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1.
Leukemia ; 2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34635784

RESUMO

FZR1 has been implicated as a master regulator of the cell cycle and quiescence, but its roles and molecular mechanisms in the pathogenesis of severe aplastic anemia (SAA) are unclear. Here, we report that FZR1 is downregulated in SAA HSCs compared with healthy control and is associated with decreased quiescence of HSC. Haploinsufficiency of Fzr1 shows impaired quiescence and self-renewal ability of HSC in two Fzr1 heterozygous knockout mouse models. Mechanistically, FZR1 insufficiency inhibits the ubiquitination of RUNX1 protein at lysine 125, leading to the accumulation of RUNX1 protein, which disturbs the quiescence of HSCs in SAA patients. Moreover, downregulation of Runx1 reversed the loss of quiescence and impaired long-term self-renew ability in Fzr1+/- HSCs in vivo and impaired repopulation capacity in BM from SAA patients in vitro. Our findings, therefore, raise the possibility of a decisive role of the FZR1-RUNX1 pathway in the pathogenesis of SAA via deregulation of HSC quiescence.

2.
Artigo em Inglês | MEDLINE | ID: mdl-34636127

RESUMO

Multiple resonance (MR) emitters are promising for highly efficient organic light-emitting diodes (OLEDs) with narrowband emission; however, they still face intractable challenges with concentration-caused emission quenching, exciton annihilation, and spectral broadening. In this study, sterically wrapped MR dopants with a fluorescent MR core sandwiched by bulk substituents were developed to address the intractable challenges by reducing intermolecular interactions. Consequently, high photo-luminance quantum yields of ≥90% and small full width at half maximums (FWHMs) of ≤25 nm over a wide range of dopant concentrations (1 wt%-20 wt%) were recorded. In addition, we demonstrated that the sandwiched MR emitter can effectively suppress Dexter interaction when doped in a thermally activated delayed fluorescence sensitizer, eliminating exciton loss through dopant triplet. Within the above dopant concentration range, the optimal emitter realizes remarkably high maximum external quantum efficiencies of 36.3%-37.2%, identical small FWHMs of 24 nm, and alleviated efficiency roll-offs in OLEDs.

3.
Metabolism ; 120: 154800, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34051224

RESUMO

OBJECTIVE: Apolipoprotein C-III (Apoc3) is a key component of triglyceride-rich lipoproteins (TRL). The Apoc3-transgenic mice are characterized by high levels of plasma triglyceride and free fatty acids (FFAs). Apoc3 stimulates human monocytes via activation of the NLRP3 inflammasome. Considering the NK cell downregulation in obese individuals and the possible stimulatory-effects of macrophages, variations of NK cell functions and underlying mechanisms were investigated in mice with Apoc3-induced hyperlipidemia. METHODS: Variations of activities and glycolipid metabolism in NK cells of the Apoc3-transgenic mice with hyperlipidemia were detected. Molecular mechanisms of lipid-induced metabolic-reprogramming in NK cells were analyzed based on the transcriptome sequencing. Finally, effects of DCs in mice with hyperlipidemia on NK cell functions were determined. RESULTS: Impaired number and function of NK cells in Apoc3TG mice was involved with the increased fatty acid oxidation and decreased glycolysis. Increased uptake of FFAs in Apoc3TG-NK cells contributed to the peroxisome proliferator-activated receptor (PPAR) activation and the downstream PTEN-AKT-mTOR/FOXO1 signaling pathway. Inhibition of PPAR or CPT1α only partly reversed the IFN-γ production of Apoc3TG-NK cells, but completely restored IFN-γ secretion by palmitic acid-treated NK cells ex vivo, indicating that other factors contributed to the Apoc3TG-NK cell downregulation. Meanwhile, Apoc3TG-DCs, which contained more lipids in the cytoplasm, depended on reactive oxygen species (ROS) to increase the expressions PD-L1, TGF-ß1, and NKG2D ligands and suppress NK cell activities. DCs of the Apoc3TG-CD36-/+ hybrid mice with less intracellular lipids and ROS production could not inhibit NK cells, indicating that intracellular FFAs promoted the immune-modulatory function of DCs. CONCLUSIONS: The downregulation of NK cell activities in individuals with Apoc3-induced hyperlipidemia was due to the increased fatty acid oxidation in NK cells and the bystander suppression caused by lipid-laden DCs. The dual recovery function of NK cells and DCs would improve the prognosis of patients with metabolic syndrome.


Assuntos
Células Dendríticas/fisiologia , Hiperlipidemias/imunologia , Células Matadoras Naturais/fisiologia , Animais , Apolipoproteína C-III/genética , Efeito Espectador/genética , Comunicação Celular/imunologia , Reprogramação Celular/genética , Células Dendríticas/metabolismo , Regulação para Baixo , Hiperlipidemias/genética , Hiperlipidemias/metabolismo , Metabolismo dos Lipídeos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Camundongos Transgênicos , Triglicerídeos/metabolismo
4.
Am J Cancer Res ; 11(4): 1540-1556, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33948372

RESUMO

MiR-15a/16 is a member of the miRNA cluster that exhibits tumor suppression and immune modulation via targeting multiple genes. Decreased miR-15a/16 expression is involved in many cancer cells. Here, miR-16 had decreased expression in NK1.1-CD4+NKG2D+ T cells and bound with the 3'-UTR of NKG2D gene. MiR-15a/16-deficient mice had many CD4+NKG2D+ T cells, which produced TGF-ß1 and IL-10 and inhibited the IFN-γ production of CD8+ T cells. Adoptive transfer of NK1.1-CD4+NKG2D+ T cells from miR-15a/16-deficient mice promoted tumor growth in vivo. However, no changes for NK1.1-CD4+NKG2D+ T cells were found in the miR-15a/16-transgenic mice. Although the miR-15a/16 transgenic mice transplanted with B16BL6 or MC38 cells exhibited rapid growth, these tumor-bearing mice did not show changes in NK1.1-CD4+NKG2D+ T cell distributions in either spleens or tumors. When NK1.1-CD4+ T cells were stimulated by α-CD3/sRAE-1 ex vivo, the NKG2D expression was difficult to induce in the T cells of miR-15a/16-transgenic mice. Finally, increased frequencies of regulatory CD4+NKG2D+ T cells with low miR-16 levels were observed in patients with late-stage colorectal cancer (Duke's C, D). Thus, miR-16 modulates NK1.1-CD4+NKG2D+ T cell functions via targeting NKG2D. Low miR-16 expression in CD4+ T cells induces the regulatory CD4+NKG2D+ T subpopulation, which promotes tumor evasion via the secretion of immune-suppressive molecules.

5.
Biochem Biophys Res Commun ; 554: 114-122, 2021 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-33784506

RESUMO

The miR-15a/16 gene cluster is located in human chromosome 13 (13q14.3) and mouse chromosome 14 (14qC3). These genes are involved in cancer development and immune regulation. Our group has previously verified the binding of the 3'-untranslated region of NKG2D gene by miR-16 through dual-luciferase reporter assay. Herein, we found that miR-16 overexpression inhibited the NKG2D expression of CD8+ T cells, and that CD8+ NKG2D+ T cell frequency increased in miR-15/16-/- mice. CD8+ NKG2D+ T cells derived of miR-15/16-/- mice displayed activatory phenotype with enhanced IFN-γ production and cytotoxicity. The transfection of lentivirus containing antago-miR-16 sequences enhanced the NKG2D expression level of CD8+ T cells. However, no significant differences in CD8+ NKG2D+ T cell frequencies existed between wild-type and miR-15/16-transgenic mice because NKG2D was not expressed on the rest CD8+ T cells. When CD8+ T cells of miR-15/16-transgenic mice were treated with IL-2 in vitro, the magnitude of NKG2D expression and activation of CD8+ T cells was lower than that of wild-type mice. miR-15/16-/- mice showed that the exacerbation of colitis induced by dextran sulfate sodium (DSS) with more CD8+ T cells accumulated in inflamed colons, whereas miR-15/16-transgenic mice ameliorated DSS-induced colitis with less infiltration of CD8+ T cells. When NKG2D+ cells were depleted with NKG2D antibody in miR-15/16-/- mice, the aggravated colitis disappeared. All these results demonstrated that NKG2D could be upregulated by decreased miR-16 in CD8+ T cells to mediate inflammation. Thus, gene therapy based on the overexpression of miR-16 in CD8+ T cells can be used for patients with inflammatory diseases.


Assuntos
Linfócitos T CD8-Positivos/metabolismo , Colite/metabolismo , MicroRNAs/metabolismo , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Animais , Colite/induzido quimicamente , Colite/genética , Colite/patologia , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/administração & dosagem , MicroRNAs/genética , Subfamília K de Receptores Semelhantes a Lectina de Células NK/genética , Regulação para Cima
6.
Cell Signal ; 76: 109800, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33011290

RESUMO

NK1.1- CD4+ NKG2D+ T cells are a subpopulation of regulatory T cells that downregulate the functions of CD4+ T, CD8+ T, natural killer (NK) cells, and macrophages through TGF-ß1 production. Early growth response genes 2 (Egr2) and 3 (Egr3) maintain immune homeostasis by modulating T lymphocyte development, inhibiting effector T cell function, and promoting the induction of regulatory T cells. Whether Egr2 and Egr3 directly regulate TGF-ß1 transcription in NK1.1- CD4+ NKG2D+ T cells remains elusive. The expression levels of Egr2 and Egr3 were higher in NK1.1- CD4+ NKG2D+ T cells than in NK1.1- CD4+ NKG2D- T cells. Egr2 and Egr3 expression were remarkably increased after stimulating NK1.1- CD4+ NKG2D+ T cells with sRAE or α-CD3/sRAE. The ectopic expression of Egr2 or Egr3 resulted in the enhancement of TGF-ß1 expression, while knockdown of Egr2 or Egr3 led to the decreased expression of TGF-ß1 in NK1.1- CD4+ NKG2D+ T cells. Egr2 and Egr3 directly bound with the TGF-ß1 promoter as demonstrated by the electrophoretic mobility shift assay and dual-luciferase gene reporter assay. Furthermore, the Egr2 and Egr3 expression of NK1.1- CD4+ NKG2D+ T cells could be induced by the AP-1 and NF-κB transcriptional factors, but had no involvement with the activation of NF-AT and STAT3. In conclusion, Egr2 and Egr3 induced by AP-1 and NF-κB directly initiate TGF-ß1 transcription in NK1.1- CD4+ NKG2D+ T cells. This study indicates that manipulating Egr2 and Egr3 expression would potentiate or alleviate the regulatory function of NK1.1- CD4+ NKG2D+ T cells and this strategy could be used in the therapy for patients with autoimmune diseases or tumor.

8.
Am J Cancer Res ; 10(2): 595-609, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32195030

RESUMO

Angiopoietin-like 4 (ANGPLT4) regulates lipid metabolism by inhibiting lipoprotein lipase. Abnormal ANGTPL4 levels are associated with metabolic syndrome, atherosclerosis, inflammation, and cancer. We show here that ANGPTL4-deficient mice have abnormally large numbers of macrophages in the spleen, and that these macrophages produce large amounts of TNF-α, CD86, and inducible nitric oxide synthase. However, recombinant ANGPTL4 protein did not inhibit macrophage function ex vivo. Glycolysis and fatty-acid synthesis were upregulated in ANGPTL4-/- macrophages, whereas fatty-acid oxidation was decreased. Elevated levels of free fatty acids in the cytoplasm of ANGPTL4-/- macrophages were confirmed. ANGPTL4-/- macrophages also displayed endoplasmic reticulum (ER) stress after stimulation with LPS. Protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling was activated, but no major change in liver kinase B1 (LKB1)/adenosine 5'-monophosphate (AMP)- activated protein kinase (AMPK) phosphorylation was observed in ANGPTL4-/- macrophages. The modulation of fatty-acid metabolism prevented ER stress and the expression of inflammatory molecules, but the activation of ANGPTL4-/- macrophages was not restored by the inhibition of glycolysis. Thus, ANGPTL4 deficiency in macrophages results in ER stress due to the cell-intrinsic reprogramming of fatty-acid metabolism. Intracellular ANGPLT4 expression could thus be manipulated to modulate macrophage function.

9.
Int Immunopharmacol ; 81: 106143, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32062080

RESUMO

Astilbin is a potential agent for autoimmune and inflammatory diseases and has a protective effect in mice with DSS-induced colitis. NK1.1- CD4+ NKG2D+ T cells are a subpopulation of regulatory T cells that produce TGF-ß1 and IL-10. Whether astilbin directly promotes the induction of NK1.1- CD4+ NKG2D+ T cells and whether these astilbin-stimulated T cells exert an immune-regulatory role remain unclear. Here, we show that astilbin efficiently induces the production of NK1.1- CD4+ NKG2D+ T cells with high expressions of TGF-ß1, IL-10, CCR6, and CCR9 in a dose-dependent manner ex vivo. These regulatory T cells also substantially inhibit the activities of CD8+ T cells and macrophages. Intraperitoneal injection of astilbin ameliorates the severity of colitis with an increase in the frequency of NK1.1- CD4+ NKG2D+ T cells in the colon tissue of DSS-treated mice. Moreover, adoptive transfer of NK1.1- CD4+ NKG2D+ T cells induced by astilbin remarkably protects against the onset of DSS-induced colitis. Finally, the PI3K, STAT3, and MAPK signaling pathways are involved in the induction of NK1.1- CD4+ NKG2D+ T cells by astilbin. Taken together, our study elucidates a new immune-regulatory mechanism of astilbin by inducing the regulatory NK1.1- CD4+ NKG2D+ T cells and indicates a potential clinical use of astilbin for patients with inflammatory bowel diseases.


Assuntos
Anti-Inflamatórios/uso terapêutico , Colite/tratamento farmacológico , Flavonóis/uso terapêutico , Linfócitos T Reguladores/imunologia , Animais , Colite/induzido quimicamente , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Humanos , Injeções Intraperitoneais , Interleucina-10/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Dodecilsulfato de Sódio , Fator de Crescimento Transformador beta1/metabolismo
10.
Iran J Pharm Res ; 18(2): 803-811, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31531063

RESUMO

The objective of this study is to investigate the anti-tumor effect of Ginkgo biloba exocarp extracts (GBEE) on B16 melanoma bearing mice and its related molecular mechanisms. The B16-F10 melanoma solid tumor model was established in C57BL/6J mice. The tumor-bearing mice were treated with GBEE (50, 100, 200 mg/kg), taking cis-Dichlorodiamineplatinum (Ⅱ) (DDP, 3 mg/kg) as positive control and normal saline (NS) as model control. After 17 days of administration, the transplanted tumors was stripped and weighed, and the inhibition rate was calculated. Quantitative Reverse Transcription Polymerase chain reaction (qRT-PCR), Western Blot and immunohistochemistry were applied to detect mRNA and protein levels of related factors in B16 transplanted tumor tissues. The results indicated that GBEE (50, 100, 200 mg/kg) inhibited the growth of B16 transplanted solid tumor in C57BL/6J mice. Meanwhile, it inhibited the expression of CD34 and reduced microvessel density (MVD) in a dose-dependent manner. Moreover, GBEE dose-dependently down-regulated the mRNA and protein levels of hypoxia inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), and vascular endothelial growth factor receptor 2 (VEGFR2). The phosphoinositide 3-kinase (PI3K) and protein kinase B (Akt) proteins were not changed obviously, but the protein levels of p-PI3K and p-Akt were down-regulated. Overall, the inhibitory effect of GBEE on the growth of B16 melanoma transplant tumor in mice is related to inhibiting angiogenesis, and the mechanism involves the regulation of PI3K/Akt/ HIF-lα/VEGF signaling pathway.

11.
Am J Transl Res ; 11(12): 7385-7397, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31934286

RESUMO

OBJECTIVE: Post-infectious irritable bowel syndrome (PI-IBS) is a common functional gastrointestinal (GI) disorder that occurs after acute GI infection. Recent studies showed that microRNAs were involved in the occurrence and development of IBS. Here, we elaborated the role of miR-510 in the occurrence of PI-IBS and analyzed its mechanism. METHODS: We detected the expressions of miR-510 and PRDX1 in colonic mucosal tissues by qRT-PCR, Western blot and immunohistochemistry. Furthermore, we transfected Caco-2 cells with miR-510 mimic, anti-miR-510, si-PRDX1, and control, then evaluated the cell viability and apoptosis by CCK8 assay and flow cytometry, assessed expression levels of PRDX1 by qRT-PCR and Western blot analysis, and pro-inflammatory cytokines by qRT-PCR and ELISA. RESULTS: MiR-510 expression was downregulated and negatively correlated with TNF-α, whereas PRDX1 expression was upregulated in PI-IBS colonic mucosal tissues. LPS at concentrations of 5 and 10 µg/ml can significantly induce inflammatory injury in Caco-2 cells. MiR-510 overexpression aggravated the injury induced by LPS, as reflected by increased cell viability, decreased apoptosis, and less production of pro-inflammatory cytokines. miR-510 mimic transfection in cells significantly suppressed the mRNA and protein expression levels of PRDX1. Furthermore, the inflammatory injury induced by LPS was exacerbated by upregulating PRDX1 expression when miR-510 was knocked down. CONCLUSION: MiR-510 downregulation in intestinal tissue might contribute to PI-IBS via targeting PRDX1. The results of this study will not only enrich the pathogenesis of PI-IBS but also make us understand the biological activity of miR-510 and provide important experimental basis for PI-IBS clinical treatment targeting miR-510.

12.
J Cell Mol Med ; 23(2): 1343-1353, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30467955

RESUMO

IL-10-producing B cells (B10) are associated with autoimmune diseases, infection and tumours. MiR-15a/16 as a tumour-suppressive gene is down-regulated in several tumours, such as chronic lymphocytic leukaemia, pituitary adenomas and prostate carcinoma. Here, increased frequency of IL-10-producing CD19+ Tim-1+ cells was seen in both aged miR-15a/16-/- mice (15-18 months) with the onset of B cell leukaemia and young knockout mice (8-12 weeks) transplanted with hepatic cancer cells. CD19+ Tim-1+ cells down-regulated the function of effector CD4+ CD25low T cells ex vivo dependent on IL-10 production, and adoptive transfer of CD19+ Tim-1+ cells promoted tumour growth in mice. IL-10 production by CD19+ Tim-1+ cells was involved with the STAT3 activation. Bioinformatics analysis shows that miR-16 targets the 3'-untranslating region (3'-UTR) of STAT3 mRNA. Overexpression of miR-16 in CD19+ Tim-1+ cells inhibited STAT3 transcription and its protein expression. Thus, the loss of miR-15a/16 promoted induction of regulatory CD19+ Tim-1+ cells in tumour microenvironment. These results confirmed that miR-15a/16 could be used in tumour therapy due to its inhibition of tumour and regulatory B cells.


Assuntos
Interleucina-10/metabolismo , Leucemia de Células B/patologia , Neoplasias Hepáticas Experimentais/patologia , MicroRNAs/fisiologia , Microambiente Tumoral , Animais , Antígenos CD19/metabolismo , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Regulação Neoplásica da Expressão Gênica , Receptor Celular 1 do Vírus da Hepatite A/metabolismo , Interleucina-10/genética , Leucemia de Células B/genética , Leucemia de Células B/imunologia , Leucemia de Células B/metabolismo , Neoplasias Hepáticas Experimentais/imunologia , Neoplasias Hepáticas Experimentais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Células Tumorais Cultivadas
13.
Scand J Immunol ; 88(3): e12703, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30047999

RESUMO

M1 macrophages are involved in inflammation by producing proinflammatory cytokines, whereas M2 macrophages are associated with wound healing and tissue regeneration by producing anti-inflammatory cytokines. MicroRNAs are involved in macrophage polarization. To evaluate whether miR-15a/16 is involved in macrophage polarization under tumour or inflammation microenvironments, we observed the growth of transplanted hepatic cancer (H22) cells or severity of dextran sulphate sodium (DSS)-induced colitis in 8-week-old miR-15a/16 knockout (KO) mice. Compared with littermate controls, the miR-15a/16-/- mice exhibited retarded tumour growth and increased sensibility to DSS-induced colitis. Meanwhile, the M1 cell frequencies were higher in tumour tissues and inflamed colons of KO mice than of littermate controls. Macrophages with miR-15a/16 deletion revealed an enhanced NF-κB transcription under the physiological state and lipopolysaccharide (LPS) or high mobility group box 1 (HMGB1) stimulation. STAT3 expression was also significantly increased in miR-15a/16-/- macrophages under LPS or HMGB1 stimulation. The polarization of M1 macrophages can be associated with the coactivation of NF-κB and STAT3. Results indicated that miR-15a/16 deficiency in the macrophages directs M1 polarization for tumour suppression and proinflammation. Thus, miR-15a/16 deletion in macrophages holds a distinct biological significance from that of the microRNA deficiency in tumour cells.


Assuntos
Colite/imunologia , Inflamação/imunologia , Neoplasias Hepáticas/imunologia , Macrófagos/fisiologia , MicroRNAs/genética , Neoplasias Experimentais/imunologia , Animais , Diferenciação Celular , Linhagem Celular Tumoral , Colite/induzido quimicamente , Colite/genética , Citocinas/metabolismo , Sulfato de Dextrana , Modelos Animais de Doenças , Humanos , Inflamação/genética , Neoplasias Hepáticas/genética , Camundongos , Camundongos Knockout , NF-kappa B/metabolismo , Neoplasias Experimentais/genética , Fator de Transcrição STAT3/metabolismo , Células Th1/imunologia , Carga Tumoral
14.
Cancer Immunol Immunother ; 67(7): 1159-1173, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29802426

RESUMO

Regulatory T cells play critical roles in self-tolerance and tumor evasion. CD4+NKG2D+ cells with regulatory activity are present in patients with NKG2DL+ tumors and juvenile systemic lupus erythematosus. We previously showed that TGF-ß-producing CD4+NKG2D+ T cells are present in pCD86-Rae-1ε transgenic mice. Here, we performed both ex vivo and in vivo studies on pCD86-Rae-1ε transgenic mice and an MC38 tumor-bearing mouse model and show that NK1.1-CD4+NKG2D+ T cells have regulatory activity in pCD86-Rae-1ε transgenic mice. Furthermore, this T-cell subset was induced in mice transplanted with NKG2DL+ tumor cells and produced TGF-ß and FasL, and secreted low amounts of IFN-γ. This T-cell subset downregulated the function of effector T cells and dendritic cells, which were abolished by anti-TGF-ß antibody. In vivo, adoptive transfer of NK1.1-CD4+NKG2D+ T cells promoted TGF-ß-dependent tumor growth in mice. We further found that ex vivo induction of NK1.1-CD4+NKG2D+ T cells was dependent on both anti-CD3 and NKG2DL stimulation. Furthermore, regulatory NK1.1-CD4+NKG2D+ T cells did not express Foxp3 or CD25 and expressed intermediate levels of T-bet. Western-blotting showed that STAT3 signaling was activated in NK1.1-CD4+NKG2D+ T cells of MC38 tumor-bearing and pCD86-Rae-1ε transgenic mice. In conclusion, we describe a regulatory NK1.1-CD4+NKG2D+ T-cell population, different from other regulatory T cells and abnormally elevated in pCD86-Rae-1ε transgenic and MC38 tumor-bearing mice.


Assuntos
Adenocarcinoma/prevenção & controle , Antígenos Ly/imunologia , Antígenos CD4/imunologia , Neoplasias do Colo/prevenção & controle , Subfamília B de Receptores Semelhantes a Lectina de Células NK/imunologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Adenocarcinoma/imunologia , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Animais , Antígenos Ly/metabolismo , Antígenos CD4/metabolismo , Neoplasias do Colo/imunologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Subfamília B de Receptores Semelhantes a Lectina de Células NK/metabolismo , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/metabolismo
15.
Am J Cancer Res ; 8(3): 489-501, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29637003

RESUMO

NK1.1-CD4+NKG2D+ cells exert their immune-regulatory function in tumor as an unconventional regulatory T cell subset through the production of TGF-ß1; however, the molecular mechanisms involving with the activation of nuclear factors for TGF-ß1 transcription remain unclear. Here we determined that the PI3K-p85α subunit was specifically activated in NK1.1-CD4+NKG2D+ cells following an 8-hour stimulation by sRAE-1 or α-CD3/sRAE-1, subsequently leading to the activation of PI3K-p110, Akt, and JNK. On the contrary, α-CD3/α-CD28 stimulation did not induce the activation of PI3K-p85 and JNK. Consequently, activation of the nuclear transcription factor AP-1 as a consequence of JNK activation regulated TGF-ß1 expression in NK1.1-CD4+NKG2D+ cells. Furthermore, activation of NF-κB in NK1.1-CD4+NKG2D+ cells resulted from both protein kinase C activation downstream of TCR/CD3 signaling and PI3K activation induced by NKG2D engagement. The STAT3-Y705 phosphorylation, as activated by PI3K, under stimulations of the sRAE-1 or α-CD3/sRAE-1 also contributed to the TGF-ß1 expression in NK1.1-CD4+NKG2D+ cells. Moreover, ChIP assay confirmed that STAT3 was capable of binding with the promoter regions of TGF-ß1. In conclusion, our data showed that the TGF-ß1 transcription in NK1.1-CD4+NKG2D+ cells induced by sRAE-1 or α-CD3/sRAE-1 was involved with the AP-1, NF-κB, and STAT3 signaling pathways; therefore, regulation of AP-1, NF-κB, and STAT3 activation may play important roles in the development and function of NK1.1-CD4+NKG2D+ cells.

16.
Cent Eur J Immunol ; 42(3): 223-230, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29204085

RESUMO

Inappropriate activation of toll-like receptor 3 (TLR3) has been implicated in the pathogenesis of autoimmune diseases, so the negative regulation of TLR3-triggered immune response has received increasing attention. Nonpathogenic immune complex (IC) has been used as treatment for many inflammatory and autoimmune diseases. However, the role of IC in the regulation of TLR3-triggered immune responses and the underlying mechanisms need to be investigated. In this study we demonstrate that IC or intravenous immunoglobulin (Ig) stimulation of B cells attenuates polyinosinic:polycytidylic acid (poly I:C)-induced CD40 expression; IC, but not Ig, can significantly inhibit poly I:C-induced pro-inflammatory tumour necrosis factor α (TNF-α) production by B cells. Moreover, IC/Ig stimulation does not alter the expression of TLR3 in B cells. Further experiments suggest that receptor for the Fc portion of IgGIIb (FcγRIIb) is involved in the suppressive effect of IC on TLR3-mediated TNF-α production, but not CD40 expression. Thus, we provide a new means of negative regulation of TLR3-triggered immune responses in B cells via FcγRIIb, and we provide a new mechanistic explanation of the therapeutic effect of nonpathogenic IC on inflammatory or autoimmune diseases.

17.
Mol Med Rep ; 16(4): 5693-5698, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28849025

RESUMO

Toll­like receptors (TLRs) serve a vital role in activating the innate immune system by sensing conserved microbial products. Fc γ receptor IIb (FcγRIIb), the inhibitory Fc receptor, exerts its immune regulatory functions by binding to the immunoglobulin G Fc domain. Although the individual roles of TLRs and FcγRIIb have been studied intensively, the cross­talk between FcγRIIb and TLR4 on B cells remains unknown. The present study demonstrated that FcγRIIb ligation by the immune complex (IC) attenuated the TLR4­triggered nuclear factor (NF)­κΒ activation, and decreased the release of interleukin (IL)­6 from B cells, via enhancing LYN proto­oncogene (Lyn) phosphorylation. In addition, IC treatment protected mice from lethal endotoxic shock. Accordingly, IC decreased the LPS­induced serum levels of IL­6, as well as intracellular IL­6 production in B cells in vivo. However, these protective and inhibitory effects of IC were not observed in FcγRIIb­/­ mice. In conclusion, the present data demonstrated that FcγRIIb inhibited TLR4 signaling in B cells by activating Lyn phosphorylation and by inhibiting NF­κΒ signaling. The present study elucidated the mechanism associated with the TLR4 and FcγRIIb cross­talk in B cells.


Assuntos
Linfócitos B/imunologia , Linfócitos B/metabolismo , NF-kappa B/metabolismo , Receptores de IgG/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Complexo Antígeno-Anticorpo/efeitos adversos , Complexo Antígeno-Anticorpo/imunologia , Citocinas/metabolismo , Mediadores da Inflamação , Lipopolissacarídeos/efeitos adversos , Lipopolissacarídeos/imunologia , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Knockout , Receptores de IgG/genética , Choque Séptico/etiologia , Choque Séptico/metabolismo , Choque Séptico/patologia , Transdução de Sinais
18.
Int J Mol Med ; 40(4): 1125-1133, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28791345

RESUMO

Neuro-oncological ventral antigen 1 (Nova1) is a well known brain-specific splicing factor. Several studies have identified Nova1 as a regulatory protein at the top of a hierarchical network. However, the function of Nova1 during hypoxia remains poorly understood. This study aimed to investigate the protective effect of Nova1 against cell hypoxia and to further explore the Bax/Bcl-2/caspase-3 pathway as a potential mechanism. During hypoxia, the survival rate of pheochromocytoma PC12 cells was gradually decreased and the apoptosis rate was gradually increased, peaking at 48 h of hypoxia. At 48 h after transfection of PC12 cells with pCMV-Myc-Nova1, the expression of Nova1 was significantly increased, with wide distribution in the cytoplasm and nucleus. Moreover, the survival rate was significantly increased and the apoptosis rate was significantly decreased. Additionally, the mRNA and protein expression levels of Bax and caspase-3 were significantly increased in the pCMV-Myc group and significantly decreased in the pCMV­Myc-Nova1 group, whereas that of Bcl-2 was significantly decreased in the pCMV-Myc group and significantly increased in the pCMV-Myc-Nova1 group. This study indicated that Nova1 could be linked to resistance to the hypoxia-induced apoptosis of PC12 cells via the Bax/Bcl-2/caspase-3 pathway, and this finding may be of significance for exploring novel mechanisms of hypoxia and the treatment of hypoxia-associated diseases.


Assuntos
Caspase 3/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas de Ligação a RNA/genética , Transdução de Sinais/genética , Proteína X Associada a bcl-2/genética , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Hipóxia Celular/genética , Núcleo Celular/genética , Núcleo Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Citoplasma/genética , Citoplasma/metabolismo , Regulação da Expressão Gênica , Oxigênio/farmacologia , Células PC12 , Plasmídeos/química , Plasmídeos/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas de Ligação a RNA/metabolismo , Ratos , Transfecção , Proteína X Associada a bcl-2/metabolismo
19.
J Cell Mol Med ; 21(9): 2046-2054, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28276625

RESUMO

Expression of surface NKG2D ligands on tumour cells, which activates nature killer (NK) cells and CD8+ T cells, is crucial in antitumour immunity. Some types of tumours have evolved mechanisms to suppress NKG2D-mediated immune cell activation, such as tumour-derived soluble NKG2D ligands or sustained NKG2D ligands produced by tumours down-regulate the expression of NKG2D on NK cells and CD8+ T cells. Here, we report that surface NKG2D ligand RAE1ε on tumour cells induces CD11b+ Gr-1+ myeloid-derived suppressor cell (MDSC) via NKG2D in vitro and in vivo. MDSCs induced by RAE1ε display a robust induction of IL-10 and arginase, and these MDSCs show greater suppressive activity by inhibiting antigen-non-specific CD8+ T-cell proliferation. Consistently, upon adoptive transfer, MDSCs induced by RAE1ε significantly promote CT26 tumour growth in IL-10- and arginase-dependent manners. RAE1ε moves cytokine balance towards Th2 but not Th1 in vivo. Furthermore, RAE1ε enhances inhibitory function of CT26-derived MDSCs and promotes IL-4 rather than IFN-γ production from CT26-derived MDSCs through NKG2D in vitro. Our study has demonstrated a novel mechanism for NKG2D ligand+ tumour cells escaping from immunosurveillance by facilitating the proliferation and the inhibitory function of MDSCs.


Assuntos
Células Supressoras Mieloides/metabolismo , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Proteínas Associadas à Matriz Nuclear/metabolismo , Proteínas de Transporte Nucleocitoplasmático/metabolismo , Animais , Antígeno CD11b/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Interleucina-10/metabolismo , Interleucina-4/metabolismo , Ligantes , Camundongos Endogâmicos BALB C , Neoplasias/patologia
20.
Transl Oncol ; 9(3): 191-6, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27267836

RESUMO

Phosphoglycerate dehydrogenase (PHGDH) plays an essential role in cancer-specific metabolic reprogramming. It has been reported as a putative metabolic oncogene in several types of human malignant tumors, such as breast cancer and melanoma. To date, PHGDH expression in colorectal cancer (CRC) as well as its association with clinicopathological characteristics and prognostic implication remain undetermined. In this study, we determined the PHGDH protein expression using tissue microarray immunohistochemistry (TMA-IHC) on 193 pairs of formalin-fixed, paraffin-embedded specimens of CRC and adjacent tissues, 25 chronic colitis, 41 low-, and 19 high-grade intraepithelial neoplasia specimens, and we also determined PHGDH mRNA level using quantitative reverse transcription PCR (qRT-PCR) on additional 23 pairs of fresh CRC tissues and adjacent tissues. We found that both PHGDH mRNA and protein was highly expressed in tumor tissues in comparison with matched adjacent non-tumor tissues, and high PHGDH protein expression was correlated with advanced TNM stage (P = .038) and larger tumor (P = .001). Multivariate Cox regression analysis showed that PHGDH protein expression (HR = 2.285, 95% CI = 1.18 to 4.41, P = .014), tumor differentiation (HR = .307, 95% CI = .154 to 0.609, P = .001), and TNM stage (HR = 1.791, 95% CI = 1.125 to 2.85, P = .014) were independent prognostic factors in CRC. Kaplan-Meier survival curves and log rank test showed that high PHGDH protein expression contributed to poor outcome in CRC patients (P < .001). In conclusion, these results suggest that assessment of PHGDH expression could be useful in identifying a high-risk subgroup of CRC.

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