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1.
Mol Immunol ; 127: 223-229, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33017719

RESUMO

E3 ligase TRAF6 plays a critical role in TLRs trigged M1 macrophage activation. However, the function of TRAF6 in IL-4-induced M2 macrophage activation has not been illuminated. We report here that deficiency of TRAF6 significantly impaired IL-4-induced genes expression in macrophage. Mechanistically, TRAF6 mediated the protein stability of STAT6, a key factor in IL-4 signaling. Overexpression of TRAF6 increased STAT6 protein level, conversely, knockdown or knockout of endogenous TRAF6 decreased it. Further study showed that TRAF6 bound STAT6 by TRAF6 C domain and reduced K48-ubiquitination of STAT6 which could induce degradation of STAT6, explaining why TRAF6 could conduct STAT6 stability. Intriguingly, the E3 ligase activity of TRAF6 was dispensable for stabilizing STAT6, despite TRAF6 promoted its K63 ubiquitination. These results indicate that TRAF6 is essential for STAT6 stability in IL-4 signaling and may act as a positive regulator in both M1 and M2 polarization.


Assuntos
Interleucina-4/metabolismo , Ativação de Macrófagos , Fator de Transcrição STAT6/metabolismo , Fator 6 Associado a Receptor de TNF/metabolismo , Animais , Biomarcadores/metabolismo , Lisina/metabolismo , Camundongos , Domínios Proteicos , Estabilidade Proteica , Células RAW 264.7 , Fator 6 Associado a Receptor de TNF/química , Ubiquitinação
2.
Chem Biol Interact ; 331: 109276, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-33002459

RESUMO

Ulcerative colitis (UC) is a chronic disease driven primarily by uncontrolled pervasive inflammatory responses affecting the colon and rectum. Currently available medications carry multiple detrimental adverse effects, which have emphasized the mandatory need for safer and more efficient novel therapeutic alternatives. Melittin is the main constituent of bee venom and exhibits potent anti-inflammatory properties. The antiulcerogenic effect of oral melittin (40 µg/kg) was explored in the current study using the acetic acid-induced colitis model. Increase in body weight and decrease in colon mass index were observed in the melittin group. Microscopically, melittin ameliorated acetic acid-induced histological damage. Melittin administration has efficiently amended the elevated levels of the cytokines, tumor necrosis factor (TNF-α) and interleukin 6 (IL-6) seen in the colitis group. This was accompanied by inhibition of the upstream signaling molecules, Toll-like receptor 4 (TLR4), tumor necrosis factor receptor (TNF-R)-associated factor (TRAF6), mitogen-activated protein kinase 38 (p38 MAPK), and nuclear factor kappaB (NF-κB) in the melittin group. Moreover, treatment with melittin resulted in marked decrease in colonic level of prostaglandin E2 (PGE2) together with the enzymes involved in its synthesis, secretory phospholipase A2 (sPLA2) and cyclooxygenase 2 (COX-2). Additionally, melittin has attenuated acetic acid-induced oxidative stress as manifested by the significant diminishment in malondialdehyde (MDA) as well as the increase in superoxide dismutase (SOD) and reduced glutathione (GSH) levels. Therefore, melittin mitigated UC pathogenesis and could be considered as a potent and promising therapeutic alternative for UC treatment.


Assuntos
Antiulcerosos/farmacologia , Meliteno/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fator 6 Associado a Receptor de TNF/metabolismo , Receptor 4 Toll-Like/metabolismo , Ácido Acético/toxicidade , Administração Oral , Animais , Antiulcerosos/uso terapêutico , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/patologia , Colo/metabolismo , Colo/patologia , Ciclo-Oxigenase 2/metabolismo , Interleucina-6/metabolismo , Malondialdeído/metabolismo , Meliteno/uso terapêutico , Camundongos , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
3.
Cell Prolif ; 53(10): e12882, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32871020

RESUMO

OBJECTIVES: Intracellular reactive oxygen species (ROS) induced by receptor activator of NF-kB ligand (RANKL) has been proven to be a critical factor in the development of osteoclasts. This study aimed to prove that schisandrin A (Sch), a novel anti-oxidant compound, is able to suppress osteoclastogenesis and prevent bone loss in ovariectomized (OVX) mice by suppressing ROS via nuclear factor erythroid 2-related factor (Nrf2). MATERIAL AND METHODS: Micro-CT was used to detect bone formation. The effects of Sch on receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)-induced reactive oxygen species (ROS) were measured by dihydroethidium (DHE) staining in vivo and 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) staining in vitro. Immunofluorescence staining was used to detect the expression of Nrf2 in vivo. siRNA was used to evaluate the effect of Nrf2 in osteoclastogenesis. RESULTS: Sch suppresses RANKL-induced ROS production by regulating nuclear factor erythroid 2-related factor (Nrf2) in vitro and vivo. Mechanistically, Sch enhances the expression of Nrf2 by regulating the degradation of Nrf2. Further, Sch suppresses phosphorylation of P65 and its nuclear translocation, as well as the degradation of IκBα. Collectively, our findings reveal that Sch protects against OVX-induced bone loss by suppressing ROS via Nrf2. CONCLUSIONS: Our results showed the potential of anti-oxidant compound schisandrin A in the treatment of osteoporosis, highlighting Nrf2 as a novel promising target in osteoclast-related disease.


Assuntos
Ciclo-Octanos/farmacologia , Lignanas/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Osteogênese/efeitos dos fármacos , Compostos Policíclicos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Feminino , Fêmur/diagnóstico por imagem , Fêmur/patologia , Macrófagos/citologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/genética , NF-kappa B/metabolismo , Osteoclastos/citologia , Osteoclastos/metabolismo , Ligante RANK/farmacologia , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Células-Tronco/citologia , Células-Tronco/metabolismo , Fator 6 Associado a Receptor de TNF/metabolismo , Regulação para Cima/efeitos dos fármacos
4.
Yonsei Med J ; 61(8): 660-669, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32734729

RESUMO

PURPOSE: Neonatal hypoxic ischemic encephalopathy (HIE) is an essential factor underlying neonatal death and disability. This study sought to explore the role of miR-146b-5p in regulating neonatal HIE. MATERIALS AND METHODS: In vitro and in vivo HIE models were established in PC12 cells and 10-day neonatal Sprague Dawley rats, respectively. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to assess miR-146b-5p expression and inflammatory factors [interleukin (IL)-6 and tumor necrosis factor (TNF)-α] in brain lesions and PC12 cells, while enzyme-linked immunosorbent assay was employed to detect the expression of oxidative stress factors (SOD and GSH-Px). Gain- and loss-assays of miR-146b-5p were conducted to verify its role in modulating the viability and apoptosis of PC12 cells under oxygen-glucose deprivation (OGD) treatment. Expression of TLR4, IRAK1, TRAF6, TAK1, and NF-κB were examined by qRT-PCR and/or Western blot. Dual luciferase activity assay was conducted to identify relationships between miR-146b-5p and IRAK1. RESULTS: In the HIE models, significant oxidative stress and inflammatory responses emerged upon upregulation of TLR4/IRAK1/TRAF6/TAK1/NF-κB signaling. Overexpression of miR-146b-5p greatly inhibited OGD-induced PC12 cell injury, inflammatory responses, and oxidative stress. Inhibiting miR-146b-5p, however, had the opposite effects. IRAK1 was found to be a target of miR-146b-5p, and miR-146b-5p overexpression suppressed the activation of IRAK1/TRAF6/TAK1/NF-κB signaling. CONCLUSION: This study demonstrated that miR-146b-5p overexpression alleviates HIE-induced neuron injury by inhibiting the IRAK1/TRAF6/TAK1/NF-κB pathway.


Assuntos
Hipóxia-Isquemia Encefálica/genética , Quinases Associadas a Receptores de Interleucina-1/metabolismo , MAP Quinase Quinase Quinases/metabolismo , MicroRNAs/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais , Fator 6 Associado a Receptor de TNF/metabolismo , Animais , Animais Recém-Nascidos , Apoptose/genética , Sequência de Bases , Modelos Animais de Doenças , Regulação para Baixo/genética , Glucose/deficiência , Inflamação/patologia , MicroRNAs/genética , Estresse Oxidativo , Oxigênio , Células PC12 , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismo
5.
Nat Commun ; 11(1): 3816, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32732870

RESUMO

Detection of microbial components such as lipopolysaccharide (LPS) by Toll-like receptor 4 (TLR4) on macrophages induces a robust pro-inflammatory response that is dependent on metabolic reprogramming. These innate metabolic changes have been compared to aerobic glycolysis in tumour cells. However, the mechanisms by which TLR4 activation leads to mitochondrial and glycolytic reprogramming are unknown. Here we show that TLR4 activation induces a signalling cascade recruiting TRAF6 and TBK-1, while TBK-1 phosphorylates STAT3 on S727. Using a genetically engineered mouse model incapable of undergoing STAT3 Ser727 phosphorylation, we show ex vivo and in vivo that STAT3 Ser727 phosphorylation is critical for LPS-induced glycolytic reprogramming, production of the central immune response metabolite succinate and inflammatory cytokine production in a model of LPS-induced inflammation. Our study identifies non-canonical STAT3 activation as the crucial signalling intermediary for TLR4-induced glycolysis, macrophage metabolic reprogramming and inflammation.


Assuntos
Interleucina-1beta/metabolismo , Macrófagos/metabolismo , Fator de Transcrição STAT3/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Linhagem Celular , Células Cultivadas , Expressão Gênica , Glicólise/efeitos dos fármacos , Inflamação/genética , Inflamação/metabolismo , Interleucina-1beta/genética , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Fator de Transcrição STAT3/genética , Serina/genética , Serina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Fator 6 Associado a Receptor de TNF/genética , Fator 6 Associado a Receptor de TNF/metabolismo , Receptor 4 Toll-Like/genética
6.
Life Sci ; 256: 117864, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32474021

RESUMO

As a major risk factor of acute kidney injury, renal ischemia/reperfusion (I/R) has a high mortality rate. Myeloid differentiation protein 2 (MD-2) is a secretory glycoprotein that plays an important role in inflammation. Our study aimed to explore the roles of MD-2 in I/R-induced inflammation and oxidative stress in vivo and in vitro. For the in vivo studies, male C57BL/6 mice were randomly divided into four groups: 1) sham, 2) I/R, 3) negative control for siRNA (siNC) and I/R treatment, or 4) MD-2 siRNA (siMD-2) and I/R. Levels of blood urea nitrogen and creatinine in the plasma were tested, and hematoxylin and eosin staining was performed at 24 h after I/R injury. The inflammatory cytokines TNF-α, IL-6, and MCP-1 were measured using ELISA and Real-time qPCR (RT-qPCR). Malondialdehyde (MDA) content and superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activity were estimated. For the in vitro studies, HK-2 cells were transfected with siMD-2 and then exposed to hypoxia/reoxygenation (H/R). Inflammatory cytokine expression and oxidative stress then were evaluated. We found decreased levels of blood urea nitrogen and creatinine levels after MD-2 silencing. MD-2 deficiency improved histological damage. MD-2 downregulation attenuated levels of inflammatory cytokines. Inhibition of MD-2 resulted in reduced MDA content and increased SOD, CAT, and GPx activity. Loss of function of MD-2 inhibited the H/R-induced production and expression of inflammatory cytokines. MD-2 silencing reduced MDA content after H/R, and MD-2 suppression enhanced SOD, CAT, and GPx activity. MD-2 deficiency also blocked H/R-mediated activation of the TLR4/TRAF6/NF-κB pathway, and pyrrolidinedithiocarbamate (PDTC) pretreatment strengthened the anti-inflammatory and antioxidant damage effects of MD-2 silencing. Taken together, our study revealed that MD-2 deficiency ameliorated renal I/R-induced inflammation and oxidative stress via inhibition of TLR4/TRAF6/NF-κB pathway.


Assuntos
Inflamação/patologia , Antígeno 96 de Linfócito/metabolismo , Estresse Oxidativo/genética , Traumatismo por Reperfusão/fisiopatologia , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/genética , Animais , Linhagem Celular , Inativação Gênica , Humanos , Inflamação/genética , Antígeno 96 de Linfócito/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , RNA Interferente Pequeno/administração & dosagem , Fator 6 Associado a Receptor de TNF/metabolismo , Receptor 4 Toll-Like/metabolismo
7.
Biochem Pharmacol ; 177: 113992, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32335141

RESUMO

IL-17A combined with TNF-α plays a vital role in inflammatory response and interference of the synergistic effect is an effective strategy for treating inflammatory diseases. Ellipticine, a natural alkaloid, has biological activities on anti-tumor and anti-HIV. However, it is still unknown whether ellipticine can inhibit IL-17A and TNF-α-mediated signaling and has treatment effect on PALI. Here, we reported that ellipticine significantly inhibited the production of pro-inflammatory cytokines and chemokines in pulmonary epithelial cell BEAS-2B treated with IL-17A and TNF-α, but not IL-17A or TNF-α alone. Meanwhile, ellipticine attenuated NF-κB and MAPKs activation in response to IL-17A and TNF-α treatment, inhibited Act1 and TRAF6-mediated NF-κB activation, and blocked the interaction of Act1 with TRAF6. Furthermore, we found that ellipticine significantly alleviated CAE and LPS-induced SAP/PALI. Ellipticine treatment dramatically reduced inflammatory cells infiltration, MPO activity, serum amylase and lipase activity and the protein concentration of BALF. Collectively, our findings indicate that ellipticine inhibits the synergistic effect of IL-17A and TNF-α by targeting on Act1 and TRAF6 interaction and is a potential therapeutic agent for the treatment of SAP/PALI.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Elipticinas/farmacologia , Interleucina-17/antagonistas & inibidores , Pancreatite/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/complicações , Lesão Pulmonar Aguda/genética , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Amilases/antagonistas & inibidores , Amilases/genética , Amilases/metabolismo , Animais , Linhagem Celular Transformada , Ceruletídeo/administração & dosagem , Modelos Animais de Doenças , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Regulação da Expressão Gênica , Células HEK293 , Humanos , Interleucina-17/farmacologia , Lipase/antagonistas & inibidores , Lipase/genética , Lipase/metabolismo , Lipopolissacarídeos/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/antagonistas & inibidores , NF-kappa B/genética , NF-kappa B/metabolismo , Pancreatite/induzido quimicamente , Pancreatite/complicações , Pancreatite/genética , Peroxidase/antagonistas & inibidores , Peroxidase/genética , Peroxidase/metabolismo , Transdução de Sinais , Fator 6 Associado a Receptor de TNF/antagonistas & inibidores , Fator 6 Associado a Receptor de TNF/genética , Fator 6 Associado a Receptor de TNF/metabolismo , Fator de Necrose Tumoral alfa/farmacologia
8.
Nat Immunol ; 21(5): 535-545, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32313245

RESUMO

Despite evidence of chronic inflammation in myelodysplastic syndrome (MDS) and cell-intrinsic dysregulation of Toll-like receptor (TLR) signaling in MDS hematopoietic stem and progenitor cells (HSPCs), the mechanisms responsible for the competitive advantage of MDS HSPCs in an inflammatory milieu over normal HSPCs remain poorly defined. Here, we found that chronic inflammation was a determinant for the competitive advantage of MDS HSPCs and for disease progression. The cell-intrinsic response of MDS HSPCs, which involves signaling through the noncanonical NF-κB pathway, protected these cells from chronic inflammation as compared to normal HSPCs. In response to inflammation, MDS HSPCs switched from canonical to noncanonical NF-κB signaling, a process that was dependent on TLR-TRAF6-mediated activation of A20. The competitive advantage of TLR-TRAF6-primed HSPCs could be restored by deletion of A20 or inhibition of the noncanonical NF-κB pathway. These findings uncover the mechanistic basis for the clonal dominance of MDS HSPCs and indicate that interfering with noncanonical NF-κB signaling could prevent MDS progression.


Assuntos
Células-Tronco Hematopoéticas/fisiologia , Inflamação/imunologia , Síndromes Mielodisplásicas/imunologia , NF-kappa B/metabolismo , Fator 6 Associado a Receptor de TNF/metabolismo , Idoso , Animais , Diferenciação Celular , Células Cultivadas , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Mielopoese , NF-kappa B/genética , Transdução de Sinais , Fator 6 Associado a Receptor de TNF/genética , Receptores Toll-Like/metabolismo , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/metabolismo
9.
Int J Mol Sci ; 21(5)2020 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-32121289

RESUMO

Osteoclast differentiation and function are crucial for maintaining bone homeostasis and preserving skeletal integrity. N6-methyladenosine (m6A) is an abundant mRNA modification that has recently been shown to be important in regulating cell lineage differentiation. Nevertheless, the effect of m6A on osteoclast differentiation remains unknown. In the present study, we observed that the m6A level and methyltransferase METTL3 expression increased during osteoclast differentiation. Mettl3 knockdown resulted in an increased size but a decreased bone-resorbing ability of osteoclasts. The expression of osteoclast-specific genes (Nfatc1, c-Fos, Ctsk, Acp5 and Dcstamp) was inhibited by Mettl3 depletion, while the expression of the cellular fusion-specific gene Atp6v0d2 was upregulated. Mechanistically, Mettl3 knockdown elevated the mRNA stability of Atp6v0d2 and the same result was obtained when the m6A-binding protein YTHDF2 was silenced. Moreover, the phosphorylation levels of key molecules in the MAPK, NF-κB and PI3K-AKT signaling pathways were reduced upon Mettl3 deficiency. Depletion of Mettl3 maintained the retention of Traf6 mRNA in the nucleus and reduced the protein levels of TRAF6. Taken together, our data suggest that METTL3 regulates osteoclast differentiation and function through different mechanisms involving Atp6v0d2 mRNA degradation mediated by YTHDF2 and Traf6 mRNA nuclear export. These findings elucidate the molecular basis of RNA epigenetic regulation in osteoclast development.


Assuntos
Adenosina/análogos & derivados , Diferenciação Celular , Núcleo Celular/metabolismo , Metiltransferases/metabolismo , Osteoclastos/citologia , Osteoclastos/metabolismo , Estabilidade de RNA/genética , Transporte Ativo do Núcleo Celular , Adenosina/metabolismo , Animais , Reabsorção Óssea/patologia , Proliferação de Células , Técnicas de Silenciamento de Genes , Camundongos , Camundongos Endogâmicos C57BL , Modelos Biológicos , NF-kappa B/metabolismo , Osteogênese , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ligante RANK/metabolismo , Células RAW 264.7 , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/metabolismo , Transdução de Sinais , Fator 6 Associado a Receptor de TNF/metabolismo , ATPases Vacuolares Próton-Translocadoras/metabolismo
10.
Mol Cell ; 78(1): 42-56.e6, 2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32035036

RESUMO

The functional relevance and mechanistic basis of the effects of the neurotransmitter dopamine (DA) on inflammation remain unclear. Here we reveal that DA inhibited TLR2-induced NF-κB activation and inflammation via the DRD5 receptor in macrophages. We found that the DRD5 receptor, via the EFD and IYX(X)I/L motifs in its CT and IC3 loop, respectively, can directly recruit TRAF6 and its negative regulator ARRB2 to form a multi-protein complex also containing downstream signaling proteins, such as TAK1, IKKs, and PP2A, that impairs TRAF6-mediated activation of NF-κB and expression of pro-inflammatory genes. Furthermore, the DA-DRD5-ARRB2-PP2A signaling axis can prevent S. aureus-induced inflammation and protect mice against S. aureus-induced sepsis and meningitis after DA treatment. Collectively, these findings provide the first demonstration of DA-DRD5 signaling acting to control inflammation and a detailed delineation of the underlying mechanism and identify the DRD5-ARRB2-PP2A axis as a potential target for future therapy of inflammation-associated diseases such as meningitis and sepsis.


Assuntos
Dopamina/fisiologia , Inflamação/metabolismo , Proteína Fosfatase 2/metabolismo , Receptores de Dopamina D5/metabolismo , Transdução de Sinais , beta-Arrestina 2/metabolismo , Motivos de Aminoácidos , Animais , Células Cultivadas , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Citocinas/genética , Citocinas/metabolismo , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Receptores de Dopamina D5/química , Fator 6 Associado a Receptor de TNF/antagonistas & inibidores , Fator 6 Associado a Receptor de TNF/metabolismo , Receptor 2 Toll-Like/antagonistas & inibidores , beta-Arrestina 2/fisiologia
11.
Mol Cell Biol ; 40(9)2020 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-32041822

RESUMO

CD40 plays an important role in immune responses by activating the c-Jun N-terminal protein kinase (JNK) and NF-κB pathways; however, the precise mechanisms governing the spatiotemporal activation of these two signaling pathways are not fully understood. Here, using four different TRAF2-deficient cell lines (A20.2J, CH12.LX, HAP1, and mouse embryonic fibroblasts [MEFs]) reconstituted with wild-type or phosphorylation mutant forms of TRAF2, along with immunoprecipitation, immunoblotting, gene expression, and immunofluorescence analyses, we report that CD40 ligation elicits TANK-binding kinase 1 (TBK1)-mediated phosphorylation of TRAF2 at Ser-11. This phosphorylation interfered with the interaction between TRAF2's RING domain and membrane phospholipids and enabled translocation of the TRAF2 complex from CD40 to the cytoplasm. We also observed that this cytoplasmic translocation is required for full activation of the JNK pathway and the secondary phase of the NF-κB pathway. Moreover, we found that in the absence of Ser-11 phosphorylation, the TRAF2 RING domain interacts with phospholipids, leading to the translocation of the TRAF2 complex to lipid rafts, resulting in its degradation and activation of the noncanonical NF-κB pathway. Thus, our results provide new insights into the CD40 signaling mechanisms whereby Ser-11 phosphorylation controls RING domain-dependent subcellular localization of TRAF2 to modulate the spatiotemporal activation of the JNK and NF-κB pathways.


Assuntos
Antígenos CD40/metabolismo , Fator 2 Associado a Receptor de TNF/metabolismo , Animais , Citoplasma/metabolismo , Citosol/metabolismo , Células HEK293 , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismo , Serina/metabolismo , Transdução de Sinais/fisiologia , Fator 2 Associado a Receptor de TNF/genética , Fator 6 Associado a Receptor de TNF/metabolismo , Fator de Transcrição RelA/metabolismo
12.
Nature ; 577(7792): 682-688, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31942069

RESUMO

Mycobacterium tuberculosis is an intracellular pathogen that uses several strategies to interfere with the signalling functions of host immune molecules. Many other bacterial pathogens exploit the host ubiquitination system to promote pathogenesis1,2, but whether this same system modulates the ubiquitination of M. tuberculosis proteins is unknown. Here we report that the host E3 ubiquitin ligase ANAPC2-a core subunit of the anaphase-promoting complex/cyclosome-interacts with the mycobacterial protein Rv0222 and promotes the attachment of lysine-11-linked ubiquitin chains to lysine 76 of Rv0222 in order to suppress the expression of proinflammatory cytokines. Inhibition of ANAPC2 by specific short hairpin RNA abolishes the inhibitory effect of Rv0222 on proinflammatory responses. Moreover, mutation of the ubiquitination site on Rv0222 impairs the inhibition of proinflammatory cytokines by Rv0222 and reduces virulence during infection in mice. Mechanistically, lysine-11-linked ubiquitination of Rv0222 by ANAPC2 facilitates the recruitment of the protein tyrosine phosphatase SHP1 to the adaptor protein TRAF6, preventing the lysine-63-linked ubiquitination and activation of TRAF6. Our findings identify a previously unrecognized mechanism that M. tuberculosis uses to suppress host immunity, and provide insights relevant to the development of effective immunomodulators that target M. tuberculosis.


Assuntos
Proteínas de Bactérias/imunologia , Proteínas de Bactérias/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Mycobacterium tuberculosis/imunologia , Tuberculose/imunologia , Ubiquitinação , Ciclossomo-Complexo Promotor de Anáfase/química , Animais , Subunidade Apc2 do Ciclossomo-Complexo Promotor de Anáfase/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Células Cultivadas , Citocinas/antagonistas & inibidores , Citocinas/imunologia , Citocinas/metabolismo , Feminino , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Lisina/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Transdução de Sinais , Fator 6 Associado a Receptor de TNF/antagonistas & inibidores , Fator 6 Associado a Receptor de TNF/metabolismo , Fator de Transcrição AP-1/metabolismo , Tuberculose/microbiologia , Virulência/imunologia
13.
Int Immunopharmacol ; 80: 106127, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31978798

RESUMO

BACKGROUND: The increased differentiation of T helper 17 cells (Th17) accelerates the development of immune thrombocytopenia (ITP), which is a common autoimmune disease with limited therapeutic methods. Recent studies have revealed that long non-coding RNAs (lncRNAs) play a critical role in autoimmune diseases, thus this study aims to investigate the effect of lncRNA GAS5 on the differentiation of Th17 cells in ITP. METHODS: The expression of GAS5 in peripheral blood mononuclear cells (PBMCs) of ITP patients and spleen tissues of ITP mice was measured by qRT-PCR. The percentage of Th17 cells in CD4+ cells was measured by flow cytometry. The combination between GAS5 and STAT3 was confirmed by RNA pull-down assay and RNA Binding Protein Immunoprecipitation (RIP). The ubiquitination of STAT3 was detected by ubiquitination assay and the interaction between STAT3 and TRAF6 was measured by Co-Immunoprecipitation (Co-IP). Finally, the effect of GAS5 on Th17 differentiation was investigated in vitro and in vivo using lentivirus (lenti)-GAS5. RESULTS: GAS5 expression was downregulated both in PBMCs of ITP patients and spleen tissues of ITP mice. Overexpression of GAS5 suppressed Th17 differentiation while had no effect on Treg differentiation in naïve CD4+ cells. RNA pull-down and RNA immunoprecipitation assays confirmed the interaction between GAS5 and STAT3. Further studies showed GAS5 accelerated the degradation of STAT3 via promoting TRAF6-mediated ubiquitination. Overexpressing GAS5 suppressed Th17 differentiation in vitro and alleviated ITP in vivo via reducing STAT3. CONCLUSION: LncRNA GAS5 inhibited Th17 differentiation through promoting the TRAF6-mediated ubiquitination of STAT3, thus relieving ITP.


Assuntos
RNA Longo não Codificante/metabolismo , Fator de Transcrição STAT3/metabolismo , Células Th17/imunologia , Trombocitopenia/genética , Adulto , Animais , Estudos de Casos e Controles , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Modelos Animais de Doenças , Regulação para Baixo/imunologia , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Proteólise , Baço/imunologia , Baço/patologia , Fator 6 Associado a Receptor de TNF/genética , Fator 6 Associado a Receptor de TNF/metabolismo , Trombocitopenia/sangue , Trombocitopenia/imunologia , Trombocitopenia/patologia , Ubiquitinação/genética
14.
Biochem Biophys Res Commun ; 523(4): 924-930, 2020 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-31964525

RESUMO

Hepatic ischemia-reperfusion (IR) injury can cause serious liver damage, leading to liver dysfunction after liver surgery, which is associated with NF-κB-mediated inflammation. The K63-linked auto-polyubiquitination of tumor necrosis factor receptor-associated factor 6 (TRAF6) is essential for the activation of NF-κB. Here, we found that OTU domain-containing protein 4 (OTUD4), a deubiquitinating enzyme (DUB), interacts with TRAF6 and decreases the K63 auto-polyubiquitination of TRAF6. In addition, the data showed that NF-κB activation was impaired and inflammatory factor levels were reduced after overexpressing OTUD4 in a hypoxia/reoxygenation (HR) model and a hepatic IR model. Additionally, the liver inflammatory response and tissue damage were ameliorated in mice overexpressing OTUD4.Taken together, these results show that OTUD4 can negatively regulate NF-κB activation by suppressing the K63-linked ubiquitination of TRAF6, thus alleviating hepatic ischemia-reperfusion injury.


Assuntos
Fígado/metabolismo , Lisina/metabolismo , Traumatismo por Reperfusão/metabolismo , Fator 6 Associado a Receptor de TNF/metabolismo , Proteases Específicas de Ubiquitina/metabolismo , Ubiquitinação , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Mediadores da Inflamação/metabolismo , Fígado/patologia , Fígado/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Células RAW 264.7
15.
Med Sci Monit ; 26: e919698, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31929494

RESUMO

BACKGROUND Inflammation and oxidative stress play important roles in the pathogenesis of acute kidney injury (AKI). TRAF6 functions as a signal transducer in the Toll-like receptor 4 signaling pathway. Several reports have previously implicated TRAF6 signaling in kidney pathology. Here, we investigated whether TRAF6 blockade can mitigate inflammatory responses and oxidative stress in AKI. MATERIAL AND METHODS C57BL/6 mice were injected with lipopolysaccharide (LPS, 15 mg/kg) to induce AKI. Double immunofluorescence staining of kidney tissues showed that TRAF6 was localized to renal tubular epithelial cells, and then a tubular epithelial cell line (NRK-52E) was used for in vitro analysis. TRAF6 was blocked in vitro using siRNA and in vivo using AAV2/2 shRNA. RESULTS The knockdown of TRAF6 in mice by AAV2-shTRAF6 significantly reduced renal inflammation, oxidative stress, apoptosis and kidney dysfunction in AKI. In vitro, silencing the expression of TRAF6 attenuated LPS(0.5 µg/mL)-induced inflammatory responses and oxidative stress and upregulated proapoptotic factors. Furthermore, the beneficial actions of TRAF6 blockade were closely associated with its ability to increase IkappaB-alpha and Nrf2. CONCLUSIONS Our findings provide direct evidence that TRAF6 mediates LPS-induced inflammation and oxidative stress, leading to renal dysfunction. We also show that TRAF6 inhibition is a potential therapeutic option to prevent AKI.


Assuntos
Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/patologia , Inflamação/patologia , Estresse Oxidativo , Substâncias Protetoras/farmacologia , Fator 6 Associado a Receptor de TNF/antagonistas & inibidores , Lesão Renal Aguda/sangue , Animais , Apoptose/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Fibrose , Técnicas de Silenciamento de Genes , Inativação Gênica , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/patologia , Lipopolissacarídeos , Masculino , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/metabolismo , Inibidor de NF-kappaB alfa/metabolismo , Estresse Oxidativo/efeitos dos fármacos , RNA Interferente Pequeno/metabolismo , Fator 6 Associado a Receptor de TNF/metabolismo , Regulação para Cima/efeitos dos fármacos
16.
Mol Med Rep ; 21(2): 795-805, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31974601

RESUMO

The aim of the present study was to investigate the involvement of B cell­activating factor (BAFF) in the pathogenesis of IgA nephropathy by activating the tumor necrosis factor receptor­associated factor 6 (TRAF6)/NF­κB signaling pathway in glomerular mesangial cells. For the clinical analysis, blood, urine and kidney tissue samples were collected from 58 patients diagnosed with primary IgA nephropathy by renal biopsy. For the in vitro study, glomerular mesangial cells were divided into five groups: Control (con)­short hairpin RNA (shRNA) (control group); con­shRNA + BAFF (20 ng/ml); con­shRNA + BAFF + BAFF­RFc chimera protein (500 µg/ml); TRAF6­shRNA; and TRAF6­shRNA + BAFF (20 ng/ml). For the in vivo experiments, 60 Sprague­Dawley rats were randomly divided into four groups: Con­small interfering RNA (siRNA) (control group); con­siRNA + IgA (IgA nephropathy group), BAFF­RFc chimera protein (2 µg/ml) + IgA, and TRAF6­siRNA (0.2 µM) + IgA. Reverse transcription­quantitative PCR was performed to evaluate the mRNA expression levels of TRAF6, connective tissue growth factor (CTGF), fibronectin (FN) and NF­κBP65. Western blot analysis was used to detect the protein expression levels of TRAF6, FN, CTGF and phosphorylated­NF­κBP65 in glomerular mesangial cells and kidney tissues. The results revealed that plasma BAFF levels were positively correlated with the severity of pathological damage in patients with IgA nephropathy. In vitro, BAFF induced the mRNA and protein expression of TRAF6, CTGF, FN and NF­κBP65 in glomerular mesangial cells. After the BAFF­RFc chimera protein was added to inhibit the binding of BAFF and BAFF­receptor (­R), this effect was reduced. In vivo, inhibition of the effects of BAFF via injection with the BAFF­R Fc chimera protein reduced kidney damage in rats suffering from IgA nephropathy. The effect on the expression of signaling pathway­associated proteins was also alleviated. In conclusion, BAFF enhanced the expression of fibroblast factors in the kidneys by activating the TRAF6/NF­κB signaling pathway.


Assuntos
Fator Ativador de Células B/metabolismo , Glomerulonefrite por IGA/metabolismo , Glomérulos Renais/patologia , Células Mesangiais/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais , Fator 6 Associado a Receptor de TNF/metabolismo , Fator Ativador de Células B/sangue , Receptor do Fator Ativador de Células B/metabolismo , Biomarcadores/metabolismo , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Creatinina/sangue , Feminino , Fibroblastos/metabolismo , Fibronectinas/metabolismo , Glomerulonefrite por IGA/sangue , Humanos , Masculino , Células Mesangiais/patologia , Pessoa de Meia-Idade , Proteinúria/sangue , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Fator de Transcrição RelA/metabolismo
17.
Mol Med Rep ; 21(2): 959-968, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31974603

RESUMO

Dental pulp inflammation is a pathological process characterized by local lesions in dental pulp and the accumulation of inflammatory mediators. DNA methylation of cytosine residues is a key epigenetic modification that is essential for gene transcription, and plays pivotal roles in inflammatory reactions and immune responses. However, the function of cytosine DNA methylation in the innate immune defense against the inflammation of dental pulp is poorly understood. To investigate the effect of DNA methylation in inflamed dental pulp upon innate immune responses, expression levels of the DNA methyltransferases (DNMT1, DNMT3a and DNMT3b) in human dental pulp cells (hDPCs) after lipopolysaccharide (LPS) stimulation were evaluated by western blotting and reverse transcription­quantitative (RT­q) PCR. Only DNMT1 expression was decreased, while the transcription of inflammatory cytokines was increased. In the immune responses of LPS­induced hDPCs, the results of RT­qPCR and ELISA showed that DNMT1 knockdown promoted the production of the pro­inflammatory cytokines, interleukin (IL)­6 and IL­8. Western blotting demonstrated that DNMT1 knockdown increased the phosphorylation levels of IKKα/ß and p38 in the NF­κB and MAPK signaling pathways, respectively. Furthermore, MeDIP and RT­qPCR analysis demonstrated that the 5­methylcytosine levels of the IL­6 and TNF receptor­associated factor 6 (TRAF6) promoters were significantly decreased in DNMT1­deficient hDPCs. Taken together, these results indicated that the expression of DNMT1 was decreased after LPS stimulation in hDPCs. DNMT1 depletion increased LPS­induced cytokine secretion, and activated NF­κB and MAPK signaling; these mechanisms may involve the decreased methylation levels of the IL­6 and TRAF6 gene promoters. This study emphasized the role of DNMT1­dependent DNA methylation on the inflammation of LPS­infected dental pulp and provides a new rationale for the investigation of the molecular mechanisms of inflamed dental pulps.


Assuntos
DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Metilação de DNA , Polpa Dentária/patologia , Inflamação/patologia , Interleucina-6/metabolismo , Fator 6 Associado a Receptor de TNF/metabolismo , 5-Metilcitosina/metabolismo , Adolescente , Adulto , Citocinas/metabolismo , Metilação de DNA/genética , Feminino , Humanos , Interleucina-8/metabolismo , Lipopolissacarídeos , Masculino , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Regiões Promotoras Genéticas/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Adulto Jovem
18.
Acta Pharmacol Sin ; 41(2): 229-236, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31431733

RESUMO

In chronic infectious diseases caused by gram-negative bacteria, such as osteomyelitis, septic arthritis, and periodontitis, osteoclastic activity is enhanced with elevated inflammation, which disturbs the bone homeostasis and results in osteolysis. Lipopolysaccharide (LPS), as a bacteria product, plays an important role in this process. Recent evidence shows that an antimalarial drug artesunate attenuates LPS-induced osteolysis independent of RANKL. In this study we evaluated the effects of artesunate on LPS-induced osteoclastogenesis in vitro and femur osteolysis in vivo, and explored the mechanisms underlying the effects of artesunate on LPS-induced osteoclast differentiation independent of RANKL. In preosteoclastic RAW264.7 cells, we found that artesunate (1.56-12.5 µM) dose dependently inhibited LPS-induced osteoclast formation accompanied by suppressing LPS-stimulated osteoclast-related gene expression (Fra-2, TRAP, Cathepsin K, ß3-integrin, DC-STAMP, and Atp6v0d2). We showed that artesunate (3.125-12.5 µM) inhibited LPS-stimulated nuclear factor of activated T cells c1 (NFATc1) but not NF-κB transcriptional activity; artesunate (6.25, 12.5 µM) significantly inhibited LPS-stimulated NFATc1 protein expression. Furthermore, artesunate treatment markedly suppressed LPS-induced Ca2+ influx, and decreased the expression of PP2B-Aα (calcineurin) and pPLCγ1 in the cells. In addition, artesunate treatment significantly decreased the expression of upstream signals TLR4 and TRAF6 during LPS-induced osteoclastogenesis. Administration of artesunate (10 mg/kg, ip) for 8 days effectively inhibited serum TNF-α levels and ameliorated LPS (5 mg/kg, ip)-induced inflammatory bone loss in vivo. Taken together, artesunate attenuates LPS-induced inflammatory osteoclastogenesis by inhibiting the expression of TLR4/TRAF6 and the downstream PLCγ1-Ca2+-NFATc1 signaling pathway. Artesunate is a valuable choice to treat bone loss induced by gram-negative bacteria infection or inflammation in RANKL-independent pathway.


Assuntos
Antimaláricos/farmacologia , Artesunato/farmacologia , Inflamação/tratamento farmacológico , Osteoclastos/efeitos dos fármacos , Animais , Antimaláricos/administração & dosagem , Artesunato/administração & dosagem , Cálcio/metabolismo , Relação Dose-Resposta a Droga , Feminino , Inflamação/patologia , Lipopolissacarídeos , Camundongos , Camundongos Endogâmicos ICR , Fatores de Transcrição NFATC/metabolismo , Osteoclastos/citologia , Osteogênese/efeitos dos fármacos , Fosfolipase C gama/metabolismo , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos , Fator 6 Associado a Receptor de TNF/metabolismo , Receptor 4 Toll-Like/metabolismo
19.
J Orthop Res ; 38(3): 670-679, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31608495

RESUMO

Lumbar facet joint osteoarthritis (LFJ OA) is regarded as one of the common causes of low back pain (LBP). The pathogenesis and underlying mechanism of this disease are largely unknown, there is still no effective disease-modifying therapy. This study aims to investigate the efficacy of exosomes derived from bone marrow mesenchymal stem cells (BMSCs) on the pathogenesis and behavioral signs of LBP in the LFJ OA mouse model. The pathogenetic change in cartilage and aberrant nerve invasion in the subchondral bone of LFJ in a mouse model after treatment with BMSC-exosomes was evaluated. BMSC-exosomes could relieve pain via abrogation of aberrant CGRP-positive nerve and abnormal H-type vessel formation in the subchondral bone of LFJ. Moreover, BMSC-exosomes attenuated cartilage degeneration and inhibited tartrate-resistant acid phosphatase expression and RANKL-RANK-TRAF6 signaling activation to facilitate subchondral bone remodeling. These results indicated that BMSC-exosomes could relive behavioral signs of LBP and pathological processes in LFJ OA. BMSC-exosomes have a prominent protective effect and might be a potential therapeutic option for the treatment of LFJ OA causing LBP. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:670-679, 2020.


Assuntos
Exossomos/metabolismo , Vértebras Lombares/patologia , Células-Tronco Mesenquimais/metabolismo , Osteoartrite/terapia , Manejo da Dor/métodos , Animais , Células da Medula Óssea/citologia , Remodelação Óssea , Cartilagem Articular/inervação , Cartilagem Articular/patologia , Processamento de Imagem Assistida por Computador/métodos , Imageamento Tridimensional , Vértebras Lombares/inervação , Camundongos , Camundongos Endogâmicos C57BL , Osteoartrite/patologia , Ligante RANK/metabolismo , Fator 6 Associado a Receptor de TNF/metabolismo
20.
Scand J Immunol ; 91(1): e12840, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31630418

RESUMO

IL-17 participates in the development of many autoimmune diseases by promoting the expression of some chemokines. Chemokine C-C motif ligand 2 (CCL2) is an important factor at the infiltration of mononuclear cells in the myocardial tissue of viral myocarditis (VMC). It was found that IL-17 could aggravate myocardial injury by upregulating CCL2. But the underlying mechanism involved in CCL2 secretion induced by IL-17 in cardiac myocytes remains unclear. This study investigated the role of transcription factor AP-1 in IL-17 induced CCL2 expression. The results showed that IL-17 mediated the activation of Act1, TRAF6, p38MAPK and c-Jun/AP-1 not Wnt or PI3K signalling pathway to upregulate CCL2 expression in cardiac myocytes. After blocking Act1/TRAF6/p38MAPK cascade and interfering AP-1 with Curcumin or c-Jun siRNA, CCL2 expression induced by IL-17 was significantly attenuated at both mRNA and protein levels. Furthermore, the phosphorylation of c-Jun was suppressed when cardiac myocytes were treated with Act1 siRNA, TRAF6 siRNA, SB203580 (p38MAPK inhibitor) or SP600125 (JNK inhibitor) in cardiac myocytes. In conclusion, IL-17 could stimulate the expression of CCL2 in cardiac myocytes via Act1/TRAF6/p38MAPK-dependent AP-1 activation, which may provide a new target for the diagnosis and treatment of VMC.


Assuntos
Quimiocina CCL2/genética , Regulação da Expressão Gênica , Interleucina-17/metabolismo , Miócitos Cardíacos/metabolismo , Fator 6 Associado a Receptor de TNF/metabolismo , Fator de Transcrição AP-1/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Animais Recém-Nascidos , Quimiocina CCL2/metabolismo , Interleucina-17/farmacologia , Camundongos , Miócitos Cardíacos/efeitos dos fármacos , Fosforilação , Transdução de Sinais/efeitos dos fármacos
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