Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 16 de 16
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
2.
Nutrients ; 13(6)2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34205057

RESUMO

COVID-19 is an unprecedented global pandemic. On 12 March 2020, a lockdown order was issued in Italy in attempt to contain the health crisis. The study aimed to assess the impact of the COVID-19 lockdown on diet, physical activity, sleep quality, and distress in an Italian cohort. An online anonymous interview, which included validated questionnaires was created to compare lifestyle habits pre- and during the lockdown. Data analysis from 604 subjects with a mean age of 29.8 years was carried out using multivariate analysis. Compared to pre-COVID-19 times, 67% of people changed their eating habits and increased consumption of foods containing added sugars. Women and men with low adherence to the Mediterranean Diet (MedDiet) were more likely to be physically inactive (p < 0.0001 and p < 0.01, respectively). Results from logistic regression showed a three times higher risk of being inactive if adherence to the MedDiet was low (p < 0.0001), especially in men between 26 and 35 years. Lower levels of distress were reported in males who were physically active (89%) (p < 0.001). Our findings may help to identify effective lifestyle interventions during restrictive conditions.


Assuntos
COVID-19 , Controle de Doenças Transmissíveis , Dieta , Exercício Físico , Comportamento Alimentar , Estilo de Vida , Pandemias , Adulto , Dieta Mediterrânea , Feminino , Comportamentos Relacionados com a Saúde , Humanos , Modelos Logísticos , Masculino , Análise Multivariada , Distanciamento Físico , Angústia Psicológica , SARS-CoV-2 , Comportamento Sedentário , Inquéritos e Questionários , Adulto Jovem
3.
Cancers (Basel) ; 13(8)2021 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-33921638

RESUMO

Cancer stem cells (CSCs) drive not only tumor initiation and expansion, but also therapeutic resistance and tumor relapse. Therefore, CSC eradication is required for effective cancer therapy. In preclinical models, CSCs demonstrated high capability to tolerate even extensive genotoxic stress, including replication stress, because they are endowed with a very robust DNA damage response (DDR). This favors the survival of DNA-damaged CSCs instead of their inhibition via apoptosis or senescence. The DDR represents a unique CSC vulnerability, but the abrogation of the DDR through the inhibition of the ATR-CHK1 axis is effective only against some subtypes of CSCs, and resistance often emerges. Here, we analyzed the impact of druggable DDR players in the response of patient-derived colorectal CSCs (CRC-SCs) to CHK1/2 inhibitor prexasertib, identifying RAD51 and MRE11 as sensitizing targets enhancing prexasertib efficacy. We showed that combined inhibition of RAD51 and CHK1 (via B02+prexasertib) or MRE11 and CHK1 (via mirin+prexasertib) kills CSCs by affecting multiple genoprotective processes. In more detail, these two prexasertib-based regimens promote CSC eradication through a sequential mechanism involving the induction of elevated replication stress in a context in which cell cycle checkpoints usually activated during the replication stress response are abrogated. This leads to uncontrolled proliferation and premature entry into mitosis of replication-stressed cells, followed by the induction of mitotic catastrophe. CRC-SCs subjected to RAD51+CHK1 inhibitors or MRE11+CHK1 inhibitors are eventually eliminated, and CRC-SC tumorspheres inhibited or disaggregated, via a caspase-dependent apoptosis. These results support further clinical development of these prexasertib-based regimens in colorectal cancer patients.

4.
Cancers (Basel) ; 13(4)2021 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-33673003

RESUMO

Colorectal cancer (CRC) is a heterogeneous disease that can currently be subdivided into four distinct consensus molecular subtypes (CMS) based on gene expression profiling. The CMS4 subtype is marked by high expression of mesenchymal genes and is associated with a worse overall prognosis compared to other CMSs. Importantly, this subtype responds poorly to the standard therapies currently used to treat CRC. We set out to explore what regulatory signalling networks underlie the CMS4 phenotype of cancer cells, specifically, by analysing which kinases were more highly expressed in this subtype compared to others. We found AKT3 to be expressed in the cancer cell epithelium of CRC specimens, patient derived xenograft (PDX) models and in (primary) cell cultures representing CMS4. Importantly, chemical inhibition or knockout of this gene hampers outgrowth of this subtype, as AKT3 controls expression of the cell cycle regulator p27KIP1. Furthermore, high AKT3 expression was associated with high expression of epithelial-mesenchymal transition (EMT) genes, and this observation could be expanded to cell lines representing other carcinoma types. More importantly, this association allowed for the identification of CRC patients with a high propensity to metastasise and an associated poor prognosis. High AKT3 expression in the tumour epithelial compartment may thus be used as a surrogate marker for EMT and may allow for a selection of CRC patients that could benefit from AKT3-targeted therapy.

5.
Cell Death Differ ; 28(7): 2060-2082, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33531658

RESUMO

Cancer stem cells (CSCs) are tumor subpopulations driving disease development, progression, relapse and therapy resistance, and their targeting ensures tumor eradication. CSCs display heterogeneous replication stress (RS), but the functionality/relevance of the RS response (RSR) centered on the ATR-CHK1 axis is debated. Here, we show that the RSR is efficient in primary CSCs from colorectal cancer (CRC-SCs), and describe unique roles for PARP1 and MRE11/RAD51. First, we demonstrated that PARP1 is upregulated in CRC-SCs resistant to several replication poisons and RSR inhibitors (RSRi). In these cells, PARP1 modulates replication fork speed resulting in low constitutive RS. Second, we showed that MRE11 and RAD51 cooperate in the genoprotection and mitosis execution of PARP1-upregulated CRC-SCs. These roles represent therapeutic vulnerabilities for CSCs. Indeed, PARP1i sensitized CRC-SCs to ATRi/CHK1i, inducing replication catastrophe, and prevented the development of resistance to CHK1i. Also, MRE11i + RAD51i selectively killed PARP1-upregulated CRC-SCs via mitotic catastrophe. These results provide the rationale for biomarker-driven clinical trials in CRC using distinct RSRi combinations.

6.
PLoS One ; 15(10): e0239803, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33031478

RESUMO

Evidence suggests a beneficial role of the Mediterranean Diet (MedDiet) on health-related quality of life (HRQoL) in healthy subjects. HRQoL is relevant in cancer therapy and disease outcomes, therefore we investigated the association between adherence to the MedDiet and HRQoL in breast cancer survivors participating in the multicentre trial DEDiCa. Diet and HRQoL were assessed at baseline in a subgroup of 309 women enrolled within 12 months of breast cancer diagnosis without metastasis (stages I-III, mean age 52±1 yrs, BMI 27±7 kg/m2). The 14-item PREDIMED questionnaire was used to analyse adherence to the MedDiet. HRQoL was assessed with three validated questionnaires measuring physical, mental, emotional and social factors: EQ-5D-3L, EORTC QLQ-C30 and EORTC QLQ-BR23. Analysis of variance (ANOVA) and multivariate analyses were performed to assess the possible role of the MedDiet on HRQoL. Patients with higher adherence to MedDiet (PREDIMED score >7) showed significantly higher scores for physical functioning (p = 0.02) and lower scores on the symptomatic pain scale (p = 0.04) assessed by the EORTC QLQ-C30 questionnaire compared to patients with a lower adherence to MedDiet (PREDIMED score ≤7). Higher scores from the EQ-5D-3L indicating higher well-being were observed mainly in participants with higher MedDiet adherence (p = 0.05). In adjusted multivariate analyses significant positive associations were found between MedDiet, physical functioning (p = 0.001) and EQ 5D-3L score (p = 0.003) while inverse associations were found with pain and insomnia symptoms (p = 0.005 and p = 0.029, respectively). These results suggest that higher adherence to the MedDiet in breast cancer survivors is associated with better aspects of quality of life, specifically higher physical functioning, better sleep, lower pain and generally higher well-being confirming findings in healthy subjects.


Assuntos
Neoplasias da Mama/terapia , Sobreviventes de Câncer/estatística & dados numéricos , Dieta Mediterrânea , Adulto , Idoso , Feminino , Humanos , Itália/epidemiologia , Pessoa de Meia-Idade , Dor , Cooperação do Paciente , Qualidade de Vida , Distúrbios do Início e da Manutenção do Sono , Inquéritos e Questionários
7.
Int Immunol ; 2020 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-32840576

RESUMO

The type I interferons (type I IFNs) are central to a vast array of immunological functions. The production of these immune-modulatory molecules is initiated at the early stages of the innate immune responses and, therefore, plays a dominant role in shaping downstream events in both innate and adaptive immunity. Indeed, the major role of IFNα/ß is the induction of priming states, relevant for the functional differentiation of T lymphocyte subsets. Among T cell subtypes, the CD4 +CD25 +Foxp3 + T regulatory cells (Tregs) represent a specialized subset of CD4 + T cells with a critical role in maintaining peripheral tolerance and immune homeostasis. Although the role of type I IFNs in maintaining the function of thymus-derived Tregs has been previously described, the direct contribution of these innate factors to peripheral Treg (pTreg) and induced Treg (iTreg) differentiation and suppressive function is still unclear. We now show that, under tolerogenic conditions, IFNα/ß play a critical role in antigen-specific and also polyclonal naïve CD4 + T cell conversion into peripheral antigen-specific CD4 +CD25 +Foxp3 + Tregs and inhibit CD4 + T helper (Th) cell expansion in mice. While type I IFNs sustain the expression and the activation of the transcription master regulators Foxp3, Stat3 and Stat5, these innate molecules reciprocally inhibit Th17 cell differentiation. Altogether, these results indicate a new pivotal role of IFNα/ß on pTreg differentiation and induction of peripheral tolerance, which may have important implications in the therapeutic control of inflammatory disorders, such as of autoimmune diseases.

8.
Nutrients ; 13(1)2020 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-33396551

RESUMO

Healthy lifestyles are associated with better health-related quality of life (HRQoL), favorable prognosis and lower mortality in breast cancer (BC) survivors. We investigated changes in HRQoL after a 12-month lifestyle modification program in 227 BC survivors participating in DEDiCa trial (Mediterranean diet, exercise, vitamin D). HRQoL was evaluated through validated questionnaires: EQ-5D-3L, EORTC-QLQ-C30 and EORTC QLQ-BR23. Baseline changes were tested using analysis of variance. Multiple regression analyses were performed to assess treatment effects on HRQoL. Increases were observed in global health status (p < 0.001), physical (p = 0.003), role (p = 0.002) and social functioning (p < 0.001), body image (p < 0.001), future perspective (p < 0.001), well-being (p = 0.001), and reductions in fatigue (p < 0.001), nausea and vomiting (p = 0.015), dyspnea (p = 0.001), constipation (p = 0.049), financial problems (p = 0.012), sexual functioning (p = 0.025), systematic therapy side effects (p < 0.001) and breast symptoms (p = 0.004). Multiple regression analyses found inverse associations between changes in BMI and global health status (p = 0.048) and between serum 25(OH)D levels and breast symptoms (p = 0.002). A healthy lifestyle treatment of traditional Mediterranean diet and exercise may impact positively on HRQoL in BC survivors possibly through reductions in body weight while vitamin D sufficiency may improve BC-related symptoms. These findings are relevant to BC survivors whose lower HRQoL negatively affects treatment compliance and disease outcomes.


Assuntos
Neoplasias da Mama/terapia , Sobreviventes de Câncer/psicologia , Estilo de Vida Saudável , Qualidade de Vida , Sobrevivência , Adulto , Neoplasias da Mama/complicações , Neoplasias da Mama/psicologia , Inquéritos sobre Dietas/estatística & dados numéricos , Dieta Mediterrânea , Suplementos Nutricionais , Terapia por Exercício , Feminino , Nível de Saúde , Humanos , Pessoa de Meia-Idade , Cooperação do Paciente/estatística & dados numéricos , Inquéritos e Questionários , Resultado do Tratamento , Vitamina D/administração & dosagem
9.
Cancers (Basel) ; 11(8)2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31366089

RESUMO

PTEN is one of the most frequently inactivated tumor suppressor genes in cancer. Loss or variation in PTEN gene/protein levels is commonly observed in a broad spectrum of human cancers, while germline PTEN mutations cause inherited syndromes that lead to increased risk of tumors. PTEN restrains tumorigenesis through different mechanisms ranging from phosphatase-dependent and independent activities, subcellular localization and protein interaction, modulating a broad array of cellular functions including growth, proliferation, survival, DNA repair, and cell motility. The main target of PTEN phosphatase activity is one of the most significant cell growth and pro-survival signaling pathway in cancer: PI3K/AKT/mTOR. Several shreds of evidence shed light on the critical role of PTEN in normal and cancer stem cells (CSCs) homeostasis, with its loss fostering the CSC compartment in both solid and hematologic malignancies. CSCs are responsible for tumor propagation, metastatic spread, resistance to therapy, and relapse. Thus, understanding how alterations of PTEN levels affect CSC hallmarks could be crucial for the development of successful therapeutic approaches. Here, we discuss the most significant findings on PTEN-mediated control of CSC state. We aim to unravel the role of PTEN in the regulation of key mechanisms specific for CSCs, such as self-renewal, quiescence/cell cycle, Epithelial-to-Mesenchymal-Transition (EMT), with a particular focus on PTEN-based therapy resistance mechanisms and their exploitation for novel therapeutic approaches in cancer treatment.

10.
Eur J Immunol ; 49(4): 534-545, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30758056

RESUMO

Dendritic cells (DCs) are key players in immunity and tolerance. Some DCs express c-kit, the receptor for stem cell factor (SCF), nevertheless c-kit functional role and the regulation of its expression in DCs are incompletely defined. We recently demonstrated that autocrine SCF sustains a pro-survival circuit, and that SCF increases phospho-AKT in c-kit+ mouse bone marrow-derived DCs (BMdDCs). Herein we observed that CpG and PolyI:C, two stimuli mimicking bacterial and viral nucleic acids respectively, strongly inhibited c-kit expression by BMdDCs and spleen DCs in vitro and in vivo. Experiments in IFNARI-/- mice showed that IFN-I pathway was required for c-kit down-regulation in cDC1s, but only partially supported it in cDC2s. Furthermore, CpG and PolyI:C strongly inhibited c-kit mRNA expression. In agreement with the reduced c-kit levels, SCF pro-survival activity was impaired. Thus in the presence of exogenously provided SCF, either PolyI:C or CpG induced spleen DC death in 2 days, while at earlier times IL-6 and IL-12 production were slightly increased. In contrast, SCF improved survival of unstimulated spleen DCs expressing high c-kit levels. Our studies suggest that c-kit down-modulation is a previously neglected component of DC response to CpG and PolyI:C, regulating DC survival and ultimately tuning immune response.


Assuntos
Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Expressão Gênica , Proteínas Proto-Oncogênicas c-kit/genética , Animais , Antígenos CD40/metabolismo , Células Cultivadas , Citocinas/biossíntese , Imunofenotipagem , Interleucina-6/biossíntese , Camundongos , Oligodesoxirribonucleotídeos/imunologia , Poli I-C/imunologia , Proteínas Proto-Oncogênicas c-kit/metabolismo , Baço
11.
Cell Biol Toxicol ; 34(6): 459-469, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29478126

RESUMO

Biobanking of molecularly characterized colorectal cancer stem cells (CSCs) generated from individual patients and growing as spheroids in defined serum-free media offer a fast, feasible, and multi-level approach for the screening of targeted therapies and drug resistance molecular studies. By combining in vitro and in vivo analyses of cetuximab efficacy with genetic data on an ongoing collection of stem cell-enriched spheroids, we describe the identification and preliminary characterization of microsatellite stable (MSS) CSCs that, despite the presence of the KRAS (G12D) mutation, display epidermal growth factor (EGF)-dependent growth and are strongly inhibited by anti-EGF-receptor (EGFR) treatment. In parallel, we detected an increased resistance to anti-EGFR therapy of microsatellite instable (MSI) CSC lines irrespective of KRAS mutational status. MSI CSC lines carried mutations in genes coding for proteins with a role in RAS and calcium signaling, highlighting the role of a genomically unstable context in determining anti-EGFR resistance. Altogether, these results argue for a multifactorial origin of anti-EGFR resistance that emerges as the effect of multiple events targeting direct and indirect regulators of the EGFR pathway. An improved understanding of key molecular determinants of sensitivity/resistance to EGFR inhibition will be instrumental to optimize the clinical efficacy of anti-EGFR agents, representing a further step towards personalized treatments.


Assuntos
Neoplasias Colorretais/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Células-Tronco Neoplásicas/efeitos dos fármacos , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/farmacologia , Bancos de Espécimes Biológicos/tendências , Cetuximab/farmacologia , Neoplasias Colorretais/fisiopatologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/fisiologia , Fator de Crescimento Epidérmico/fisiologia , Receptores ErbB/fisiologia , Humanos , Mutação , Panitumumabe , Medicina de Precisão/métodos , Proteínas Proto-Oncogênicas p21(ras)/genética , Esferoides Celulares/fisiologia , Células Tumorais Cultivadas/fisiologia
12.
Gut ; 67(5): 903-917, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-28389531

RESUMO

OBJECTIVE: Cancer stem cells (CSCs) are responsible for tumour formation and spreading, and their targeting is required for tumour eradication. There are limited therapeutic options for advanced colorectal cancer (CRC), particularly for tumours carrying RAS-activating mutations. The aim of this study was to identify novel CSC-targeting strategies. DESIGN: To discover potential therapeutics to be clinically investigated as single agent, we performed a screening with a panel of FDA-approved or investigational drugs on primary CRC cells enriched for CSCs (CRC-SCs) isolated from 27 patients. Candidate predictive biomarkers of efficacy were identified by integrating genomic, reverse-phase protein microarray (RPPA) and cytogenetic analyses, and validated by immunostainings. DNA replication stress (RS) was increased by employing DNA replication-perturbing or polyploidising agents. RESULTS: The drug-library screening led to the identification of LY2606368 as a potent anti-CSC agent acting in vitro and in vivo in tumour cells from a considerable number of patients (∼36%). By inhibiting checkpoint kinase (CHK)1, LY2606368 affected DNA replication in most CRC-SCs, including RAS-mutated ones, forcing them into premature, lethal mitoses. Parallel genomic, RPPA and cytogenetic analyses indicated that CRC-SCs sensitive to LY2606368 displayed signs of ongoing RS response, including the phosphorylation of RPA32 and ataxia telangiectasia mutated serine/threonine kinase (ATM). This was associated with mutation(s) in TP53 and hyperdiploidy, and made these CRC-SCs exquisitely dependent on CHK1 function. Accordingly, experimental increase of RS sensitised resistant CRC-SCs to LY2606368. CONCLUSIONS: LY2606368 selectively eliminates replication-stressed, p53-deficient and hyperdiploid CRC-SCs independently of RAS mutational status. These results provide a strong rationale for biomarker-driven clinical trials with LY2606368 in patients with CRC.


Assuntos
Antineoplásicos/farmacologia , Quinase 1 do Ponto de Checagem/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Pirazinas/farmacologia , Pirazóis/farmacologia , Linhagem Celular Tumoral , Quinase 1 do Ponto de Checagem/genética , Neoplasias Colorretais/genética , Replicação do DNA/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Mutação , Células-Tronco Neoplásicas/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Proteína Supressora de Tumor p53/genética
13.
Front Immunol ; 8: 147, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28261209

RESUMO

Stem cell factor (SCF), the ligand of c-kit, is a key cytokine for hematopoiesis. Hematopoietic precursors express c-kit, whereas differentiated cells of hematopoietic lineage are negative for this receptor, with the exception of NK cells, mast cells, and a few others. While it has long been recognized that dendritic cells (DCs) can express c-kit, several questions remain concerning the SCF/c-kit axis in DCs. This is particularly relevant for DCs found in those organs wherein SCF is highly expressed, including the bone marrow (BM). We characterized c-kit expression by conventional DCs (cDCs) from BM and demonstrated a higher proportion of c-kit+ cells among type 1 cDC subsets (cDC1s) than type 2 cDC subsets (cDC2s) in both humans and mice, whereas similar levels of c-kit expression were observed in cDC1s and cDC2s from mouse spleen. To further study c-kit regulation, DCs were generated with granulocyte-macrophage colony-stimulating factor (GM-CSF) from mouse BM, a widely used protocol. CD11c+ cells were purified from pooled non-adherent and slightly adherent cells collected after 7 days of culture, thus obtaining highly purified BM-derived DCs (BMdDCs). BMdDCs contained a small fraction of c-kit+ cells, and by replating them for 2 days with GM-CSF, we obtained a homogeneous population of c-kit+ CD40hi MHCIIhi cells. Not only did BMdDCs express c-kit but they also produced SCF, and both were striking upregulated if GM-CSF was omitted after replating. Furthermore, a small but significant reduction in BMdDC survival was observed upon SCF silencing. Incubation of BMdDCs with SCF did not modulate antigen presentation ability of these cells, nor it did regulate their membrane expression of the chemokine receptor CXCR4. We conclude that the SCF/c-kit-mediated prosurvival circuit may have been overlooked because of the prominent use of GM-CSF in DC cultures in vitro, including those human DC cultures destined for the clinics. We speculate that DCs more prominently rely on SCF in vivo in some microenvironments, with potential implications for graft-versus-host disease and antitumor immunity.

14.
Stem Cells Transl Med ; 5(4): 511-23, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26956206

RESUMO

UNLABELLED: Colorectal cancer (CRC) therapy mainly relies on the use of conventional chemotherapeutic drugs combined, in a subset of patients, with epidermal growth factor receptor [EGFR]-targeting agents. Although CRC is considered a prototype of a cancer stem cell (CSC)-driven tumor, the effects of both conventional and targeted therapies on the CSC compartment are largely unknown. We have optimized a protocol for colorectal CSC isolation that allowed us to obtain CSC-enriched cultures from primary tumor specimens, with high efficiency. CSC isolation was followed by in vitro and in vivo validation, genetic characterization, and drug sensitivity analysis, thus generating panels of CSC lines with defined patterns of genetic mutations and therapy sensitivity. Colorectal CSC lines were polyclonal and maintained intratumor heterogeneity in terms of somatically acquired mutations and differentiation state. Such CSC-enriched cultures were used to investigate the effects of both conventional and targeted therapies on the CSC compartment in vivo and to generate a proteomic picture of signaling pathways implicated in sensitivity/resistance to anti-EGFR agents. We propose CSC lines as a sound preclinical framework to test the effects of therapies in vitro and in vivo and to identify novel determinants of therapy resistance. SIGNIFICANCE: Colorectal cancer stem cells (CSCs) have been shown to be responsible for tumor propagation, metastatic dissemination, and relapse. However, molecular pathways present in CSCs, as well as mechanisms of therapy resistance, are mostly unknown. Taking advantage of genetically characterized CSC lines derived from colorectal tumors, this study provides an extensive analysis of CSC response to EGFR-targeted therapy in vivo and an overview of factors implicated in therapy response or resistance. Furthermore, the implementation of a biobank of molecularly annotated CSC lines provides an innovative resource for future investigations in colorectal cancer.


Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Células-Tronco Neoplásicas/patologia , Animais , Células Cultivadas , Feminino , Perfilação da Expressão Gênica , Humanos , Camundongos Endogâmicos NOD , Camundongos SCID , Camundongos Transgênicos , Análise em Microsséries , Modelos Biológicos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteômica , Transdução de Sinais/genética
15.
Eur J Immunol ; 42(5): 1129-39, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22539288

RESUMO

CD127 is the IL-7 receptor α-chain and its expression is tightly regulated during T-cell differentiation. We previously showed that the bone marrow (BM) is a key organ for proliferation and maintenance of both antigen-specific and CD44(high) memory CD8(+) T cells. Interestingly, BM memory CD8(+) T cells express lower levels of membrane CD127 than do the corresponding spleen and lymph node cells. We investigated the requirements for CD127 downmodulation by CD44(high) memory-phenotype CD8(+) T cells in the BM of C57BL/6 mice. By comparing genetically modified (i.e. CD127tg, IL-7 KO, IL-15 KO, IL-15Rα KO) with wild-type (WT) mice, we found that the key molecule regulating CD127 downmodulation was IL-15 but not IL-7, and that the intact CD127 gene was required, including the promoter. Indeed, CD127 mRNA transcript levels were lower in CD44(high) CD8(+) T cells from the BM than in those from the spleen of WT mice, indicating organ-specific regulation. Although levels of the CD127 transactivator Foxo1 were low in BM CD44(high) CD8(+) T cells, Foxo1 was not involved in IL-15-induced CD127 downmodulation. Thus, recirculating CD44(high) CD8(+) T cells passing through the BM transiently downregulate CD127 in response to IL-15, with implications for human therapies acting on the IL-7/CD127 axis, for example cytokine treatments in cancer patients.


Assuntos
Medula Óssea/imunologia , Linfócitos T CD8-Positivos/imunologia , Memória Imunológica , Interleucina-15/imunologia , Receptores de Interleucina-7/antagonistas & inibidores , Animais , Linfócitos T CD8-Positivos/metabolismo , Regulação para Baixo/imunologia , Feminino , Proteína Forkhead Box O1 , Fatores de Transcrição Forkhead/análise , Receptores de Hialuronatos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Regiões Promotoras Genéticas , Receptores de Interleucina-7/genética , Receptores de Interleucina-7/imunologia , Baço/imunologia
16.
J Immunol ; 184(11): 5969-79, 2010 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-20427775

RESUMO

Type I IFNs are central to a vast array of immunological functions. Their early induction in innate immune responses provides one of the most important priming mechanisms for the subsequent establishment of adaptive immunity. The outcome is either promotion or inhibition of these responses, but the conditions under which one or the other prevails remain to be defined. The main objective of the current study was to determine the involvement of IFN-alpha on murine CD4(+)CD25(-) Th cell activation, as well as to define the role played by this cytokine on CD4(+)CD25(+) regulatory T (Treg) cell proliferation and function. Although IFN-alpha promotes CD4(+)CD25(-) Th cells coincubated with APCs to produce large amounts of IL-2, the ability of these cells to respond to IL-2 proliferative effects is prevented. Moreover, in medium supplemented with IFN-alpha, IL-2-induced CD4(+)CD25(+) Treg cell proliferation is inhibited. Notably, IFN-alpha also leads to a decrease of the CD4(+)CD25(+) Treg cell suppressive activity. Altogether, these findings indicate that through a direct effect on APC activation and by affecting CD4(+)CD25(+) Treg cell-mediated suppression, IFN-alpha sustains and drives CD4(+)CD25(-) Th cell activation.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Interferon-alfa/imunologia , Ativação Linfocitária/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia , Animais , Western Blotting , Proliferação de Células , Separação Celular , Células Cultivadas , Técnicas de Cocultura , Feminino , Citometria de Fluxo , Interleucina-2/biossíntese , Interleucina-2/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Receptor de Interferon alfa e beta/imunologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...