Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 17 de 17
Filtrar
1.
Nat Immunol ; 15(11): 1055-1063, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25282159

RESUMO

TRPV1 is a Ca(2+)-permeable channel studied mostly as a pain receptor in sensory neurons. However, its role in other cell types is poorly understood. Here we found that TRPV1 was functionally expressed in CD4(+) T cells, where it acted as a non-store-operated Ca(2+) channel and contributed to T cell antigen receptor (TCR)-induced Ca(2+) influx, TCR signaling and T cell activation. In models of T cell-mediated colitis, TRPV1 promoted colitogenic T cell responses and intestinal inflammation. Furthermore, genetic and pharmacological inhibition of TRPV1 in human CD4(+) T cells recapitulated the phenotype of mouse Trpv1(-/-) CD4(+) T cells. Our findings suggest that inhibition of TRPV1 could represent a new therapeutic strategy for restraining proinflammatory T cell responses.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Inflamação/imunologia , Ativação Linfocitária/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Canais de Cátion TRPV/genética , Anilidas/farmacologia , Animais , Linfócitos T CD4-Positivos/citologia , Cálcio/metabolismo , Canais de Cálcio/imunologia , Sinalização do Cálcio/efeitos dos fármacos , Sinalização do Cálcio/imunologia , Capsaicina/farmacologia , Células Cultivadas , Cinamatos/farmacologia , Colite/imunologia , Humanos , Interleucina-10/genética , Intestinos/imunologia , Intestinos/patologia , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fármacos do Sistema Sensorial/farmacologia , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/biossíntese
2.
Gut ; 66(9): 1584-1596, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-27325418

RESUMO

OBJECTIVE: Transient receptor potential ankyrin-1 (TRPA1) and transient receptor potential vanilloid-1 (TRPV1) are calcium (Ca2+)-permeable ion channels mostly known as pain receptors in sensory neurons. However, growing evidence suggests their crucial involvement in the pathogenesis of IBD. We explored the possible contribution of TRPA1 and TRPV1 to T-cell-mediated colitis. DESIGN: We evaluated the role of Trpa1 gene deletion in two models of experimental colitis (ie, interleukin-10 knockout and T-cell-adoptive transfer models). We performed electrophysiological and Ca2+ imaging studies to analyse TRPA1 and TRPV1 functions in CD4+ T cells. We used genetic and pharmacological approaches to evaluate TRPV1 contribution to the phenotype of Trpa1-/- CD4+ T cells. We also analysed TRPA1 and TRPV1 gene expression and TRPA1+TRPV1+ T cell infiltration in colonic biopsies from patients with IBD. RESULTS: We identified a protective role for TRPA1 in T-cell-mediated colitis. We demonstrated the functional expression of TRPA1 on the plasma membrane of CD4+ T cells and identified that Trpa1-/- CD4+ T cells have increased T-cell receptor-induced Ca2+ influx, activation profile and differentiation into Th1-effector cells. This phenotype was abrogated upon genetic deletion or pharmacological inhibition of the TRPV1 channel in mouse and human CD4+ T cells. Finally, we found differential regulation of TRPA1 and TRPV1 gene expression as well as increased infiltration of TRPA1+TRPV1+ T cells in the colon of patients with IBD. CONCLUSIONS: Our study indicates that TRPA1 inhibits TRPV1 channel activity in CD4+ T cells, and consequently restrains CD4+ T-cell activation and colitogenic responses. These findings may therefore have therapeutic implications for human IBD.


Assuntos
Colite , Doenças Inflamatórias Intestinais , Canais de Cátion TRPV , Canais de Potencial de Receptor Transitório , Animais , Biópsia/métodos , Linfócitos T CD4-Positivos/metabolismo , Células Cultivadas , Colite/genética , Colite/metabolismo , Colite/patologia , Colo/metabolismo , Colo/patologia , Modelos Animais de Doenças , Expressão Gênica/fisiologia , Humanos , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/patologia , Camundongos , Fatores de Proteção , Estatística como Assunto , Canal de Cátion TRPA1 , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo , Canais de Potencial de Receptor Transitório/genética , Canais de Potencial de Receptor Transitório/metabolismo
3.
Diabetes ; 72(9): 1235-1250, 2023 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-37257047

RESUMO

In obesity, CD11c+ innate immune cells are recruited to adipose tissue and create an inflammatory state that causes both insulin and catecholamine resistance. We found that ablation of Gnas, the gene that encodes Gαs, in CD11c expressing cells protects mice from obesity, glucose intolerance, and insulin resistance. Transplantation studies showed that the lean phenotype was conferred by bone marrow-derived cells and did not require adaptive immunity. Loss of cAMP signaling was associated with increased adipose tissue norepinephrine and cAMP signaling, and prevention of catecholamine resistance. The adipose tissue had reduced expression of catecholamine transport and degradation enzymes, suggesting that the elevated norepinephrine resulted from decreased catabolism. Collectively, our results identified an important role for cAMP signaling in CD11c+ innate immune cells in whole-body metabolism by controlling norepinephrine levels in white adipose tissue, modulating catecholamine-induced lipolysis and increasing thermogenesis, which, together, created a lean phenotype. ARTICLE HIGHLIGHTS: We undertook this study to understand how immune cells communicate with adipocytes, specifically, whether cAMP signaling in the immune cell and the adipocyte are connected. We identified a reciprocal interaction between CD11c+ innate immune cells and adipocytes in which high cAMP signaling in the immune cell compartment induces low cAMP signaling in adipocytes and vice versa. This interaction regulates lipolysis in adipocytes and inflammation in immune cells, resulting in either a lean, obesity-resistant, and insulin-sensitive phenotype, or an obese, insulin-resistant phenotype.


Assuntos
Dieta Hiperlipídica , Resistência à Insulina , Obesidade , Animais , Camundongos , Tecido Adiposo Branco/metabolismo , Catecolaminas/metabolismo , Dieta Hiperlipídica/efeitos adversos , Insulina/metabolismo , Resistência à Insulina/fisiologia , Camundongos Endogâmicos C57BL , Norepinefrina/metabolismo , Obesidade/etiologia , Obesidade/metabolismo
4.
J Exp Clin Cancer Res ; 42(1): 26, 2023 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-36670473

RESUMO

BACKGROUND: Individuals with certain chronic inflammatory lung diseases have a higher risk of developing lung cancer (LC). However, the underlying mechanisms remain largely unknown. Here, we hypothesized that chronic exposure to house dust mites (HDM), a common indoor aeroallergen associated with the development of asthma, accelerates LC development through the induction of chronic lung inflammation (CLI).  METHODS: The effects of HDM and heat-inactivated HDM (HI-HDM) extracts were evaluated in two preclinical mouse models of LC (a chemically-induced model using the carcinogen urethane and a genetically-driven model with oncogenic KrasG12D activation in lung epithelial cells) and on murine macrophages in vitro. Pharmacological blockade or genetic deletion of the Nod-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome, caspase-1, interleukin-1ß (IL-1ß), and C-C motif chemokine ligand 2 (CCL2) or treatment with an inhaled corticosteroid (ICS) was used to uncover the pro-tumorigenic effect of HDM.  RESULTS: Chronic intranasal (i.n) instillation of HDM accelerated LC development in the two mouse models. Mechanistically, HDM caused a particular subtype of CLI, in which the NLRP3/IL-1ß signaling pathway is chronically activated in macrophages, and made the lung microenvironment conducive to tumor development. The tumor-promoting effect of HDM was significantly decreased by heat treatment of the HDM extract and was inhibited by NLRP3, IL-1ß, and CCL2 neutralization, or ICS treatment. CONCLUSIONS: Collectively, these data indicate that long-term exposure to HDM can accelerate lung tumorigenesis in susceptible hosts (e.g., mice and potentially humans exposed to lung carcinogens or genetically predisposed to develop LC).


Assuntos
Asma , Neoplasias Pulmonares , Humanos , Animais , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pyroglyphidae , Pulmão/patologia , Asma/metabolismo , Asma/patologia , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/metabolismo , Modelos Animais de Doenças , Microambiente Tumoral
5.
Mol Cell Proteomics ; 7(12): 2311-22, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18632594

RESUMO

Unmethylated CpG dinucleotides, present in bacterial DNA, are recognized in vertebrates via the Toll-like receptor 9 (TLR9) and are known to act as an anticancer agent by stimulating immune cells to induce a proinflammatory response. Although the effects of CpG-oligodeoxynucleotides (CpG-ODNs) in immune cells have been widely studied, little is known regarding their molecular effects in TLR9-positive tumor cells. To better understand the role of these bacterial motifs in cancer cells, we analyzed proteome modifications induced in TLR9-positive tumor cells in vitro and in vivo after CpG-ODN treatment in a rat colon carcinoma model. Proteomics analysis of tumor cells by two-dimensional gel electrophoresis followed by mass spectrometry identified several proteins modulated by bacterial CpG motifs. Among them, several are related to autophagy including potential autophagic substrates. In addition, we observed an increased glyceraldehyde-3-phosphate dehydrogenase expression, which has been shown to be sufficient to trigger an autophagic process. Autophagy is a self-digestion pathway whereby cytoplasmic material is sequestered by a structure termed the autophagosome for subsequent degradation and recycling. As bacteria are known to trigger autophagy, we assessed whether bacterial CpG motifs might induce autophagy in TLR9-positive tumor cells. We showed that CpG-ODN can induce autophagy in rodent and human tumor cell lines and was TLR9-dependent. In addition, an increase in the number of autophagosomes can also be observed in vivo after CpG motif intratumoral injection. Our findings bring new insights on the effect of bacterial CpG motifs in tumor cells and may be relevant for cancer treatment and more generally for gene therapy approaches in TLR9-positive tissues.


Assuntos
Autofagia/efeitos dos fármacos , Neoplasias/patologia , Oligodesoxirribonucleotídeos/farmacologia , Proteômica , Animais , Linhagem Celular Tumoral , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Neoplasias do Colo/ultraestrutura , Eletroforese em Gel Bidimensional , Humanos , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/ultraestrutura , Redes e Vias Metabólicas/efeitos dos fármacos , Camundongos , Proteínas de Neoplasias/metabolismo , Neoplasias/ultraestrutura , Fagossomos/efeitos dos fármacos , Fagossomos/ultraestrutura , Ratos , Solubilidade/efeitos dos fármacos , Receptor Toll-Like 9/metabolismo
7.
Int J Mol Med ; 21(3): 309-15, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18288378

RESUMO

Bacterial DNA contains unmethylated cytosine-phosphate-guanine (CpG) motifs which are recognized by mammalian immune cells as a danger signal indicating an infection. These immunostimulatory properties led to the use of oligodeoxynucleotides bearing CpG motifs (CpG-ODN) for cancer treatment in preclinical and clinical studies. Although naked DNA administration presently represents 18% of the gene therapy clinical trials worldwide, most of the work regarding the effects of unmethylated CpG sequences was performed using CpG-ODN. In the present study, we analyzed early induced tumor microenvironment modifications in a rat liver metastasis model after intratumoral injection of a plasmid used in suicide gene therapy. We first showed that plasmidic CpG motifs were active, i.e. able to induce IFN-gamma secretion by rat splenocytes. Then, we compared tumor-infiltrating immune cells 24 h after injection of native or SssI-treated plasmid, in which immunostimulatory CpG motifs have been inactivated by methylation. The presence of active plasmidic CpG sequences within the tumor was associated with a decrease in the number of tumor-infiltrating conventional dendritic cells and an upregulation of the CCR7 chemokine receptor responsible for lymph node homing. We also observed an increase in plasmacytoid dendritic cells and natural killer cell infiltration within the tumors as well as an increased mRNA expression of three cytokines/chemokines (IL-1beta, IL-10 and IL-18). These data suggest that, although suicide plasmid injection without prodrug treatment is not sufficient to observe a therapeutic effect, the presence of plasmidic CpG motifs within the tumor induces the recruitment and activation of the immune cells involved in antitumor response. These early cellular and molecular events should facilitate the induction of the immune response against tumor antigens released after in situ drug production.


Assuntos
Ilhas de CpG/genética , Modelos Animais de Doenças , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundário , Plasmídeos/genética , Animais , Sequência de Bases , Movimento Celular , Quimiocinas/genética , Quimiocinas/metabolismo , Células Dendríticas/patologia , Regulação Neoplásica da Expressão Gênica , Interferon gama/metabolismo , Células Matadoras Naturais/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Baço/citologia , Baço/metabolismo
8.
Semin Immunopathol ; 38(3): 309-19, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26468011

RESUMO

The transient receptor potential (TRP) family of ion channels is widely expressed in many cell types and plays various physiological roles. Growing evidence suggests that certain TRP channels are functionally expressed in the immune system. Indeed, an increasing number of reports have demonstrated the functional expression of several TRP channels in innate and adaptive immune cells and have highlighted their critical role in the activation and function of these cells. However, very few reviews have been entirely dedicated to this subject. Here, we will summarize the recent findings with regards to TRP channel expression in T cells and discuss their emerging role as regulators of T cell activation and functions. Moreover, these studies suggest that beyond their pharmaceutical interest in pain management, certain TRP channels may represent potential novel therapeutic targets for various immune-related diseases.


Assuntos
Linfócitos T/metabolismo , Canais de Potencial de Receptor Transitório/genética , Canais de Potencial de Receptor Transitório/metabolismo , Animais , Sinalização do Cálcio , Suscetibilidade a Doenças , Regulação da Expressão Gênica , Humanos , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Família Multigênica , Isoformas de Proteínas , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/imunologia
9.
Sci Rep ; 6: 29294, 2016 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-27388773

RESUMO

The transient receptor potential vanilloid 1 (TRPV1) channel is abundantly expressed in peripheral sensory neurons where it acts as an important polymodal cellular sensor for heat, acidic pH, capsaicin, and other noxious stimuli. The oral cavity is densely innervated by afferent sensory neurons and is a highly specialized organ that protects against infections as well as physical, chemical, and thermal stresses in its capacity as the first part of the digestive system. While the function of TRPV1 in sensory neurons has been intensively studied in other organs, its physiological role in periodontal tissues is unclear. In this study we found that Trpv1(-/-) mice developed severe bone loss in an experimental model of periodontitis. Chemical ablation of TRPV1-expressing sensory neurons recapitulated the phenotype of Trpv1(-/-) mice, suggesting a functional link between neuronal TRPV1 signaling and periodontal bone loss. TRPV1 activation in gingival nerves induced production of the neuropeptide, calcitonin gene-related peptide (CGRP), and CGRP treatment inhibited osteoclastogenesis in vitro. Oral administration of the TRPV1 agonist, capsaicin, suppressed ligature-induced bone loss in mice with fewer tartrate-resistant acid phosphatase (TRAP)-positive cells in alveolar bone. These results suggest that neuronal TRPV1 signaling in periodontal tissue is crucial for the regulation of osteoclastogenesis via the neuropeptide CGRP.


Assuntos
Reabsorção Óssea , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Neurônios/metabolismo , Osteogênese , Periodontite/patologia , Canais de Cátion TRPV/metabolismo , Animais , Modelos Animais de Doenças , Camundongos , Camundongos Knockout
10.
Nat Commun ; 7: 11551, 2016 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-27187615

RESUMO

The ERK1/2 MAPK signalling module integrates extracellular cues that induce proliferation and differentiation of epithelial lineages, and is an established oncogenic driver, particularly in the intestine. However, the interrelation of the ERK1/2 module relative to other signalling pathways in intestinal epithelial cells and colorectal cancer (CRC) is unclear. Here we show that loss of Erk1/2 in intestinal epithelial cells results in defects in nutrient absorption, epithelial cell migration and secretory cell differentiation. However, intestinal epithelial cell proliferation is not impeded, implying compensatory mechanisms. Genetic deletion of Erk1/2 or pharmacological targeting of MEK1/2 results in supraphysiological activity of the ERK5 pathway. Furthermore, targeting both pathways causes a more effective suppression of cell proliferation in murine intestinal organoids and human CRC lines. These results suggest that ERK5 provides a common bypass route in intestinal epithelial cells, which rescues cell proliferation upon abrogation of ERK1/2 signalling, with therapeutic implications in CRC.


Assuntos
Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/patologia , Enterócitos/enzimologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Sistema de Sinalização das MAP Quinases , Proteína Quinase 7 Ativada por Mitógeno/metabolismo , Animais , Carcinogênese/metabolismo , Carcinogênese/patologia , Diferenciação Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Homeostase , Humanos , Íleo/patologia , Íleo/ultraestrutura , Integrases/metabolismo , Síndromes de Malabsorção/enzimologia , Síndromes de Malabsorção/patologia , Camundongos Endogâmicos C57BL , Modelos Biológicos , Organoides/metabolismo , Síndrome de Emaciação
11.
Mol Cell Oncol ; 2(1): e975619, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-27308393

RESUMO

TRP channels are associated with the development and progression of cancer but their precise molecular roles in these processes are unclear. Recently, we showed that the transient receptor potential cation channel, subfamily V, member 1 (TRPV1) ion channel is part of a negative feedback loop downstream of epidermal growth factor receptor signaling that suppresses intestinal tumorigenesis.

12.
J Clin Invest ; 124(9): 3793-806, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25083990

RESUMO

The intestinal epithelium has a high rate of turnover, and dysregulation of pathways that regulate regeneration can lead to tumor development; however, the negative regulators of oncogenic events in the intestinal epithelium are not fully understood. Here we identified a feedback loop between the epidermal growth factor receptor (EGFR), a known mediator of proliferation, and the transient receptor potential cation channel, subfamily V, member 1 (TRPV1), in intestinal epithelial cells (IECs). We found that TRPV1 was expressed by IECs and was intrinsically activated upon EGFR stimulation. Subsequently, TRPV1 activation inhibited EGFR-induced epithelial cell proliferation via activation of Ca2+/calpain and resulting activation of protein tyrosine phosphatase 1B (PTP1B). In a murine model of multiple intestinal neoplasia (Apc(Min/+) mice), TRPV1 deficiency increased adenoma formation, and treatment of these animals with an EGFR kinase inhibitor reversed protumorigenic phenotypes, supporting a functional association between TRPV1 and EGFR signaling in IECs. Administration of a TRPV1 agonist suppressed intestinal tumorigenesis in Apc(Min/+) mice, similar to--as well as in conjunction with--a cyclooxygenase-2 (COX-2) inhibitor, which suggests that targeting both TRPV1 and COX-2 has potential as a therapeutic approach for tumor prevention. Our findings implicate TRPV1 as a regulator of growth factor signaling in the intestinal epithelium through activation of PTP1B and subsequent suppression of intestinal tumorigenesis.


Assuntos
Receptores ErbB/fisiologia , Neoplasias Intestinais/prevenção & controle , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Canais de Cátion TRPV/fisiologia , Animais , Cálcio/metabolismo , Canais de Cálcio/fisiologia , Calpaína/fisiologia , Proliferação de Células , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ativação Enzimática , Humanos , Camundongos , Transdução de Sinais , Canais de Cátion TRPV/antagonistas & inibidores
13.
J Clin Invest ; 122(3): 963-73, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22326954

RESUMO

cAMP, the intracellular signaling molecule produced in response to GPCR signaling, has long been recognized as an immunosuppressive agent that inhibits T cell receptor activation and T cell function. However, recent studies show that cAMP also promotes T cell-mediated immunity. Central to cAMP production downstream of GPCR activation is the trimeric G protein Gs. In order to reconcile the reports of divergent effects of cAMP in T cells and to define the direct effect of cAMP in T cells, we engineered mice in which the stimulatory Gα subunit of Gs (Gαs) could be deleted in T cells using CD4-Cre (Gnas(ΔCD4)). Gnas(ΔCD4) CD4(+) T cells had reduced cAMP accumulation and Ca2(+) influx. In vitro and in vivo, Gnas(ΔCD4) CD4(+) T cells displayed impaired differentiation to specific Th subsets: Th17 and Th1 cells were reduced or absent, but Th2 and regulatory T cells were unaffected. Furthermore, Gnas(ΔCD4) CD4(+) T cells failed to provoke colitis in an adoptive transfer model, indicating reduced inflammatory function. Restoration of cAMP levels rescued the impaired phenotype of Gnas(ΔCD4) CD4(+) T cells, reinstated the PKA-dependent influx of Ca2(+), and enhanced the ability of these cells to induce colitis. Our findings thus define an important role for cAMP in the differentiation of Th subsets and their subsequent inflammatory responses, and provide evidence that altering cAMP levels in CD4(+) T cells could provide an immunomodulatory approach targeting specific Th subsets.


Assuntos
AMP Cíclico/metabolismo , Subunidades alfa Gs de Proteínas de Ligação ao GTP/metabolismo , Linfócitos T/citologia , Animais , Linfócitos T CD4-Positivos/citologia , Cálcio/química , Diferenciação Celular , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Inflamação , Interferon gama/metabolismo , Interleucina-17/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Fenótipo , Células Th17/citologia
14.
Cancer Lett ; 298(2): 264-72, 2010 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-20702033

RESUMO

Vascular endothelial growth factor is a potent pro-angiogenic growth factor which is also known to alter tumor microenvironment by inhibiting dendritic cell differentiation and promoting accumulation of myeloid-derived suppressor cells. In the present study, we analyzed the modifications induced by intratumoral expression of sFLT-1, a soluble VEGF receptor, in a rat metastatic colon carcinoma model. We generated colon cancer cell lines stably expressing sFLT-1 or a mock construct. Human umbilical vein endothelial cells cultured with conditioned medium from sFLT-1-expressing tumor cells exhibit a significantly decreased survival, demonstrating the functionality of the secreted sFLT-1. Invivo, sFLT-1 expression induced a 30% decrease in microvessel density in 15-day old experimental liver metastasis from colon carcinoma. Tumor growth was inhibited by 63% and 52% in left and right liver lobes respectively within 25days. In these tumors, sFLT-1 expression was associated with a decreased myeloid cell infiltration and a modification in the expression of several cytokines/chemokines. Altogether, these results suggest that VEGF trapping by sFLT-1 intratumoral expression results in reduced vascularization, tumor growth inhibition and modification of immune tumor microenvironment.


Assuntos
Neoplasias do Colo/metabolismo , Modelos Animais de Doenças , Neoplasias Hepáticas/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quimiocinas/genética , Quimiocinas/metabolismo , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Meios de Cultivo Condicionados/farmacologia , Citocinas/genética , Citocinas/metabolismo , Células Endoteliais/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/secundário , Masculino , Camundongos , Células Mieloides/metabolismo , Células Mieloides/patologia , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Ratos , Ratos Endogâmicos , Transfecção , Carga Tumoral , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética
16.
Autophagy ; 4(8): 1086-9, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18927486

RESUMO

In addition to its clean-up function, autophagy is considered as an innate immunity mechanism due to its role in the removal of intracellular pathogens. Toll-like receptors (TLRs) are crucial components of innate immunity involved in the recognition of a diverse array of microbial products. Recent works demonstrated that different pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS) and single-strand RNA are able to induce autophagy via different TLRs in immune cells. In a recent report, we showed that bacterial CpG motifs, another PAMP, can induce autophagy in rodent and human tumor cell lines and that this process is TLR9-dependent. In addition, an increase in the number of autophagosomes can also be observed in vivo after the intratumoral injection of CpG motifs. These results extend the link between TLRs and autophagy to non-immune tumor cells and may be relevant for cancer treatment and more generally for gene therapy approaches in TLR9-positive tissues. In this addendum, we discuss the potential mechanisms and the consequences of the CpG-induced autophagy in tumor cells.


Assuntos
Autofagia/imunologia , Ilhas de CpG/imunologia , Neoplasias/imunologia , Receptores Toll-Like/imunologia , Humanos , Ligantes , Lipopolissacarídeos/imunologia , Neoplasias/patologia , Oligodesoxirribonucleotídeos/imunologia , Oligodesoxirribonucleotídeos/farmacologia , Receptores Toll-Like/agonistas
17.
Bull Cancer ; 94(3): 243-52, 2007 Mar.
Artigo em Francês | MEDLINE | ID: mdl-17371766

RESUMO

Despite the great promise of gene therapy, its application in humans has been hampered by the inability to efficiently and safely deliver the gene of interest to the target tissue. The severe toxic side effects observed in some clinical trials using viral vectors have regained interest in non-viral methods. These non-viral approaches are associated with low toxicity and immunogenicity as well as an easy and inexpensive manufacturing. The two major problems encountered with these vectors are the low gene transfer efficiency and the transient transgene expression. In this regard, cancer appears as a disease of choice for the use of non-viral vectors as (i) long term transgene expression is not always required, (ii) the low gene transfer efficiency can be relayed by immune system activation and/or local bystander effects. This review focuses on non-viral gene therapy applications for treatment of cancer, and particularly on naked DNA or DNA in association with liposomes (lipoplexes).


Assuntos
DNA/administração & dosagem , Técnicas de Transferência de Genes , Terapia Genética/métodos , Lipossomos/administração & dosagem , Neoplasias/terapia , Animais , Núcleo Celular/metabolismo , Ilhas de CpG/genética , DNA/farmacocinética , Endossomos/metabolismo , Expressão Gênica , Vetores Genéticos , Humanos , Lipossomos/química , Lipossomos/farmacocinética , Camundongos , Neoplasias/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA