmacologia , 1,2-Dipalmitoilfosfatidilcolina/química , Células Cultivadas , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Glicolipídeos/química , Antígenos HLA-DR/genética , Antígenos HLA-DR/metabolismo , Humanos , Interleucina-1/genética , Interleucina-1/metabolismo , Lipossomos/química , Monócitos/imunologia , Receptores CCR7/genética , Receptores CCR7/metabolismo , Trissacarídeos/química
13.
J Agric Food Chem ; 67(17): 5033-5042, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30964671

RESUMO

Many studies have shown that fluorosis due to long-term fluoride intake has damaging effects on the heart. However, the mechanisms underlying cardiac fluorosis have not been illuminated in detail. We performed high-throughput transcriptome sequencing (RNA-Seq) on rat cardiac tissue to explore the molecular effects of NaF exposure. In total, 372 and 254 differentially expressed genes (DEGs) were identified between a group given 30 mg/L NaF and control and between a group given 90 mg/L NaF and control, respectively. The transcript levels of most of these genes were significantly down-regulated and many were distributed in the Toll-like receptor signaling pathway. Transcriptome analysis revealed that herpes simplex infection, ECM-receptor interaction, influenza A, cytokine-cytokine receptor interaction, apoptosis, and Toll-like receptor signaling pathway were significantly affected. IL-6 and IL-10 may play a crucial role in the cardiac damage caused by NaF as external stimuli according to protein-protein interaction (PPI) network analysis. The results of qRT-PCR and Western blotting showed a marked decreased mRNA and protein levels of IL-1, IL-6, and IL-10 in the low concentration fluoride (LF) and high concentration fluoride (HF) groups, which was in agreement with RNA-Seq results. This is the first study to investigate NaF-induced cardiotoxicity at a transcriptome level.


Assuntos
Cardiotoxicidade/etiologia , Cardiotoxicidade/metabolismo , Fluoretos/toxicidade , Receptores Toll-Like/metabolismo , Animais , Cardiotoxicidade/genética , Perfilação da Expressão Gênica , Humanos , Interleucina-1/genética , Interleucina-1/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Ligação Proteica/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Receptores Toll-Like/genética
14.
Proc Natl Acad Sci U S A ; 116(12): 5514-5522, 2019 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-30819901

RESUMO

Interleukin-37 (IL-37), a member of the IL-1 family of cytokines, is a fundamental suppressor of innate and acquired immunities. Here, we used an integrative approach that combines biophysical, biochemical, and biological studies to elucidate the unique characteristics of IL-37. Our studies reveal that single amino acid mutations at the IL-37 dimer interface that result in the stable formation of IL-37 monomers also remain monomeric at high micromolar concentrations and that these monomeric IL-37 forms comprise higher antiinflammatory activities than native IL-37 on multiple cell types. We find that, because native IL-37 forms dimers with nanomolar affinity, higher IL-37 only weakly suppresses downstream markers of inflammation whereas lower concentrations are more effective. We further show that IL-37 is a heparin binding protein that modulates this self-association and that the IL-37 dimers must block the activity of the IL-37 monomer. Specifically, native IL-37 at 2.5 nM reduces lipopolysaccharide (LPS)-induced vascular cell adhesion molecule (VCAM) protein levels by ∼50%, whereas the monomeric D73K mutant reduced VCAM by 90% at the same concentration. Compared with other members of the IL-1 family, both the N and the C termini of IL-37 are extended, and we show they are disordered in the context of the free protein. Furthermore, the presence of, at least, one of these extended termini is required for IL-37 suppressive activity. Based on these structural and biological studies, we present a model of IL-37 interactions that accounts for its mechanism in suppressing innate inflammation.


Assuntos
Tolerância Imunológica , Imunidade Inata , Interleucina-1/metabolismo , Linhagem Celular , Cristalografia por Raios X , Humanos , Tolerância Imunológica/imunologia , Tolerância Imunológica/fisiologia , Interleucina-1/genética , Interleucina-1/fisiologia , Espectroscopia de Ressonância Magnética , Multimerização Proteica
15.
J Mol Neurosci ; 68(2): 204-213, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30919248

RESUMO

To explore the correlations between AMP-activated protein kinase (AMPK) expression and brain inflammatory response and neurological function factors in rats with chronic renal failure. Chronic renal failure models in rats were established, and the healthy control group (normal group) was set. Chronic renal failure model rats were divided into model group (without any treatment), control group (intraperitoneal injection of normal saline), A-769662 group (intraperitoneal injection of AMPK specific activator), and compound C group (intraperitoneal injection of AMPK specific inhibitor). The results of HE staining showed renal tissue enlargement, and significant pathological changes. Compared with the normal group, AMPK level in peripheral blood and AMPK mRNA and protein expressions in brain tissue were significantly reduced, and AMPK pathway activation was significantly inhibited in other groups. Compared with the model group, rats in the A-769662 group had significantly decreased serum creatinine (Scr) and blood urea nitrogen (BUN) levels and γ-aminobutyric acid (γ-GABA) content, significantly increased brain-derived neurotrophic factor (BDNF) positive expressions and 5-hydroxytryptamine (5-HT) content, and decreased interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α), and intercellular adhesion molecule 1 (ICAM-1) expressions (all P < 0.05), while it was just the opposite in compound C group (all P < 0.05). There is an apparent correlation between AMPK expression and brain inflammatory response in chronic renal failure rats. AMPK is expected to be an important pathway in the treatment of uremic encephalopathy.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Encéfalo/metabolismo , Interleucina-1/metabolismo , Falência Renal Crônica/metabolismo , Proteínas Quinases/genética , Fator de Necrose Tumoral alfa/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/metabolismo , Interleucina-1/genética , Masculino , Proteínas Quinases/metabolismo , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/genética
16.
Nat Commun ; 10(1): 1376, 2019 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-30914642

RESUMO

IL-9-producing CD4+ (Th9) cells are a subset of CD4+ T-helper cells that are endowed with powerful antitumor capacity. Both IL-4 and TGF-ß have been reported to be indispensable for Th9 cell-priming and differentiation. Here we show, by contrast, that Th9 cell development can occur in the absence of TGF-ß signaling. When TGF-ß was replaced by IL-1ß, the combination of IL-1ß and IL-4 efficiently promoted IL-9-producing T cells (Th9IL-4+IL-1ß). Th9IL-4+ IL-1ß cells are phenotypically distinct T cells compared to classic Th9 cells (Th9IL-4+TGF-ß) and other Th cells, and are enriched for IL-1 and NF-κB gene signatures. Inhibition of NF-κB but not TGF-ß-signaling negates IL-9 production by Th9IL-4+IL-1ß cells. Furthermore, when compared with classic Th9IL-4+TGF-ß cells, Th9IL-4+IL-1ß cells are less exhausted, exhibit cytotoxic T effector gene signature and tumor killing function, and exert a superior antitumor response in a mouse melanoma model. Our study thus describes an alternative pathway for Th9 cell differentiation and provides a potential avenue for antitumor therapies.


Assuntos
Interleucina-1beta/farmacologia , Interleucina-4/farmacologia , Linfopoese/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Fator de Crescimento Transformador beta/farmacologia , Animais , Diferenciação Celular/imunologia , Linhagem Celular Tumoral , Interleucina-1/genética , Interleucina-1/imunologia , Interleucina-9 , Linfopoese/imunologia , Melanoma Experimental/imunologia , Camundongos , NF-kappa B/genética , NF-kappa B/imunologia , Fenótipo , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Linfócitos T Citotóxicos/citologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Auxiliares-Indutores/imunologia , Transcriptoma
17.
Med Hypotheses ; 125: 139-143, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30902143

RESUMO

Atherosclerosis, a chronic inflammatory disease of the arteries associated with lipids and other metabolic alterations is a leading cause of death all around the world and its rate is raising as a result of unhealthy lifestyles. Reports by World Health Organization indicate that 31% of all death occurrences are due to heart attacks and strokes. Today, the most common medicines for treating atherosclerosis are statins which are HMG-coA reductase inhibitors. Beside their benefits in treating atherosclerosis, some side effects have been reported as well. Thus, therapeutic methods based on statins should be evaluated to result in more beneficial effects. Since atherosclerosis is an inflammatory disorder, an anti-inflammatory component can decrease the impact of this disease. Interleukin-38, a newly discovered anti-inflammatory cytokine, which acts as an Interleukin-36 receptor antagonist can block Nuclear Factor KB and Activator protein-1 signaling pathways, and block atherogenic core formation accordingly. This novel proposed immune gene therapy can be applied to atherosclerosis treatment in a trial study. In this hypothesis, Interleukin-38 gene is transferred into bone marrow Mesenchymal Stem Cells of atherosclerotic mouse model Apo E-/- via an adenoviral vector. It is expected that Interleukin-38 gene expression by Mesenchymal Stem Cells can efficiently remedy atherosclerosis without the side effects of statins.


Assuntos
Aterosclerose/terapia , Terapia Genética/métodos , Interleucina-1/genética , Interleucina-1/fisiologia , Animais , Sistema Imunitário , Inflamação , Mediadores da Inflamação/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Knockout para ApoE , Modelos Teóricos , Transdução de Sinais
18.
Int J Rheum Dis ; 22(6): 1123-1129, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30843355

RESUMO

AIM: This study aims to discuss plasma and messenger RNA (mRNA) levels of interleukin (IL)-37 in rheumatoid arthritis (RA) patients and evaluate the potential of plasma IL-37 as a biomarker for RA. METHOD: Plasma IL-37 levels and IL-37 mRNA relative concentrations were measured by enzyme-linked immunosorbent assay (ELISA) and quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). We discussed the association of IL-37 levels and clinical, laboratory parameters in RA patients in a training cohort. Plasma IL-37 levels were tested for discriminatory capacity by receiver operating characteristic (ROC) curve analysis. We then validated plasma IL-37 expression in a cohort of 598 patients (230 RA, 107 systemic lupus erythematosus [SLE], 100 osteoarthritis [OA], 62 gout, 51 primary Sjögren's syndrome [pSS], 48 ankylosing spondylitis [AS]). RESULTS: Both plasma levels of IL-37 and mRNA levels of IL-37 were elevated in RA patients compared to those in healthy controls in the training cohort, and there was a good diagnostic ability to predict RA (area under the curve [AUC] = 0.97). Plasma IL-37 levels were significantly related to Disease Activity Score of 28 joints - erythrocyte sedimentation rate (DAS28-ESR) (rs  = 0.459, P < 0.001). The levels of IL-37 mRNA were related to plasma IL-37 levels (rs  = 0.642, P < 0.001), DAS28-ESR (r = 0.641, P < 0.001) and C-reactive protein (rs  = 0.603, P < 0.001). In the validation cohort, when plasma IL-37 in RA patients compared with that in SLE, OA, gout, pSS and AS patients, the AUC was 0.86, 0.87, 0.91, 0.87, 0.92, respectively. CONCLUSION: IL-37 expression was increased in RA patients, and correlated with disease activity. IL-37 may be a biomarker for the diagnosis of RA.


Assuntos
Artrite Reumatoide/sangue , Interleucina-1/sangue , Adulto , Idoso , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/genética , Biomarcadores/sangue , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Interleucina-1/genética , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , RNA Mensageiro/sangue , RNA Mensageiro/genética , Reprodutibilidade dos Testes , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Regulação para Cima
19.
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
20.
Med Sci Monit ; 25: 984-990, 2019 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-30716059

RESUMO

BACKGROUND The expression and mechanism of IL-1, IL-2, IL-8, BMP, FGF1, and IGF-1 in Sprague-Dawley (SD) rats with lumbar disc herniation were investigated. MATERIAL AND METHODS Immunohistochemical methods were applied to identify IL-1, IL-2, IL-8, BMP, FGF1, and IGF-1. PI3K, AKT protein, and mRNA expression were detected and analyzed by Western blot analysis. We selected 30 healthy SD rats and divided them into 2 groups to construct an animal model that was validated by immediate CT scanning. Cartilage tissues from the lumbar disc herniation (experimental) group and control group were obtained and compared. RESULTS The expression of BMP was not significantly different between the control group and the experimental group (P>0.05). FGF1: There was no significant difference in the expression of FGF1 (P>0.05) between the control group and the experimental group. Compared with the control group, the expression of IGF-1 in the experimental group was significantly higher (P<0.05); the expression of IL-1 in the experimental group was significantly higher (P<0.05); and the expression of IL-2 in the experimental group was also significantly higher (P<0.05). There was no significant difference in IL-8 between the experimental group and the control group (P>0.05). The expression levels of PI3K and AKT protein and mRNA were significantly higher than those in healthy controls (P<0.05). CONCLUSIONS After lumbar disc herniation occurred, the IGF-1 was first activated; the PI3K/AKT signaling pathway was later activated, which resulted in the expression of IL-1 and IL-2 inflammation-related factors being increased.


Assuntos
Deslocamento do Disco Intervertebral/metabolismo , Vértebras Lombares/metabolismo , Vértebras Lombares/fisiopatologia , Animais , Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/metabolismo , Fator 1 de Crescimento de Fibroblastos/genética , Fator 1 de Crescimento de Fibroblastos/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Interleucina-1/genética , Interleucina-1/metabolismo , Interleucina-2/genética , Interleucina-2/metabolismo , Disco Intervertebral , Deslocamento do Disco Intervertebral/fisiopatologia , Região Lombossacral , Masculino , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
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