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1.
J Agric Food Chem ; 67(24): 6773-6784, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31154759

RESUMO

The aim of this study was to evaluate the immunomodulatory effects of atractylodin, a polyethylene alkyne, on the maturation of bone marrow-derived dendritic cells (BM-DC) as well as its antirheumatic effect on collagen-induced arthritis (CIA) in DBA/1 mice. Our results indicate that atractylodin effectively suppressed the secretion of pro-inflammatory cytokines, expression of costimulatory molecules, and p38 MAPK, ERK, and NF-κBp65 signaling pathways in LPS-incubated dendritic cells (DCs). Additionally, the proliferation and cytokine secretion (IFN-γ and IL-17A) of CD8+ and CD4+ T cells were reduced. In a murine CIA model, intraperitoneal injection of atractylodin significantly alleviated the severity of the disease progression, as indicated by reduced paw swelling, clinical arthritis scores, and pathological changes of joint tissues. In addition, the overall proliferation of T cells stimulated by type II collagen and the abundance of Th1 and Th17 in the spleens were also significantly decreased with atractylodin treatments. Furthermore, atractylodin significantly downregulated the expression levels of CD40, CD80, and CD86 of DCs in the spleens. In conclusion, this study shows for the first time that atractylodin has potential to manipulate the maturation of BM-DCs and should be further explored as a therapeutic agent in the treatment of rheumatoid arthritis (RA).


Assuntos
Artrite Reumatoide/tratamento farmacológico , Atractylodes/química , Diferenciação Celular/efeitos dos fármacos , Colágeno Tipo II/efeitos adversos , Células Dendríticas/citologia , Furanos/administração & dosagem , Animais , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/imunologia , Artrite Reumatoide/fisiopatologia , Proliferação de Células/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Modelos Animais de Doenças , Humanos , Interferon gama/genética , Interferon gama/imunologia , Interleucina-17/genética , Interleucina-17/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Células Th17/imunologia , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/imunologia
2.
J Agric Food Chem ; 67(22): 6169-6176, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31117553

RESUMO

Dietary choline and its containing foods are biotransformed to trimethylamine (TMA) via gut microbial metabolism. Subsequently, as an intermediate molecule, TMA is quickly transported and oxidized in the liver by hepatic flavin monooxygenases to form trimethylamine oxide (TMAO). TMAO was treated as a waste byproduct from choline metabolism, but recent convincing evidence demonstrated the association between the small molecule TMAO and inflammation-related diseases, including blood vessel inflammation and vascular diseases. The scope of this study is to investigate the preventive effect of nobiletin on TMAO-induced blood vessel inflammation. Our results from Western blot showed that the inhibition of TMAO-induced cardiovascular inflammation was correlated with nobiletin-mediated inhibitory effects on NF-κB and MAPK/ERK related pathways. More specifically, nobiletin prevented the oxidative damage of vascular sites (proximal aorta), inhibited the activity of MAPK/ERK, reduced the expression of NF-κB p65 and phospho-NF-κB p65, and consequently decreased the inflammatory response. Flow cytometry analyses showed that nobiletin decreased TMAO-induced apoptosis of HUVEC cells and counteracted TMAO-induced HUVEC cell proliferation. Results from HE staining and immunohistochemical results also showed that nobiletin reduced the degree of inflammation of the proximal aorta in Sprague-Dawley rats. In summary, nobiletin significantly reduced TMAO-induced vascular inflammation via inhibition of the NF-κB/MAPK pathways.


Assuntos
Flavonas/administração & dosagem , Quinases de Proteína Quinase Ativadas por Mitógeno/imunologia , Fator de Transcrição RelA/imunologia , Doenças Vasculares/prevenção & controle , Animais , Aorta/efeitos dos fármacos , Aorta/imunologia , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Fígado/efeitos dos fármacos , Fígado/imunologia , Masculino , Metilaminas/efeitos adversos , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Ratos , Ratos Sprague-Dawley , Fator de Transcrição RelA/genética , Doenças Vasculares/induzido quimicamente , Doenças Vasculares/genética , Doenças Vasculares/imunologia
3.
Food Funct ; 10(5): 2906-2913, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31070650

RESUMO

Dysfunction of the intestinal epithelial barrier plays an important role in the pathogenesis of several intestinal diseases, including celiac disease, inflammatory bowel disease, and irritable bowel syndrome. The present research was carried out to investigate the protective effect of total polysaccharides of adlay bran (TPA) on TNF-α-evoked epithelial barrier dysfunction in Caco-2 cells. Caco-2 cells were treated with or without TPA in the absence or presence of TNF-α, and transepithelial electrical resistance (TEER) and Phenol Red flux were assayed to evaluate the intestinal epithelial barrier function. The results indicated that TPA suppressed the TNF-α-induced release of pro-inflammatory factors. Furthermore, TPA obviously assuaged both the increased paracellular permeability and the decrease of TEER in TNF-α-challenged Caco-2 cells. Furthermore, TPA obviously assuaged TNF-α-evoked up-regulation of IL-8 and IL-6 expression, down-regulation of occludin and ZO-3 expression, and markedly suppressed the activation and protein expression of NF-κB p65. Our results indicated that TPA assuages the TNF-α-evoked dysfunction of the intestinal epithelial barrier by inhibiting the NF-κB p65-mediated inflammatory response.


Assuntos
Coix/química , Mucosa Intestinal/imunologia , Extratos Vegetais/farmacologia , Polissacarídeos/farmacologia , Fator de Necrose Tumoral alfa/imunologia , Células CACO-2 , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/imunologia , Humanos , Interleucina-6/genética , Interleucina-6/imunologia , Interleucina-8/genética , Interleucina-8/imunologia , Mucosa Intestinal/efeitos dos fármacos , Ocludina/genética , Ocludina/imunologia , Fosforilação , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/imunologia , Fator de Necrose Tumoral alfa/genética
4.
Nat Commun ; 10(1): 1604, 2019 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-30962431

RESUMO

Self-assembling natural drug hydrogels formed without structural modification and able to act as carriers are of interest for biomedical applications. A lack of knowledge about natural drug gels limits there current application. Here, we report on rhein, a herbal natural product, which is directly self-assembled into hydrogels through noncovalent interactions. This hydrogel shows excellent stability, sustained release and reversible stimuli-responses. The hydrogel consists of a three-dimensional nanofiber network that prevents premature degradation. Moreover, it easily enters cells and binds to toll-like receptor 4. This enables rhein hydrogels to significantly dephosphorylate IκBα, inhibiting the nuclear translocation of p65 at the NFκB signalling pathway in lipopolysaccharide-induced BV2 microglia. Subsequently, rhein hydrogels alleviate neuroinflammation with a long-lasting effect and little cytotoxicity compared to the equivalent free-drug in vitro. This study highlights a direct self-assembly hydrogel from natural small molecule as a promising neuroinflammatory therapy.


Assuntos
Antraquinonas/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Portadores de Fármacos/química , Inflamação/tratamento farmacológico , Microglia/efeitos dos fármacos , Animais , Antraquinonas/química , Antraquinonas/farmacocinética , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacocinética , Linhagem Celular , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/farmacocinética , Avaliação Pré-Clínica de Medicamentos , Liberação Controlada de Fármacos , Hidrogéis/administração & dosagem , Hidrogéis/química , Hidrogéis/farmacocinética , Inflamação/imunologia , Inflamação/patologia , Lipopolissacarídeos/imunologia , Camundongos , Microglia/imunologia , Microglia/patologia , Microscopia Eletrônica de Varredura , Inibidor de NF-kappaB alfa/imunologia , Inibidor de NF-kappaB alfa/metabolismo , Nanofibras/administração & dosagem , Nanofibras/química , Nanofibras/ultraestrutura , Fosforilação/efeitos dos fármacos , Fosforilação/imunologia , Compostos Fitoquímicos/administração & dosagem , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacocinética , Rheum/química , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Receptor 4 Toll-Like/metabolismo , Fator de Transcrição RelA/imunologia , Fator de Transcrição RelA/metabolismo
5.
Int Immunopharmacol ; 68: 204-212, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30654310

RESUMO

Accumulating evidence indicates that microRNA-146a (miR-146a), a well-known anti-inflammatory miRNA, acts as a negative feedback regulator of the innate immune response, but its role in modulation of inflammatory bowel disease (IBD) remains unclear and the issue related to the stability of exogenous miR-146a in blood is up in the air. In this study, extracellular vesicles (EVs) from cultured medium of bone-marrow mesenchymal stem cells (BMSCs) transfected with recombinant lentiviruses can serve as a stable delivery system and overexpress miR-146a, which significantly inhibited TNF receptor-associated factor 6 (TRAF6) and IL-1 receptor-associated kinase 1 (IRAK1) expression in TNBS-induced colitis of rats. Moreover, the increased phosphorylation levels of NF-κB p65 and IκBα were down-regulated by the administration of EVs containing miR-146a. Coupled with the associated influence of over-expressed miR-146a on phosphorylated proteins above, the production of inflammation factors such as tumor necrosis factor-α (TNF-α), Interleukin-6 (IL-6) and Interleukin-1ß is apparently suppressed by this non-coding RNA. Collectively, these data elucidated that EVs containing miR-146a ameliorates experimental colitis caused 2,4,6­trinitrobenzenesulfonic acid (TNBS) by targeting TRAF6 and IRAK1.


Assuntos
Colite/imunologia , Vesículas Extracelulares/imunologia , Quinases Associadas a Receptores de Interleucina-1/imunologia , Células-Tronco Mesenquimais/imunologia , MicroRNAs/imunologia , Fator 6 Associado a Receptor de TNF/imunologia , Animais , Células Cultivadas , Colite/induzido quimicamente , Colite/patologia , Colo/imunologia , Colo/patologia , Citocinas/imunologia , Modelos Animais de Doenças , Masculino , Ratos Sprague-Dawley , Fator de Transcrição RelA/imunologia , Ácido Trinitrobenzenossulfônico
6.
Mol Cell ; 73(1): 22-35.e6, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30527665

RESUMO

Aberrant expression of programmed death ligand-1 (PD-L1) in tumor cells promotes cancer progression by suppressing cancer immunity. The retinoblastoma protein RB is a tumor suppressor known to regulate the cell cycle, DNA damage response, and differentiation. Here, we demonstrate that RB interacts with nuclear factor κB (NF-κB) protein p65 and that their interaction is primarily dependent on CDK4/6-mediated serine-249/threonine-252 (S249/T252) phosphorylation of RB. RNA-seq analysis shows a subset of NF-κB pathway genes including PD-L1 are selectively upregulated by RB knockdown or CDK4/6 inhibitor. S249/T252-phosphorylated RB inversely correlates with PD-L1 expression in patient samples. Expression of a RB-derived S249/T252 phosphorylation-mimetic peptide suppresses radiotherapy-induced upregulation of PD-L1 and augments therapeutic efficacy of radiation in vivo. Our findings reveal a previously unrecognized tumor suppressor function of hyperphosphorylated RB in suppressing NF-κB activity and PD-L1 expression and suggest that the RB-NF-κB axis can be exploited to overcome cancer immune evasion triggered by conventional or targeted therapies.


Assuntos
Antígeno B7-H1/metabolismo , Neoplasias da Próstata/metabolismo , Proteína do Retinoblastoma/metabolismo , Fator de Transcrição RelA/metabolismo , Evasão Tumoral , Animais , Antineoplásicos Imunológicos/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Quimiorradioterapia/métodos , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Células PC-3 , Fosforilação , Neoplasias da Próstata/genética , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/terapia , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Tolerância a Radiação , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/imunologia , Transdução de Sinais , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
7.
J Integr Med ; 16(3): 199-207, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29691190

RESUMO

OBJECTIVE: Aging is associated with the development of diseases because of immunosuppression and altered functioning of the neuroendocrine system. The medicinal properties of Morinda citrifolia L. have been widely exploited for the treatment of age-associated diseases. This study aims to investigate the in vitro and in vivo effects of noni (M. citrifolia) fruit juice (NFJ) on neuro-immunomodulation in the lymph node lymphocytes of F344 rats. METHODS: Lymphocytes isolated from axillary and inguinal lymph nodes of young (3-4 months) and old (18-21 months) rats were treated in vitro with different concentrations (0.0001%, 0.01%, and 1%) of NFJ for a period of 24 h. In the in vivo study, old (16-17 months) male F344 rats were treated with 5 mL/kg body weight of 5%, 10% and 20% of NFJ, twice a day, by oral gavage, and lymph node lymphocytes were isolated after 60 d. Concanavalin A (Con A)-induced lymphocyte proliferation, interleukin-2 (IL-2) and interferon-γ (IFN-γ) production and expression of intracellular markers, such as phospho-extracellular signal-regulated kinase (p-ERK1/2), phospho-cAMP response element-binding protein, phospho-protein kinase B (p-Akt), phospho-tyrosine hydroxylase (p-TH), phospho-nuclear factor of κ light polypeptide gene enhancer in B-cells inhibitor-α (p-IκB-α) and phospho-nuclear factor-κB (p-NF-κB p65 and p50) were examined in the lymphocytes of lymph nodes. RESULTS: NFJ increased Con A-induced lymphocyte proliferation, IL-2 and IFN-γ production, and p-ERK1/2 expression both in vitro and in vivo. In in vivo NFJ-treated old rats, lymph node lymphocytes showed increased expression of p-TH and Akt, nitric oxide production and decreased expression of p-NF-κB p65 and p50. CONCLUSION: These results suggest that the immunostimulatory properties of NFJ are facilitated through intracellular signaling pathways involving ERK1/2, Akt and NF-κB.


Assuntos
Adjuvantes Imunológicos/metabolismo , Envelhecimento/imunologia , Sucos de Frutas e Vegetais/análise , Linfonodos/imunologia , Linfócitos/imunologia , Morinda/química , Preparações de Plantas/metabolismo , Envelhecimento/metabolismo , Animais , Proliferação de Células , Frutas/química , Frutas/metabolismo , Humanos , Interleucina-2/imunologia , Linfonodos/citologia , Linfócitos/citologia , Masculino , Morinda/metabolismo , NF-kappa B/imunologia , Ratos , Ratos Endogâmicos F344 , Fator de Transcrição RelA/imunologia
8.
Chin J Nat Med ; 16(3): 184-193, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29576054

RESUMO

Salvianolic acid A (SAA) is a water-soluble component from the root of Salvia Miltiorrhiza Bge, a traditional Chinese medicine, which has been used for the treatment of cerebrovascular diseases for centuries. The present study aimed to determine the brain protective effects of SAA against cerebral ischemia reperfusion injury in rats, and to figure out whether SAA could protect the blood brain barrier (BBB) through matrix metallopeptidase 9 (MMP-9) inhibition. A focal cerebral ischemia reperfusion model was induced by middle cerebral artery occlusion (MCAO) for 1.5-h followed by 24-h reperfusion. SAA was administered intravenously at doses of 5, 10, and 20 mg·kg-1. SAA significantly reduced the infarct volumes and neurological deficit scores. Immunohistochemical analyses showed that SAA treatments could also improve the morphology of neurons in hippocampus CA1 and CA3 regions and increase the number of neurons. Western blotting analyses showed that SAA downregulated the levels of MMP-9 and upregulated the levels of tissue inhibitor of metalloproteinase 1 (TIMP-1) to attenuate BBB injury. SAA treatment significantly prevented MMP-9-induced degradation of ZO-1, claudin-5 and occludin proteins. SAA also prevented cerebral NF-κB p65 activation and reduced inflammation response. Our results suggested that SAA could be a promising agent to attenuate cerebral ischemia reperfusion injury through MMP-9 inhibition and anti-inflammation activities.


Assuntos
Anti-Inflamatórios/administração & dosagem , Barreira Hematoencefálica/enzimologia , Isquemia Encefálica/tratamento farmacológico , Ácidos Cafeicos/administração & dosagem , Medicamentos de Ervas Chinesas/administração & dosagem , Lactatos/administração & dosagem , Metaloproteinase 9 da Matriz/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Salvia miltiorrhiza/química , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/imunologia , Encéfalo , Isquemia Encefálica/enzimologia , Isquemia Encefálica/genética , Humanos , Masculino , Metaloproteinase 9 da Matriz/genética , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/imunologia , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/imunologia
9.
Int J Biol Macromol ; 116: 831-839, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29409765

RESUMO

A purified polysaccharide, designated CALB-4, was acquired from Fructus aurantii that is the traditional edible/medicina plant in China. The present study was performed to characterize the CALB-4 and to evaluate its immunomodulatory activities on human peripheral blood mononuclear cells (PBMCs). The structure of CALB-4 was characterized by partial acid hydrolysis, periodate oxidation, Smith degradation, and methylation analysis combined with gas chromatography-mass spectrometry (GC-MS), Infrared Spectroscopy (IR) and scanning electron microscopy (SEM). The results indicated that CALB-4 was elucidated as a pectic polysaccharide and its main chain is composed of Man, Gal UA and Gal, interspersed with Ara, Rha, Man and Gal. Furthermore, immunological tests showed that CALB-4 exhibits the immunoenhancement effects. The mechanism for this action might be attributed to the increase of the cytoplasmic concentration of pro-IL-1 via the up-regulation of several mitogen-activated protein kinases (MAPKs) and the nuclear translocation of p65. This study clarified that CALB-4 could be as an efficacious biological response modifier in immunotherapy.


Assuntos
Fatores Imunológicos , Leucócitos Mononucleares/imunologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Pectinas , Plantas Medicinais/química , China , Humanos , Fatores Imunológicos/química , Fatores Imunológicos/isolamento & purificação , Fatores Imunológicos/farmacologia , Leucócitos Mononucleares/patologia , Sistema de Sinalização das MAP Quinases/imunologia , Estrutura Molecular , Pectinas/química , Pectinas/isolamento & purificação , Pectinas/farmacologia , Relação Estrutura-Atividade , Fator de Transcrição RelA/imunologia
10.
J Immunol ; 200(3): 1198-1206, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29288203

RESUMO

IL-33 is an IL-1 cytokine superfamily member. Binding of IL-33 to the IL-33R induces activation of the canonical NF-κB signaling and activation of MAPKs. In bone marrow-derived dendritic cells, IL-33 induces the production of IL-6, IL-13, and TNF-α. However, the signaling pathways resulting in IL-33-induced effector functions of dendritic cells are unknown. In this article, we show that the IL-33-induced cytokine production is only partly dependent on p65. Thereby, p65 mediates the production of IL-6, but not of IL-13, whereas the p38-Mapk-activated protein kinases 2/3 (MK2/3) signaling module mediates the IL-13, but not the IL-6, production. In addition, GM-CSF, which is critical for the differentiation and proliferation of bone marrow-derived dendritic cells, potentiates the p65-dependent IL-6 and the p38-MK2/3-dependent IL-13 production. Furthermore, we found that effective TNF-α production is only induced in the presence of GM-CSF and IL-33 via the p38-MK2/3 signaling module. Taken together, we found that the p38-MK2/3 signaling module is essential to mediate IL-33-induced cytokine production in dendritic cells.


Assuntos
Células Dendríticas/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Interleucina-33/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Proteínas Serina-Treonina Quinases/imunologia , Proteínas Quinases p38 Ativadas por Mitógeno/imunologia , Animais , Células da Medula Óssea/imunologia , Células Cultivadas , Interleucina-13/biossíntese , Interleucina-6/biossíntese , Sistema de Sinalização das MAP Quinases/imunologia , Camundongos , Camundongos Knockout , Fator de Transcrição RelA/imunologia , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/imunologia
11.
J Ethnopharmacol ; 214: 292-300, 2018 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-28689797

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Pudilan xiaoyan oral liquid (PDL), collected in Chinese Pharmacopoeia, has been used clinically for treating inflammatory diseases such as upper respiratory tract infection diseases. However, its potential anti-inflammation and the mechanism are still unclear. MATERIALS AND METHODS: lipopolysaccharide (LPS) was used to induce respiratory inflammation of mice by intratracheal administration. UPLC/MS was performed for components analysis of PDL. Enzyme-linked immune sorbent assay (ELISA) was conducted for determining interleukin-6(IL-6), interleukin-1ß(IL-1ß) and tumor necrosis factor-α(TNF-α) in serum and supernatant of tracheal tissue while Nitric oxide assay kit for nitric oxide (NO) content. Hematoxylin-Eosin (HE) staining was applied to evaluate pathological lesions. Western blotting analysis (WB) and Immunohistochemistry(IHC) were employed for the determination of Toll-like receptors 4(TLR4), TNF-α, IL-6, inducible nitric oxide synthase(iNOS) and nuclear factor-kappa B p65 (NF-κB p65) protein expressions. RESULTS: Seven major compounds of PDL were analyzed simultaneously. The treatment of PDL could attenuate LPS-induced histopathological damage of tracheal tissues, followed by reducing pro-inflammation mediators including TNF-α and IL-6 in serum and supernatant of tracheal tissue. LPS-induced nitroxidative stress including NO content and iNOS expression was inhibited significantly by PDL. Furthermore, PDL also down-regulated NF-kB p65 phosphorylation and TLR4 expressions. CONCLUSION: The results indicated that the PDL had a protective effect on LPS-induced respiratory inflammation injury in mice. Our findings for the first time provide experimental evidence for the application of PDL on respiratory inflammation injury in clinical practice.


Assuntos
Anti-Inflamatórios/administração & dosagem , Medicamentos de Ervas Chinesas/administração & dosagem , Lipopolissacarídeos , Lesão Pulmonar/prevenção & controle , Pulmão/efeitos dos fármacos , Estresse Nitrosativo/efeitos dos fármacos , Receptor 4 Toll-Like/efeitos dos fármacos , Fator de Transcrição RelA/metabolismo , Administração Oral , Animais , Modelos Animais de Doenças , Mediadores da Inflamação/sangue , Interleucina-1beta/sangue , Interleucina-6/sangue , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/imunologia , Lesão Pulmonar/metabolismo , Masculino , Camundongos Endogâmicos ICR , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Fosforilação , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Receptor 4 Toll-Like/imunologia , Receptor 4 Toll-Like/metabolismo , Fator de Transcrição RelA/imunologia , Fator de Necrose Tumoral alfa/sangue
12.
Front Immunol ; 9: 2978, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30619335

RESUMO

Viruses and hosts are situated in a molecular arms race. To avoid morbidity and mortality, hosts evolved antiviral restriction factors. These restriction factors exert selection pressure on the viruses and drive viral evolution toward increasingly efficient immune antagonists. Numerous viruses exploit cellular DNA damage-binding protein 1 (DDB1)-containing Cullin RocA ubiquitin ligases (CRLs) to induce the ubiquitination and subsequent proteasomal degradation of antiviral factors expressed by their hosts. To establish a comprehensive understanding of the underlying protein interaction networks, we performed immuno-affinity precipitations for a panel of DDB1-interacting proteins derived from viruses such as mouse cytomegalovirus (MCMV, Murid herpesvirus [MuHV] 1), rat cytomegalovirus Maastricht MuHV2, rat cytomegalovirus English MuHV8, human cytomegalovirus (HCMV), hepatitis B virus (HBV), and human immunodeficiency virus (HIV). Cellular interaction partners were identified and quantified by mass spectrometry (MS) and validated by classical biochemistry. The comparative approach enabled us to separate unspecific interactions from specific binding partners and revealed remarkable differences in the strength of interaction with DDB1. Our analysis confirmed several previously described interactions like the interaction of the MCMV-encoded interferon antagonist pM27 with STAT2. We extended known interactions to paralogous proteins like the interaction of the HBV-encoded HBx with different Spindlin proteins and documented interactions for the first time, which explain functional data like the interaction of the HIV-2-encoded Vpr with Bax. Additionally, several novel interactions were identified, such as the association of the HIV-2-encoded Vpx with the transcription factor RelA (also called p65). For the latter interaction, we documented a functional relevance in antagonizing NF-κB-driven gene expression. The mutation of the DDB1 binding interface of Vpx significantly impaired NF-κB inhibition, indicating that Vpx counteracts NF-κB signaling by a DDB1- and CRL-dependent mechanism. In summary, our findings improve the understanding of how viral pathogens hijack cellular DDB1 and CRLs to ensure efficient replication despite the expression of host restriction factors.


Assuntos
HIV-2/imunologia , Ligação Proteica/imunologia , Fator de Transcrição RelA/genética , Proteínas Virais Reguladoras e Acessórias/metabolismo , Viroses/imunologia , Animais , Citomegalovirus/imunologia , Proteínas de Ligação a DNA/imunologia , Proteínas de Ligação a DNA/metabolismo , Fibroblastos , Regulação da Expressão Gênica/imunologia , Células HEK293 , HIV-2/genética , HIV-2/metabolismo , Vírus da Hepatite B/imunologia , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunoprecipitação/métodos , Espectrometria de Massas/métodos , Camundongos , Muromegalovirus/imunologia , Células NIH 3T3 , Cultura Primária de Células , Mapeamento de Interação de Proteínas/métodos , Fator de Transcrição RelA/imunologia , Fator de Transcrição RelA/metabolismo , Ubiquitina-Proteína Ligases/imunologia , Ubiquitina-Proteína Ligases/metabolismo , Proteínas Virais Reguladoras e Acessórias/genética , Proteínas Virais Reguladoras e Acessórias/imunologia , Viroses/virologia
13.
Front Immunol ; 9: 2844, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30619251

RESUMO

Inflammation urges most of the characteristics of plaques involved in the pathogenesis of myocardial ischemia/reperfusion injury (MI/RI). In addition, inflammatory signaling pathways not only mediate the properties of plaques that precipitate ischemia/reperfusion (I/R) but also influence the clinical consequences of the post-infarction remodeling and heart failure. Here, we studied whether Ginkgolide B (GB), an effective anti-inflammatory monomer, improved MI/RI via suppression of inflammation. Left anterior descending (LAD) coronary artery induced ischemia/reperfusion (I/R) of rats or A20 silencing mice, as well as hypoxia/reoxygenation (H/R) induced damages of primary cultured rat neonatal ventricular myocytes or A20 silencing ventricular myocytes, respectively, served as MI/RI model in vivo and in vitro to discuss the anti-I/R injury properties of GB. We found that GB significantly alleviated the symptoms of MI/RI evidently by reducing infarct size, preventing ultrastructural changes of myocardium, depressing Polymorphonuclears (PMNs) infiltration, lessening histopathological damage and suppressing the excessive inflammation. Further study demonstrated that GB remarkably inhibited NF-κB p65 subunit translocation, IκB-α phosphorylation, IKK-ß activity, as well as the downstream inflammatory cytokines and proteins expressions via zinc finger protein A20. In conclusion, GB could alleviate MI/RI-induced inflammatory response through A20-NF-κB signal pathway, which may give us new insights into the preventive strategies for MI/RI disease.


Assuntos
Cardiotônicos/farmacologia , Proteínas de Ligação a DNA/imunologia , Ginkgolídeos/farmacologia , Lactonas/farmacologia , Traumatismo por Reperfusão Miocárdica , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição RelA/imunologia , Animais , Modelos Animais de Doenças , Masculino , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/imunologia , Traumatismo por Reperfusão Miocárdica/patologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/imunologia
14.
Cell Death Dis ; 8(10): e3115, 2017 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-29022897

RESUMO

Amyloid-beta (Aß) is a hallmark component of age-related macular degeneration (AMD), which induces secretion of pro-inflammatory cytokines from retinal pigment epithelium (RPE). Previous studies have shown that p50/RelA (p65), a member of NF-κB family, is an essential pro-inflammatory transcription factor responding to Aß1-40 stimulation, but few focused on the other two Rel transcription factor members - RelB and c-Rel - and their role in Aß1-40-mediated inflammation. It was reported that RelA, RelB and c-Rel are also implicated in various NF-κB-mediated inflammatory diseases. Therefore, we infer that Aß1-40-mediated inflammation targets not only the classical inflammation regulator, RelA, but also RelB and c-Rel. In this study, we demonstrate that intravitreally injected Aß1-40 mice develop AMD-like pathologic changes, coupled with Rel protein (RelA, RelB and c-Rel) synthesis and nuclear translocation. To focus on the interaction mechanism of Rel proteins, we found that RelB and c-Rel formed a heterodimer with RelA in mice model. We also found that c-Rel silencing decreased the levels of Aß1-40-dependent RelA expression, indicating that RelB and c-Rel may interact with RelA as coactivator and c-Rel is required to activate the expression of RelA. Moreover, Rel protein silencing decreased the expression of distinct pro-inflammatory cytokines. Together, we demonstrate that besides RelA, RelB and c-Rel can also be activated by Aß1-40, all of which mediate pro-inflammatory cytokine transcription and RPE damage. Our findings imply that RPE-mediated inflammation under the stimulation of Aß1-40 is multi-targeted and RelA, RelB and c-Rel proteins may be the new targets of anti-inflammatory agents.


Assuntos
Peptídeos beta-Amiloides/imunologia , Degeneração Macular/patologia , Fragmentos de Peptídeos/imunologia , Proteínas Proto-Oncogênicas c-rel/imunologia , Epitélio Pigmentado da Retina/metabolismo , Fator de Transcrição RelA/imunologia , Fator de Transcrição RelB/imunologia , Peptídeos beta-Amiloides/administração & dosagem , Animais , Células Cultivadas , Eletrorretinografia , Regulação da Expressão Gênica , Inflamação/imunologia , Degeneração Macular/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Subunidade p50 de NF-kappa B/imunologia , Fragmentos de Peptídeos/administração & dosagem , Proteínas Proto-Oncogênicas c-rel/genética , Interferência de RNA , RNA Interferente Pequeno/genética , Epitélio Pigmentado da Retina/citologia , Fator de Transcrição RelA/genética , Fator de Transcrição RelB/genética
15.
Cell Immunol ; 319: 53-60, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28847568

RESUMO

Chronic skin inflammation in atopic eczema is associated with elevated expression of proinflammatory genes and activation of innate immune responses in keratinocytes. MicroRNAs (miRNAs) are short, single-stranded RNA molecules that silence genes via the degradation of target mRNAs or inhibition of translation. Recent studies have demonstrated that miR-124 is associated with regulation of inflammation factors in several diseases. The aim of this study was to investigate the role of miR-124 in skin inflammation of atopic eczema. We showed that miR-124 expression is decreased in chronic lesional skin of patients with atopic eczema, and could be strongly inhibited by IFN-γ and TNF-α. Through Western blot, real-time PCR and luciferase assays, we revealed that miR-124 inhibited the expression of p65, a member of NF-κB family which can regulate many factors involved in the immune response and inflammatory reactions, through direct targeting. Further, upon IFN-γ or TNF-α stimulation, IL8, CCL5 and CCL8 showed to be significantly upregulated by IFN-γ or TNF-α, downregulated by miR-124; the promotive effect of IFN-γ and TNF-α could be partially reversed by miR-124. The levels of IL8, CCL5 and CCL8 could be significantly downregulated by p65 knockdown, upregulated by miR-124 inhibition; the suppressive effect of p65 knockdown could be partially reversed by miR-124. Moreover, contrary to miR-124, p65, IL8, CCL5 and CCL8 mRNA expression was upregulated in chronic lesional skin of patients with atopic eczema, and all inversely correlated with miR-124. Taken together, our data demonstrate that miR-124 controls NF-κB-dependent inflammatory responses in keratinocytes and chronic skin inflammation in atopic eczema; rescuing miR-124 expression presents a promising strategy for atopic eczema treatment.


Assuntos
Dermatite Atópica/imunologia , Queratinócitos/imunologia , MicroRNAs/imunologia , Fator de Transcrição RelA/imunologia , Sequência de Bases , Quimiocina CCL5/genética , Quimiocina CCL5/imunologia , Quimiocina CCL8/genética , Quimiocina CCL8/imunologia , Dermatite Atópica/genética , Dermatite Atópica/patologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Interferon gama/farmacologia , Interleucina-8/genética , Interleucina-8/imunologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/patologia , MicroRNAs/genética , Cultura Primária de Células , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/imunologia , Transdução de Sinais , Pele/efeitos dos fármacos , Pele/imunologia , Pele/patologia , Fator de Transcrição RelA/antagonistas & inibidores , Fator de Transcrição RelA/genética , Fator de Necrose Tumoral alfa/farmacologia
16.
Mol Med Rep ; 16(5): 6389-6395, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28849172

RESUMO

The active ingredient in Artemisia carvifolia, artemisinin, may alleviate inflammation and toxicity. Artemisinin and its derivatives are first­line anti­malarial drugs currently, which have rapid effects on fever caused by malaria parasites with fewer side effects. The present study investigated the effects of Artesunate in a mouse nephritis model. Mice were injected intraperitoneally with 500 µl pristine to induce nephritis, and were treated with 28.8 mg/kg Artesunate. Subsequently, proteinuria, renal function, and tumor necrosis factor (TNF)­α and interleukin (IL)­6 levels were assessed to evaluate the effects of Artesunate on nephritis. Western blot analysis was used to measure the protein expression levels of α­smooth muscle actin (SMA), TLR4, myeloid differentiation primary response gene 88 (MyD88), NF­κB p65 and transforming growth factor (TGF)­ß1 to investigate the underlying mechanisms of Artesunate on nephritis. The results demonstrated that Artesunate reduced proteinuria and preserved renal function in nephritis mice. Artesunate attenuated TNF­α and IL­6 levels, suppressed α­SMA, TLR4, MyD88, NF­κB p65 and TGF­ß1 protein expression, and decreased caspase­3 activity in nephritis mice. These results indicated that the effects of Artesunate may prevent nephritis and inhibit inflammation via the TLR4/NF­κB signaling pathway in mice. Therefore, Artesunate may be a potential therapeutic agent to prevent nephritis.


Assuntos
Anti-Inflamatórios/farmacologia , Artemisininas/farmacologia , Nefrite/tratamento farmacológico , Proteinúria/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/genética , Fator de Transcrição RelA/genética , Actinas/genética , Actinas/imunologia , Administração Oral , Animais , Artesunato , Compostos de Bifenilo/toxicidade , Carbamatos/toxicidade , Feminino , Regulação da Expressão Gênica , Interleucina-6/genética , Interleucina-6/imunologia , Rim/efeitos dos fármacos , Rim/imunologia , Rim/patologia , Testes de Função Renal , Camundongos , Camundongos Endogâmicos BALB C , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/imunologia , Nefrite/induzido quimicamente , Nefrite/genética , Nefrite/patologia , Niacinamida/análogos & derivados , Niacinamida/toxicidade , Proteinúria/induzido quimicamente , Proteinúria/genética , Proteinúria/patologia , Pirazóis/toxicidade , Transdução de Sinais/imunologia , Receptor 4 Toll-Like/imunologia , Fator de Transcrição RelA/imunologia , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
17.
Cell Death Dis ; 8(8): e3004, 2017 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-28817116

RESUMO

Tanshinones belong to a group of lipophilic constituents of Salvia miltiorrhiza Bunge (Danshen), which is widely used in traditional Chinese medicine. A deluge of studies demonstrated that tanshinones exert anti-inflammatory effects, but the underlying mechanisms remain unclear to date. This study investigated the anti-inflammatory effects and mechanisms of total tanshinones (TTN). TTN suppressed the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) and the secretion of TNF-α, IL-6, and IL-1ß in RAW264.7 cells, bone marrow-derived macrophages, and THP-1 cells. TTN attenuated the LPS-induced transcriptional activity of NF-κB and decreased IκB-α and IKK phosphorylation and NF-κB/p65 nuclear translocation. Furthermore, TTN inhibited the LPS-induced transcriptional activity of AP-1, which was induced by the reduction of JNK1/2, ERK1/2, and p38MAPK phosphorylation. TTN blocked LPS-induced Toll-like receptor 4 (TLR4) dimerization, which consequently decreased MyD88 recruitment and TAK1 phosphorylation. In addition, TTN pretreatment effectively inhibited xylene-induced ear edema and LPS-induced septic death and improved LPS-induced acute kidney injury in mice. TTN exerts anti-inflammatory effects in vitro and in vivo by blocking TLR4 dimerization to activate MyD88-TAK1-NF-κB/MAPK signaling cascades, which provide the molecular basis of the anti-inflammatory effect of Danshen and suggest that TTN is a potential agent for the treatment of inflammatory diseases.


Assuntos
Anti-Inflamatórios/farmacologia , Diterpenos de Abietano/farmacologia , Edema/tratamento farmacológico , Fator 88 de Diferenciação Mieloide/imunologia , Salvia miltiorrhiza/química , Sepse/tratamento farmacológico , Receptor 4 Toll-Like/imunologia , Animais , Anti-Inflamatórios/isolamento & purificação , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/imunologia , Diterpenos de Abietano/isolamento & purificação , Orelha , Edema/induzido quimicamente , Edema/genética , Edema/imunologia , Regulação da Expressão Gênica , Humanos , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Lipopolissacarídeos/farmacologia , Camundongos , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/imunologia , Fator 88 de Diferenciação Mieloide/genética , Inibidor de NF-kappaB alfa/genética , Inibidor de NF-kappaB alfa/imunologia , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/imunologia , Multimerização Proteica , Células RAW 264.7 , Sepse/induzido quimicamente , Sepse/genética , Sepse/imunologia , Transdução de Sinais , Células THP-1 , Receptor 4 Toll-Like/antagonistas & inibidores , Receptor 4 Toll-Like/genética , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/imunologia , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
18.
Cell Physiol Biochem ; 42(4): 1550-1558, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28723692

RESUMO

BACKGROUND: Activation of dendritic cells (DCs) is necessary to initiate immune responses. Angiotensin II (Ang II) has been reported to have a proinflammatory and immunomodulatory function. However, the role of Ang II in regulation of DCs and the underlying mechanisms remain illdefined. METHODS: The effects of Ang II on the proliferation, maturation, phagocytosis, migration, and communication with T cells of DCs were analysed utilizing MTT, flow cytometry, ELISA, transwell assay and mixed lymphocyte culture. RESULTS: We found that Ang II treatment significantly inhibited proliferation and phagocytic activity of DCs, but promoted the DC maturation and migration well as the expression of pro-inflammatory cytokines by DCs. In addition, Ang II also stimulated DC-mediated T cell proliferation. These effects were associated with activation of p65/NF-κB, ERK1/2 and STAT1 signaling pathways in DCs. CONCLUSIONS: Our results demonstrate that Ang II activates DCs partially through p65/NF-κB, ERK1/2 and STAT1 pathways, and suggest a potential therapeutic target of DC-mediated inflammatory disorders.


Assuntos
Angiotensina II/farmacologia , Células Dendríticas/efeitos dos fármacos , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/genética , Fator de Transcrição STAT1/genética , Linfócitos T/efeitos dos fármacos , Fator de Transcrição RelA/genética , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/imunologia , Diferenciação Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Técnicas de Cocultura , Células Dendríticas/citologia , Células Dendríticas/imunologia , Regulação da Expressão Gênica , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Proteína Quinase 1 Ativada por Mitógeno/imunologia , Proteína Quinase 3 Ativada por Mitógeno/imunologia , Fagocitose/efeitos dos fármacos , Cultura Primária de Células , Fator de Transcrição STAT1/imunologia , Transdução de Sinais , Baço/citologia , Baço/efeitos dos fármacos , Baço/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia , Fator de Transcrição RelA/imunologia
19.
Tumour Biol ; 39(6): 1010428317705572, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28631557

RESUMO

Osteosarcoma is one of the most lethal malignancies, and the prognosis remains dismal due to the paucity of effective therapeutic targets. Bmi-1 and TRIM-14 are associated with the initiation and progression of osteosarcoma, which could promote angiogenesis, invasion, and apoptotic resistance in bone cancer tissue. In this study, we constructed a bispecific antibody of BsAbBmi/TRIM targeting Bmi-1 and TRIM-14 and investigated the therapeutic value in bone carcinoma cells and xenograft mice. Our results showed that Bmi-1 and TRIM-14 expression levels were markedly upregulated correlated with nuclear factor-κB nuclear translocation in bone cancer cells and clinical carcinoma tissues. Results have demonstrated that overexpression of Bmi-1 and TRIM-14 promoted growth, proliferation, aggressiveness, and apoptosis resistance of osteosarcoma cells. BsAbBmi/TRIM administration significantly inhibited nuclear factor-κB expression derived by matrix metalloproteinase-9 promoter. BsAbBmi/TRIM administration inhibited growth of osteosarcoma cells and downregulated Bmi-1 and TRIM-14 expression levels. Data also demonstrated that migration and invasion of osteosarcoma cells were also inhibited by BsAbBmi/TRIM. In addition, results illustrated that BsAbBmi/TRIM inhibited tumor growth and tumorigenicity by blockaded sensor expression in nuclear factor-κB signal pathway. Furthermore, in vivo study showed that BsAbBmi/TRIM treatment markedly inhibited the tumorigenicity and growth of osteosarcoma cells compared to either AbBmi-1 or AbTRIM-14 treatment. Notably, survival of xenograft mice was prolonged by BsAbBmi/TRIM treatment compared to either AbBmi-1 or AbTRIM-14 treatment. In conclusion, these results provided new evidence that BsAbBmi/TRIM inhibited the progression of osteosarcoma, which suggest that BsAbBmi/TRIM may be a novel anti-cancer agent for osteosarcoma therapy.


Assuntos
Proteínas de Transporte/imunologia , Osteossarcoma/tratamento farmacológico , Osteossarcoma/imunologia , Complexo Repressor Polycomb 1/imunologia , Fator de Transcrição RelA/genética , Animais , Anticorpos Biespecíficos/administração & dosagem , Anticorpos Biespecíficos/imunologia , Apoptose/efeitos dos fármacos , Proteínas de Transporte/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Humanos , Imunoterapia , Metaloproteinase 9 da Matriz/genética , Camundongos , NF-kappa B/genética , NF-kappa B/imunologia , Osteossarcoma/genética , Osteossarcoma/patologia , Complexo Repressor Polycomb 1/genética , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição RelA/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
20.
J Cell Mol Med ; 21(11): 2884-2895, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28597963

RESUMO

The immune inflammatory response plays a crucial role in many cardiac pathophysiological processes, including ischaemic cardiac injury and the post-infarction repair process. MicroRNAs (miRNAs) regulate the development and function of dendritic cells (DCs), which are key players in the initiation and regulation of immune responses; however, the underlying regulatory mechanisms remain unclear. Here, we used the supernatants of necrotic primary cardiomyocytes (Necrotic-S) to mimic the myocardial infarction (MI) microenvironment to investigate the role of miRNAs in the regulation of DC-mediated inflammatory responses. Our results showed that Necrotic-S up-regulated the DC maturation markers CD40, CD83 and CD86 and increased the production of inflammatory cytokines, concomitant with the up-regulation of miR-181a and down-regulation of miR-150. Necrotic-S stimulation activated the JAK/STAT pathway and promoted the nuclear translocation of c-Fos and NF-κB p65, and silencing of STAT1 or c-Fos suppressed Necrotic-S-induced DC maturation and inflammatory cytokine production. The effects of Necrotic-S on DC maturation and inflammatory responses, its activation of the JAK/STAT pathway and the induction of cardiomyocyte apoptosis under conditions of hypoxia were suppressed by miR-181a or miR-150 overexpression. Taken together, these data indicate that miR-181a and miR-150 attenuate DC immune inflammatory responses via JAK1-STAT1/c-Fos signalling and protect cardiomyocytes from cell death under conditions of hypoxia.


Assuntos
Células Dendríticas/imunologia , Janus Quinase 1/imunologia , MicroRNAs/imunologia , Miócitos Cardíacos/imunologia , Proteínas Proto-Oncogênicas c-fos/imunologia , Fator de Transcrição STAT1/imunologia , Animais , Antígenos CD/genética , Antígenos CD/imunologia , Apoptose/genética , Antígeno B7-2/genética , Antígeno B7-2/imunologia , Células da Medula Óssea/imunologia , Células da Medula Óssea/patologia , Antígenos CD40/genética , Antígenos CD40/imunologia , Células Dendríticas/patologia , Regulação da Expressão Gênica , Imunoglobulinas/genética , Imunoglobulinas/imunologia , Janus Quinase 1/genética , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Modelos Biológicos , Infarto do Miocárdio/genética , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/patologia , Miócitos Cardíacos/patologia , Necrose/genética , Necrose/imunologia , Necrose/patologia , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-fos/genética , Fator de Transcrição STAT1/genética , Transdução de Sinais , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/imunologia
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