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1.
Food Funct ; 10(9): 6135-6146, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31497826

RESUMO

Osteoarthritis (OA) is a degenerative joint disease, whose progression is closely related to the inflammatory environment. Urolithin A (UA), a natural metabolite of a class of compounds (ellagitannins and ellagic acid) found in pomegranates and other fruits and nuts, has been proved to exert anti-inflammatory effects in a variety of diseases. However, the exact role of UA in OA development is still unclear. In the present study, we examined the latent mechanism of UA and its protective role in the progression of OA by both in vitro and in vivo experiments. In vitro, UA inhibited the interleukin-1 beta (IL-1ß) induced over-production of nitric oxide (NO), prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in a concentration-dependent manner in human OA chondrocytes. Furthermore, by downregulating the expression of metalloproteinase 13 (MMP13) and thrombospondin motifs 5 (ADAMTS5), UA attenuated the degradation of the extracellular matrix (ECM) induced by IL-1ß. Mechanistically, UA was found to suppress the activation of PI3K/Akt/NF-κB pathways. In vivo, in a surgically induced mouse OA model, UA-induced protective effects in OA development could be detected. In summary, this research suggested that UA may be adopted as a new therapeutic agent for the treatment of OA.


Assuntos
Cumarínicos/administração & dosagem , Interleucina-1beta/imunologia , NF-kappa B/imunologia , Osteoartrite/tratamento farmacológico , Fosfatidilinositol 3-Quinases/imunologia , Proteínas Proto-Oncogênicas c-akt/imunologia , Animais , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/imunologia , Dinoprostona/imunologia , Humanos , Interleucina-1beta/genética , Interleucina-6/genética , Interleucina-6/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/genética , Óxido Nítrico/imunologia , Osteoartrite/genética , Osteoartrite/imunologia , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/efeitos dos fármacos
3.
Int Immunopharmacol ; 75: 105794, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31398659

RESUMO

Acute lung injury (ALI) and its severe manifestation of acute respiratory distress syndrome (ARDS) in human lung are induced by inflammatory cytokines and endogenous factors such as miRNAs. However, the role of miR-150 in lipopolysaccharide (LPS)-induced ALI is not clear. Here, we found miR-150 expression was significantly reduced in the serum of patients with ARDS, and negatively associated with the disease severity and 28-day survival of ARDS. In vivo, miR-150 decreased total cell and neutrophil counts, and production of inflammatory cytokines interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) as well as levels of total protein, albumin and IgM in the bronchoalveolar lavage (BAL) fluid in LPS-induced ALI mice. Meanwhile, miR-150 improved the 72 h survival rate of LPS-induced ALI mice. In-vitro assays demonstrated that miR-150 alleviated LPS-induced A549 cell apoptosis, autophagy, and release of inflammatory cytokines. Further, AKT3 was a direct target of miR-150. Silencing of AKT3 partially reversed LPS-induced A549 cell injury, and enhanced the protective effects of miR-150. In addition, miR-150 or si-AKT3 effectively inhibited the phosphorylation levels of c-Jun N-terminal kinase (JNK) and nuclear factor-κB (NF-κB) (p65 and IκBα). In conclusion, miR-150 alleviated LPS-induced acute lung injury via directly targeting AKT3 expression or regulating JNK and NF-κB pathways, which may be a promising therapeutic strategy to treat ALI/ARDS.


Assuntos
Lesão Pulmonar Aguda , MicroRNAs/imunologia , Proteínas Proto-Oncogênicas c-akt/imunologia , Síndrome do Desconforto Respiratório do Adulto , Células A549 , Lesão Pulmonar Aguda/sangue , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/imunologia , Adulto , Idoso , Animais , Feminino , Inativação Gênica , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/imunologia , Lipopolissacarídeos , Masculino , Camundongos Endogâmicos BALB C , MicroRNAs/sangue , Pessoa de Meia-Idade , NF-kappa B/imunologia , Proteínas Proto-Oncogênicas c-akt/genética , Síndrome do Desconforto Respiratório do Adulto/sangue , Síndrome do Desconforto Respiratório do Adulto/genética , Síndrome do Desconforto Respiratório do Adulto/imunologia
4.
Nat Cell Biol ; 21(8): 1027-1040, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31332347

RESUMO

Sensing cytosolic DNA through the cGAS-STING pathway constitutes a widespread innate immune mechanism to monitor cellular damage and microbial invasion. Evading this surveillance is crucial in tumorigenesis, but the process remains largely unexplored. Here, we show that the receptor tyrosine kinase HER2 (also known as ErbB-2 or Neu) potently inhibits cGAS-STING signalling and prevents cancer cells from producing cytokines, entering senescence and undergoing apoptosis. HER2, but not EGFR, associates strongly with STING and recruits AKT1 (also known as PKB) to directly phosphorylate TBK1, which prevents the TBK1-STING association and TBK1 K63-linked ubiquitination, thus attenuating STING signalling. Unexpectedly, we observed that DNA sensing robustly activates the HER2-AKT1 axis, resulting in negative feedback. Accordingly, genetic or pharmacological targeting of the HER2-AKT1 cascade augments damage-induced cellular senescence and apoptosis, and enhances STING-mediated antiviral and antitumour immunity. Thus, our findings reveal a critical function of the oncogenic pathway in innate immune regulation and unexpectedly connect HER2-AKT1 signalling to the surveillance of cellular damage and antitumour immunity.


Assuntos
Imunidade Inata/imunologia , Proteínas de Membrana/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor ErbB-2/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Proteínas de Membrana/imunologia , Fosforilação , Proteínas Proto-Oncogênicas c-akt/imunologia , Receptor ErbB-2/imunologia , Ubiquitinação/imunologia
5.
Int Immunopharmacol ; 74: 105665, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31254957

RESUMO

Neonatal necrotizing enterocolitis (NEC) is a life-threatening disease with severe inflammation and intestinal cell apoptosis. Tauroursodeoxycholic acid (TUDCA) is a recognized endoplasmic reticulum stress (ERS) inhibitor which can inhibit cell apoptosis. Recently, intestinal cell apoptosis has been demonstrated to be vital for the pathogenesis of NEC. The purpose of the present study was to investigate the potential of TUDCA in the treatment of NEC and the possible mechanisms in vivo and in vitro. Our results showed that TUDCA reduced mortality rates, prolonged survival times, significantly diminished intestinal damage, and inhibited intestinal inflammation in the mouse model of NEC. The protective effect of TUDCA on the NEC mouse model was realized through inhibiting the expression levels of ERS markers and inhibiting the apoptosis of intestinal cells. In addition, TUDCA increased the expression of phospho-Akt (p-Akt). Furthermore, we confirmed that TUDCA inhibited the apoptosis of intestinal cells by modulating the PERK-eIF2α ERS pathway and the Akt pathway in vitro studies. Besides, TUDCA effects were impaired by AKT specific inhibitor MK2206 in vitro studies. Therefore, these results indicated that TUDCA alleviated intestinal injury in a mouse model of NEC and inhibited ERS-mediated intestinal cell apoptosis by activating the Akt pathway.


Assuntos
Enterocolite Necrosante/tratamento farmacológico , Substâncias Protetoras/uso terapêutico , Ácido Tauroquenodesoxicólico/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Citocinas/sangue , Citocinas/genética , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Enterocolite Necrosante/imunologia , Enterocolite Necrosante/patologia , Enterócitos/efeitos dos fármacos , Enterócitos/patologia , Feminino , Intestinos/efeitos dos fármacos , Intestinos/patologia , Camundongos Endogâmicos C57BL , Substâncias Protetoras/farmacologia , Proteínas Proto-Oncogênicas c-akt/imunologia , Ácido Tauroquenodesoxicólico/farmacologia
6.
J Agric Food Chem ; 67(26): 7485-7495, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31180669

RESUMO

Ochratoxin A (OTA) is a mycotoxin produced by Aspergillus and Penicillium, contaminating in a wide variety of foods and feeds. Mycotoxins, including OTA, could cause immunosuppression in almost all previous studies in vivo. However, the vast majority of results in vitro showed that mycotoxins caused immunostimulation. Why the results of studies in vitro are contrary to studies in vivo is unknown. Our study aims to explore the underlying reason and mechanism of the paradoxical effect. In this study, porcine alveolar macrophage cell line 3D4/21 was chosen as an in vitro model and treated with 1.0 µg/mL OTA for different times. Some indexes, such as expression of inflammatory cytokines, migration, phagocytosis, macrophage polarization, autophagy-related proteins, and Akt1 phosphorylation, were detected. The results showed that pro-inflammatory cytokine expression, migration, and phagocytosis were increased, with macrophage polarization to the M1 phenotype at 24 h of OTA exposure. Surprisedly, anti-inflammatory cytokine expression was increased, cell phagocytosis and migration were decreased, and macrophage polarization was switched from M1 to M2 at 72 h of OTA exposure. Furthermore, we found that long-time exposure of OTA also suppressed autophagy, and the autophagy activator blocked the OTA-induced immunosuppression. Phosphorylation of Akt1 plays a positive role in autophagy inhibition. In conclusion, long-time instead of short-time exposure of OTA in vitro induced immunosuppression. The immunosuppression mechanism of OTA in vitro involved inhibition of autophagy through upregulating p-Akt1. Our results provide new insight into research on the mechanism of mycotoxin-induced immunosuppression in vitro.


Assuntos
Imunossupressores/toxicidade , Macrófagos Alveolares/efeitos dos fármacos , Ocratoxinas/toxicidade , Animais , Autofagia/efeitos dos fármacos , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Citocinas/genética , Citocinas/imunologia , Imunossupressores/administração & dosagem , Macrófagos Alveolares/imunologia , Ocratoxinas/administração & dosagem , Fagocitose/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/imunologia , Suínos , Fatores de Tempo
7.
Nat Commun ; 10(1): 2042, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053703

RESUMO

Metabolic pathways that regulate T-cell function show promise as therapeutic targets in diverse diseases. Here, we show that at rest cultured human effector memory and central memory CD4+ T-cells have elevated levels of glycolysis and oxidative phosphorylation (OXPHOS), in comparison to naïve T-cells. Despite having low resting metabolic rates, naive T-cells respond to TCR stimulation with robust and rapid increases in glycolysis and OXPHOS. This early metabolic switch requires Akt activity to support increased rates of glycolysis and STAT5 activity for amino acid biosynthesis and TCA cycle anaplerosis. Importantly, both STAT5 inhibition and disruption of TCA cycle anaplerosis are associated with reduced IL-2 production, demonstrating the functional importance of this early metabolic program. Our results define STAT5 as a key node in modulating the early metabolic program following activation in naive CD4+ T-cells and in turn provide greater understanding of how cellular metabolism shapes T-cell responses.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Fator de Transcrição STAT5/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Células Cultivadas , Ciclo do Ácido Cítrico/imunologia , Glicólise/imunologia , Voluntários Saudáveis , Humanos , Memória Imunológica , Ativação Linfocitária , Fosforilação Oxidativa , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-akt/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Fator de Transcrição STAT5/imunologia
8.
Int Immunopharmacol ; 72: 275-283, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31005037

RESUMO

Candida albicans infection-induced acute lung injury is one of the most prevalent diseases in immunosuppressive individual. Nevertheless, the mechanism by which Candida albicans induced acute lung injury remains unclear. The present study investigated the mechanism by which Candida albicans induced acute lung injury in mice. Mice were randomly divided into four groups and intratracheally injected with 60 µl Candida albicans (106 CFU) or normal saline. Half of the mice were sacrificed at 6 h after Candida albicans. The rest of the mice for survival test were observed until 7 d after Candida albicans. As expected, immunosuppression aggravated Candida albicans-induced acute lung injury and death in mice. Additionally, Candida albicans infection elevated mRNA levels of pro-inflammatory and chemokines in lungs and the levels of IL-6, IL-1ß and IL-17 in serum. Further study showed that Candida albicans promoted nuclear translocation of NF-κB p50 and p65 subunits in pulmonary epithelial cells and interstitial cells. Candida albicans induced pulmonary p38, ERK1/2 and Akt phosphorylation in normal and immunosuppressive mice. Moreover, Candida albicans infection activated pulmonary STAT3 signaling in normal and immunosuppressive mice. Overall, these results suggest that Candida albicans induced acute lung injury and death may be through activating several inflammatory signaling pathways.


Assuntos
Lesão Pulmonar Aguda/imunologia , Candidíase/imunologia , Imunossupressão , Lesão Pulmonar Aguda/etiologia , Animais , Candida albicans , Candidíase/complicações , Ciclofosfamida , Citocinas/sangue , Dexametasona , Inflamação/imunologia , Pulmão/imunologia , Masculino , Camundongos Endogâmicos BALB C , Proteínas Quinases Ativadas por Mitógeno/imunologia , NF-kappa B/imunologia , Proteínas Proto-Oncogênicas c-akt/imunologia , Fator de Transcrição STAT3/imunologia , Transdução de Sinais
9.
Int Immunopharmacol ; 72: 308-321, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31005041

RESUMO

Candida albicans is a commensal fungus that associates with human hosts. Under normal circumstances this interaction does not produce any severe life-threatening disease, as macrophages of the innate immune system will result in its clearance. However, disorders may arise in immunosuppressed individuals. To understand the bioactivity of Candida albicans cell wall polysaccharides, which represent an important component of its function, mannoprotein from this fungus was extracted, purified and analyzed. Mannoprotein with α-(1,2) and α-(1,6) linkages was investigated with use of HPLC and NMR. Co-incubation of mannoprotein with macrophages resulted in a mannoprotein with the potential to polarize macrophages to M1 and promote phagocytosis/microbial killing ability thus increasing the clearance of pathogens through Akt2. Moreover, mannoprotein within the cell wall promoted cell proliferation and inhibited apoptosis by activation of the Akt signaling pathway. Collectively, α-(1,6)(1,2)-mannoprotein, one of the five polysaccharides extracted from the cell wall of Candida albicans, demonstrates immune-enhancing effects by activation of the Akt signaling pathway. These findings provide important new insights into the biological effects of polysaccharides on macrophages. Such information can then serve as the foundation for the development of novel anti-fungal medications.


Assuntos
Candida albicans , Macrófagos/imunologia , Glicoproteínas de Membrana/imunologia , Proteínas Proto-Oncogênicas c-akt/imunologia , Animais , Apoptose , Linhagem Celular , Proliferação de Células , Parede Celular , Citocinas/genética , Citocinas/imunologia , Camundongos , Óxido Nítrico/imunologia , Fagocitose , Transdução de Sinais
10.
J Immunol ; 202(10): 2924-2944, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30988120

RESUMO

Clonal expansion of B cell chronic lymphocytic leukemia (B-CLL) occurs within lymphoid tissue pseudofollicles. IL-15, a stromal cell-associated cytokine found within spleens and lymph nodes of B-CLL patients, significantly boosts in vitro cycling of blood-derived B-CLL cells following CpG DNA priming. Both IL-15 and CpG DNA are elevated in microbe-draining lymphatic tissues, and unraveling the basis for IL-15-driven B-CLL growth could illuminate new therapeutic targets. Using CpG DNA-primed human B-CLL clones and approaches involving both immunofluorescent staining and pharmacologic inhibitors, we show that both PI3K/AKT and JAK/STAT5 pathways are activated and functionally important for IL-15→CD122/ɣc signaling in ODN-primed cells expressing activated pSTAT3. Furthermore, STAT5 activity must be sustained for continued cycling of CFSE-labeled B-CLL cells. Quantitative RT-PCR experiments with inhibitors of PI3K and STAT5 show that both contribute to IL-15-driven upregulation of mRNA for cyclin D2 and suppression of mRNA for DNA damage response mediators ATM, 53BP1, and MDC1. Furthermore, protein levels of these DNA damage response molecules are reduced by IL-15, as indicated by Western blotting and immunofluorescent staining. Bioinformatics analysis of ENCODE chromatin immunoprecipitation sequencing data from cell lines provides insight into possible mechanisms for STAT5-mediated repression. Finally, pharmacologic inhibitors of JAKs and STAT5 significantly curtailed B-CLL cycling when added either early or late in a growth response. We discuss how the IL-15-induced changes in gene expression lead to rapid cycling and possibly enhanced mutagenesis. STAT5 inhibitors might be an effective modality for blocking B-CLL growth in patients.


Assuntos
Ciclina D2/imunologia , Dano ao DNA/imunologia , Interleucina-15/imunologia , Leucemia Linfocítica Crônica de Células B/imunologia , Proteínas Proto-Oncogênicas c-akt/imunologia , Fator de Transcrição STAT5/imunologia , Transdução de Sinais/imunologia , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas Mutadas de Ataxia Telangiectasia/imunologia , Proteínas de Ciclo Celular/imunologia , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/imunologia , Regulação para Cima/imunologia
11.
Biomed Pharmacother ; 114: 108796, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30921706

RESUMO

B-cell activating factor from the tumor necrosis factor family (BAFF) has revealed its critical role in B cell proliferation and survival, as well as the pathogenesis of T-cell mediated autoimmune disease. However, the effect and molecular mechanisms of BAFF on T cell physiological function have not been fully elucidated. In this study it was seen that BAFF can promote the vitality of purified T cells, increase the proportion of CD3+CD4+, CD4+CD25+, CD4+CD154+, and CD4+CD69+ subgroups and reduce the proportion of CD4+CD62L+ subgroups. Negating BAFF activity with Atacicept (TACI-Fc) reverses vitality and activation of T cells. Furthermore, immunofluorescence detection revealed that BAFF promotes the expression of BAFF receptor (BAFF-R) and transmembrane activator and CAML interactor (TACI) in T cells. Flow cytometry displayed that BAFF/BAFF-R activates the PI3K-Akt signaling pathway while the application of PI3K inhibitor (wortmannin) illuminated that BAFF induces T cell vitality and activation through the PI3K-Akt signaling pathway. We conclude that BAFF is involved in not only the physiology of B cells, but also that of T cells. BAFF affects physiological T-cell activation through BAFF-R-mediated activation of the PI3K-Akt signaling pathway which mirrors one of the pathological mechanisms of T cell-mediated autoimmune diseases.


Assuntos
Fator Ativador de Células B/imunologia , Ativação Linfocitária/imunologia , Fosfatidilinositol 3-Quinases/imunologia , Proteínas Proto-Oncogênicas c-akt/imunologia , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Animais , Antígenos CD/imunologia , Receptor do Fator Ativador de Células B/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
12.
J Immunol ; 202(5): 1441-1452, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30692211

RESUMO

Akt isoforms play key roles in multiple cellular processes; however, the roles of Akt-1 and Akt-2 isoforms in the development of T cell-mediated autoimmunity are poorly defined. In this study, we showed that Akt1-/- mice develop ameliorated experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, whereas Akt2-/- mice develop exacerbated EAE, compared with wild-type mice. At the cellular level, Akt-1 appears to inhibit proliferation of thymus-derived regulatory T cells (tTregs), which facilitates Ag-specific Th1/Th17 responses. In a sharp contrast to Akt-1, Akt-2 potentiates tTreg proliferation in vitro and in vivo and suppresses Ag-specific Th1/Th17 responses. Furthermore, treating mice with established EAE with a specific Akt-1 inhibitor suppressed disease progression. Our data demonstrate that Akt-1 and Akt-2 differentially regulate the susceptibility of mice to EAE by controlling tTreg proliferation. Our data also indicate that targeting Akt-1 is a potential therapeutic approach for multiple sclerosis in humans.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Proteínas Proto-Oncogênicas c-akt/imunologia , Linfócitos T Reguladores/imunologia , Timo/imunologia , Animais , Proliferação de Células , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Proto-Oncogênicas c-akt/deficiência , Células Th1/imunologia , Células Th17/imunologia
13.
J Surg Res ; 236: 311-318, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30694771

RESUMO

BACKGROUND: Despite melatonin treatment diminishes inflammatory mediator production and improves organ injury after acute pancreatitis (AP), the mechanisms remain unknown. This study explores whether melatonin improves liver damage after AP through protein kinase B (Akt)-dependent peroxisome proliferator activated receptor (PPAR)-γ pathway. METHODS: Male Sprague-Dawley rats were subjected to cerulein-induced AP. Animals were treated with vehicle, melatonin, and melatonin plus phosphoinositide 3-kinase (PI3K)/Akt inhibitor wortmannin 1 h following the onset of AP. Various indicators and targeted proteins were checked at 8 h in the sham and AP groups. RESULTS: At 8 h after AP, serum alanine aminotransferase/aspartate aminotransferase levels, histopathology score of hepatic injury, liver myeloperoxidase activity, and proinflammatory cytokine production were significantly increased and liver tissue adenosine triphosphate concentration was lower compared with shams. AP resulted in a marked decrease in liver Akt phosphorylation and PPAR-γ expression in comparison with the shams (relative density, 0.442 ± 0.037 versus. 1.098 ± 0.069 and 0.390 ± 0.041 versus ± 1.080 0.063, respectively). Melatonin normalized AP-induced reduction in liver tissue Akt activation (1.098 ± 0.054) and PPAR-γ expression (1.145 ± 0.083) as well as attenuated the increase in liver injury markers and proinflammatory mediator levels, which was abolished by coadministration of wortmannin. CONCLUSIONS: Collectively, our findings suggest that melatonin improves AP-induced liver damage in rats, at least in part, via Akt-dependent PPAR-γ pathway.


Assuntos
Falência Hepática/prevenção & controle , Fígado/efeitos dos fármacos , Melatonina/administração & dosagem , Pancreatite/complicações , Transdução de Sinais/efeitos dos fármacos , Administração Intravenosa , Animais , Ceruletídeo/toxicidade , Modelos Animais de Doenças , Humanos , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Fígado/imunologia , Fígado/patologia , Falência Hepática/diagnóstico , Falência Hepática/imunologia , Testes de Função Hepática , Masculino , PPAR gama/imunologia , PPAR gama/metabolismo , Pancreatite/induzido quimicamente , Pancreatite/imunologia , Fosforilação/efeitos dos fármacos , Fosforilação/imunologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/imunologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/imunologia , Resultado do Tratamento , Wortmanina/administração & dosagem
14.
Mol Immunol ; 107: 10-20, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30639474

RESUMO

The present study was undertaken to determine whether extracellular calreticulin (CRT) participates in the regulation of ICAM-1in rheumatoid arthritis (RA) and further explore the potential mechanism. Our results showed that ICAM-1 and VCAM-1 levels were positively correlated with CRT levels in RA serum and synovial fluid, respectively. In RA synovial tissue, increased co-expressions of CRT and ICAM-1 in vascular endothelium and perivascular areas and elevated co-location of CRT and VCAM-1 localized predominantly to lining layer were observed compared to those in OA. In in vitro HUVECs model, enhanced ICAM-1expression and increased phosphorylation levels of Akt and eNOS were detected in the presence of CRT. Increased phosphorylated eNOS was significantly inhibited by a PI3K inhibitor LY294002 and elevated ICAM-1expression was partially blocked by the inhibitors of both PI3K and eNOS (L-NAME). It has been certified that the RNA-binding protein TTP targets AU-rich elements in the ICAM-1 3'-UTR and suppresses ICAM-1 expression. Knocking down TTP in HUVECs led to an increased induction of ICAM-1 by CRT. We have currently known that activation of p38 downstream kinase MK-2 leads to phosphorylation and inactivation of human TTP. The block of p38 MAPK/MK-2 signaling led to decreased protein expression and mRNA stability of TTP and ICAM-1. Furthermore, L-NAME and/or LY294002 pre-treated HUVECs manifested decreased p38 and MK-2 phosphorylation, which was accompanied by reduced TTP and ICAM-1 protein expression as well as decreased mRNA stability. Our results suggested that CRT could promote ICAM-1 expression in endothelial cells through PI3K/Akt/eNOS/p38 MAPK signaling mediated TTP accumulation, probably in an inactive form, which may provide a possible proinflammatory mechanism of CRT in RA.


Assuntos
Artrite Reumatoide/imunologia , Calreticulina/imunologia , Células Endoteliais da Veia Umbilical Humana/imunologia , Molécula 1 de Adesão Intercelular/imunologia , Sistema de Sinalização das MAP Quinases/imunologia , Tristetraprolina/imunologia , Regulação para Cima/imunologia , Artrite Reumatoide/patologia , Cromonas/farmacologia , Feminino , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Morfolinas/farmacologia , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Óxido Nítrico Sintase Tipo III/imunologia , Fosfatidilinositol 3-Quinases/imunologia , Proteínas Proto-Oncogênicas c-akt/imunologia , Membrana Sinovial/imunologia , Membrana Sinovial/patologia , Proteínas Quinases p38 Ativadas por Mitógeno/imunologia
15.
Cell Signal ; 53: 122-131, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30291869

RESUMO

Ambient particulate matter (PM) promotes the development and exacerbation of chronic respiratory diseases, including chronic obstructive pulmonary disease (COPD) and asthma, by increasing inflammation and mucus hypersecretion. However, the biological mechanisms underlying PM-induced airway inflammation and mucus hypersecretion remain unclear. Amphiregulin (AREG) is an important ligand for epidermal growth factor receptor (EGFR) and participates in the regulation of several biological functions. Here, the PM-exposed human bronchial epithelial cell (HBEC) model was used to define the role of AREG in PM-induced inflammation and mucus hypersecretion and its related signaling pathways. The expression of AREG was significantly increased in a dose-dependent manner in HBECs subjected to PM exposure. Moreover, PM could induce inflammation and mucus hypersecretion by upregulating the expression of IL-1α, IL-1ß, and Muc-5ac in HBECs. The EGFR, AKT, and ERK signaling pathways were also activated in a time- and dose-dependent manner. The AREG siRNA markedly attenuated PM-induced inflammation and mucus hypersecretion, and activation of the EGFR-AKT/ERK pathway. Exogenous AREG significantly increased the expression of IL-1α, IL-1ß, and Muc-5ac, and induced activation of the EGFR-AKT/ERK pathway in HBECs. Further, under PM exposure, exogenous AREG significantly potentiated PM-induced inflammation and mucus hypersecretion, and activation of the EGFR-AKT/ERK pathway. Tumor-necrosis factor-alpha converting enzyme (TACE) and EGFR specific inhibitor pretreatment showed that AREG was secreted by TACE-mediated cleavage to regulate PM-induced inflammation and mucus hypersecretion by binding to the EGFR. Moreover, according to the inhibitory effect of specific inhibitors of the class I PI3K isoforms, AKT and ERK, PM-induced inflammation and mucus hypersecretion was regulated by PI3Kα activation and its downstream AKT and ERK pathways. This study strongly suggests the adverse effect of AREG in PM-induced inflammation and mucus hypersecretion via the EGFR-PI3Kα-AKT/ERK pathway. These findings contribute to a better understanding of the biological mechanisms underlying exacerbation of chronic respiratory diseases induced by PM exposure.


Assuntos
Anfirregulina/imunologia , Material Particulado/efeitos adversos , Pneumonia/etiologia , Mucosa Respiratória/imunologia , Transdução de Sinais , Linhagem Celular , Receptores ErbB/imunologia , Humanos , Sistema de Sinalização das MAP Quinases , Fosfatidilinositol 3-Quinases/imunologia , Pneumonia/imunologia , Proteínas Proto-Oncogênicas c-akt/imunologia
16.
Curr Protein Pept Sci ; 20(1): 82-91, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30264678

RESUMO

Programmed death ligand 1 (PD-L1) is a cell membrane protein that binds to programmed cell death protein 1 (PD-1) on the effector T cells and transduces immunosuppressive signals. It is now clear that the expression of the PD-L1 protein on the tumor cell surface is critical for tumor cells to escape immunosuppression. At present, more attention is focused on the transcriptional regulation of PDL1 mRNA. However, PD-L1 protein is the functional unit involved in immunotherapy response. It is essential to deeply understand how this membrane protein is regulated post-transcriptionally in tumors and immune cells. In this review, we summarize the recent progress on the translation, modification and transport of PD-L1 protein.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica , Imunoterapia/métodos , Neoplasias/terapia , Receptor de Morte Celular Programada 1/imunologia , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Quinases Ciclina-Dependentes/genética , Quinases Ciclina-Dependentes/imunologia , Humanos , MicroRNAs/genética , MicroRNAs/imunologia , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/patologia , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/imunologia , Receptor de Morte Celular Programada 1/genética , Ligação Proteica , Biossíntese de Proteínas , Processamento de Proteína Pós-Traducional , Transporte Proteico , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/imunologia , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/imunologia
17.
J Clin Invest ; 129(3): 1047-1060, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30521495

RESUMO

ARHGEF1 is a RhoA-specific guanine nucleotide exchange factor expressed in hematopoietic cells. We used whole-exome sequencing to identify compound heterozygous mutations in ARHGEF1, resulting in the loss of ARHGEF1 protein expression in 2 primary antibody-deficient siblings presenting with recurrent severe respiratory tract infections and bronchiectasis. Both ARHGEF1-deficient patients showed an abnormal B cell immunophenotype, with a deficiency in marginal zone and memory B cells and an increased frequency of transitional B cells. Furthermore, the patients' blood contained immature myeloid cells. Analysis of a mediastinal lymph node from one patient highlighted the small size of the germinal centers and an abnormally high plasma cell content. On the molecular level, T and B lymphocytes from both patients displayed low RhoA activity and low steady-state actin polymerization (even after stimulation of lysophospholipid receptors). As a consequence of disturbed regulation of the RhoA downstream target Rho-associated kinase I/II (ROCK), the patients' lymphocytes failed to efficiently restrain AKT phosphorylation. Enforced ARHGEF1 expression or drug-induced activation of RhoA in the patients' cells corrected the impaired actin polymerization and AKT regulation. Our results indicate that ARHGEF1 activity in human lymphocytes is involved in controlling actin cytoskeleton dynamics, restraining PI3K/AKT signaling, and confining B lymphocytes and myelocytes within their dedicated functional environment.


Assuntos
Linfócitos B , Transdução de Sinais , Linfócitos B/imunologia , Linfócitos B/patologia , Feminino , Centro Germinativo/imunologia , Centro Germinativo/patologia , Humanos , Memória Imunológica/genética , Masculino , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/imunologia , /imunologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/imunologia , Fatores de Troca de Nucleotídeo Guanina Rho/deficiência , Fatores de Troca de Nucleotídeo Guanina Rho/imunologia , Irmãos , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Linfócitos T/patologia , Quinases Associadas a rho/genética , Quinases Associadas a rho/imunologia , Proteína rhoA de Ligação ao GTP/genética
18.
Immunol Cell Biol ; 97(5): 470-484, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30582666

RESUMO

Inappropriate functioning of the immune system is observed during sustained systemic inflammation, which might lead to immune deficiencies, autoimmune disorders and cancer. Primary lymphoid organs may progress to a deregulated proliferative state in response to inflammatory signals in order to intensify host defense mechanisms and exacerbate an inflammatory niche. Fluoxetine, a selective serotonin reuptake inhibitor, has recently been projected as an anti-inflammatory agent. This study had been designed to evaluate the potential novel role of fluoxetine in reversing inflammation-induced immune dysfunction. Lipopolysaccharide (LPS) administration in Swiss albino mice potentiated a systemic inflammatory response, along with increased proliferation of thymocytes and peripheral blood mononuclear cells, as evident from increased Ki-67 expression. The proliferative changes in the immune system were mainly associated with increased phosphorylation of PI3k, AKT and IκB along with elevated NFκB-p65 nuclear translocation. The Ki-67high thymocytes obtained from LPS administered mice demonstrated significantly low p53 nuclear activity, which was established to be mediated by NFκB through reduced nuclear translocation of p53 during LPS-induced proliferative conditions, thereby blocking p53-dependent apoptosis. Fluoxetine supplementation not only reversed the proinflammatory condition, but also induced selective apoptosis in the proliferation-dictated Ki-67high thymocytes possibly by modulating the hypothalamus-pituitary-adrenal axis and inducing glucocorticoid receptor activation and apoptosis in these proliferation-biased immune cells, authenticating a novel antiproliferative role of an established drug.


Assuntos
Apoptose/efeitos dos fármacos , Fluoxetina/farmacologia , Antígeno Ki-67/imunologia , Timócitos/imunologia , Animais , Apoptose/imunologia , Inflamação/induzido quimicamente , Inflamação/imunologia , Inflamação/patologia , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Fosfatidilinositol 3-Quinases/imunologia , Proteínas Proto-Oncogênicas c-akt/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Timócitos/patologia , Fator de Transcrição RelA/imunologia
19.
Vet Microbiol ; 227: 103-111, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30473339

RESUMO

Mammary epithelial cells (MECs) play an important role in debating Streptococcus uberis (S. uberis) infection. Toll like receptor (TLR) engagement leads to the recruitment of phosphatidylinositol 3 kinases (PI3K). In order to investigate the relationship of TLRs/NF-κB and PI3K/Akt/mTOR signaling pathways in S. uberis infection in MECs, we challenged MECs (EpH4-Ev) with S. uberis 0140 J and quantified the adaptor molecules in these two signaling pathways, as-well-as proinflammatory cytokines and cell damage. The results indicate that the host's responses to virulent S. uberis infection are complex. In MECs, both TLR2 and TLR4 are detecting S. uberis infection and TLR2 is the principal receptor. The role of the PI3K/Akt/mTOR pathway in inflammatory regulation is independent of the activation of TLRs/NF-κB. Cross-talk between PI3K/Akt/mTOR and TLRs/NF-κB signaling pathways promote inflammation. This study increases our understanding of the molecular defense mechanisms of MECs in S. uberis mastitis, and provides theoretical support for the prevention of this disease.


Assuntos
Glândulas Mamárias Animais/microbiologia , NF-kappa B/imunologia , Fosfatidilinositol 3-Quinases/imunologia , Proteínas Proto-Oncogênicas c-akt/imunologia , Streptococcus/imunologia , Serina-Treonina Quinases TOR/imunologia , Receptores Toll-Like/imunologia , Animais , Bovinos , Células Epiteliais/imunologia , Células Epiteliais/microbiologia , Feminino , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Inflamação/microbiologia , Glândulas Mamárias Animais/citologia , Glândulas Mamárias Animais/imunologia , Mastite/imunologia , Mastite/microbiologia , NF-kappa B/genética , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/imunologia , Streptococcus/patogenicidade , Serina-Treonina Quinases TOR/genética , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/imunologia , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/imunologia , Receptores Toll-Like/genética
20.
Mol Immunol ; 104: 100-107, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30448607

RESUMO

Epidemiological studies suggested that periodontitis is a risk factor for pregnancy complications including preterm birth. Porphyromonas gingivalis, a vital periodontal pathogen found in amniotic fluid and intact membranes of women who deliver preterm low birth weight infants, is thought to contribute to preterm labor. However, molecular and cellular interactions between P. gingivalis and placental cells are not clear. In this study, we investigated the effect of P. gingivalis on human extravillous trophoblasts and observed that it triggered apoptosis and inflammation and that Akt was activated in this process. In addition, when Akt activation was inhibited, apoptosis and inflammation was significantly increased. Thus, P. gingivalis infection contributes to preterm low birth weight infants by triggering excessive inflammation and increasing apoptosis in trophoblasts and that the Phosphatidylinositol 3-Kinase/Akt signaling pathway is involved in the regulation of Pg-induced apoptosis and inflammation.


Assuntos
Apoptose/imunologia , Infecções por Bacteroidaceae/imunologia , Fosfatidilinositol 3-Quinases/imunologia , Porphyromonas gingivalis/imunologia , Proteínas Proto-Oncogênicas c-akt/imunologia , Transdução de Sinais/imunologia , Trofoblastos/imunologia , Infecções por Bacteroidaceae/patologia , Linhagem Celular , Humanos , Inflamação/imunologia , Inflamação/microbiologia , Inflamação/patologia , Trofoblastos/microbiologia , Trofoblastos/patologia
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