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1.
J Immunol ; 195(4): 1713-22, 2015 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-26136430

RESUMO

TGF-ß1 is a master cytokine in immune regulation, orchestrating both pro- and anti-inflammatory reactions. Recent studies show that whereas TGF-ß1 induces a quiescent microglia phenotype, it plays a pathogenic role in the neurovascular unit and triggers neuronal hyperexcitability and epileptogenesis. In this study, we show that, in primary glial cultures, TGF-ß signaling induces rapid upregulation of the cytokine IL-6 in astrocytes, but not in microglia, via enhanced expression, phosphorylation, and nuclear translocation of SMAD2/3. Electrophysiological recordings show that administration of IL-6 increases cortical excitability, culminating in epileptiform discharges in vitro and spontaneous seizures in C57BL/6 mice. Intracellular recordings from layer V pyramidal cells in neocortical slices obtained from IL-6 -: treated mice show that during epileptogenesis, the cells respond to repetitive orthodromic activation with prolonged after-depolarization with no apparent changes in intrinsic membrane properties. Notably, TGF-ß1 -: induced IL-6 upregulation occurs in brains of FVB/N but not in brains of C57BL/6 mice. Overall, our data suggest that TGF-ß signaling in the brain can cause astrocyte activation whereby IL-6 upregulation results in dysregulation of astrocyte -: neuronal interactions and neuronal hyperexcitability. Whereas IL-6 is epileptogenic in C57BL/6 mice, its upregulation by TGF-ß1 is more profound in FVB/N mice characterized as a relatively more susceptible strain to seizure-induced cell death.


Assuntos
Epilepsia/metabolismo , Interleucina-6/metabolismo , Neuroglia/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Eletroencefalografia , Epilepsia/genética , Epilepsia/fisiopatologia , Regulação da Expressão Gênica/efeitos dos fármacos , Interleucina-6/genética , Camundongos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Especificidade de Órgãos/genética , Fosforilação/efeitos dos fármacos , Transporte Proteico , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/administração & dosagem , Fator de Crescimento Transformador beta/farmacologia
2.
J Immunol ; 190(7): 3500-9, 2013 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-23475218

RESUMO

In this study, we assessed the involvement of IL-1ß in early angiogenic responses induced by malignant cells using Matrigel plugs supplemented with B16 melanoma cells. We found that during the angiogenic response, IL-1ß and vascular endothelial growth factor (VEGF) interact in a newly described autoinduction circuit, in which each of these cytokines induces the other. The IL-1ß and VEGF circuit acts through interactions between bone marrow-derived VEGF receptor 1(+)/IL-1R1(+) immature myeloid cells and tissue endothelial cells. Myeloid cells produce IL-1ß and additional proinflammatory cytokines, which subsequently activate endothelial cells to produce VEGF and other proangiogenic factors and provide the inflammatory microenvironment for angiogenesis and tumor progression. These mechanisms were also observed in a nontumor early angiogenic response elicited in Matrigel plugs by either rIL-1ß or recombinant VEGF. We have shown that IL-1ß inhibition stably reduces tumor growth by limiting inflammation and inducing the maturation of immature myeloid cells into M1 macrophages. In sharp contrast, only transient inhibition of tumor growth was observed after VEGF neutralization, followed by tumor recurrence mediated by rebound angiogenesis. This occurs via the reprogramming of VEGF receptor 1(+)/IL-1R1(+) cells to express hypoxia inducible factor-1α, VEGF, and other angiogenic factors, thereby directly supporting proliferation of endothelial cells and blood vessel formation in a paracrine manner. We suggest using IL-1ß inhibition as an effective antitumor therapy and are currently optimizing the conditions for its application in the clinic.


Assuntos
Interleucina-1beta/metabolismo , Melanoma Experimental/metabolismo , Neovascularização Patológica/metabolismo , Animais , Anticorpos Monoclonais/farmacologia , Citocinas/farmacologia , Progressão da Doença , Expressão Gênica , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/genética , Melanoma Experimental/genética , Camundongos , Camundongos Knockout , Células Mieloides/metabolismo , Neovascularização Patológica/genética , Fenótipo , Microambiente Tumoral/genética , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
3.
Eur J Immunol ; 43(3): 758-69, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23255172

RESUMO

Stress activates the hypothalamic-pituitary-adrenocortical axis to promote the release of corticosterone (CORT), which consequently suppresses pathogenic stimulation of the immune system. Paradoxically, however, stress often promotes autoimmunity through yet unknown mechanisms. Here we investigated how chronic variable stress (CVS), and the associated alterations in CORT levels, affect the susceptibility to experimental autoimmune encephalomyelitis (EAE) in female and male C57BL/6 mice. Under baseline (nonstressed) conditions, females exhibited substantially higher CORT levels and an attenuated EAE with less mortality than males. However, CVS induced a significantly worsened EAE in females, which was prevented if CORT signaling was blocked. In addition, females under CVS conditions showed a shift toward proinflammatory Th1/Th17 versus Th2 responses and a decreased proportion of CD4(+) CD25(+) Treg cells. This demonstrates that whereas C57BL/6 female mice generally exhibit higher CORT levels and an attenuated form of EAE than males, they become less responsive to the immunosuppressive effects of CORT under chronic stress and thereby prone to a higher risk of destructive autoimmunity.


Assuntos
Autoimunidade , Suscetibilidade a Doenças/imunologia , Glucocorticoides/fisiologia , Estresse Fisiológico/imunologia , Animais , Ansiedade , Corticosterona/imunologia , Corticosterona/farmacologia , Encefalomielite Autoimune Experimental/etiologia , Feminino , Glucocorticoides/farmacologia , Sistema Hipotálamo-Hipofisário/fisiologia , Terapia de Imunossupressão , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sistema Hipófise-Suprarrenal/fisiologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th17/imunologia
4.
Glia ; 60(7): 1160-71, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22511296

RESUMO

Microglia are myeloid-derived cells that colonize the central nervous system (CNS) at early stages of development and constitute up to 20% of the glial populations throughout life. While extensive progress has been recently made in identifying the cellular origin of microglia, the mechanism whereby the cells acquire the unique ramified and quiescent phenotype within the CNS milieu remains unknown. Here, we show that upon co-culturing of either CD117(+) /Lin(-) hematopoietic progenitors or CD11c(+) bone marrow derived cells with organotypic hippocampal slices or primary glia, the cells acquire a ramified morphology concomitant with reduced levels of CD86, MHCII, and CD11c and up-regulation of the microglial cell-surface proteins CX(3) CR1 and Iba-1. We further demonstrate that the transforming growth factor beta (TGF-ß) signaling pathway via SMAD2/3 phosphorylation is essential for both primary microglia and myeloid-derived cells in order to acquire their quiescent phenotype. Our study suggests that the abundant expression of TGF-ß within the CNS during development and various inflammatory processes plays a key role in promoting the quiescent phenotype of microglia and may thus serve as a target for therapeutic strategies aimed at modulating the function of microglia in neurodegenerative diseases such as Alzheimer's and prion.


Assuntos
Células da Medula Óssea/metabolismo , Microglia/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/farmacologia , Animais , Células da Medula Óssea/efeitos dos fármacos , Receptor 1 de Quimiocina CX3C , Células Cultivadas , Técnicas de Cocultura , Camundongos , Microglia/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Receptores de Quimiocinas/metabolismo , Regulação para Cima/efeitos dos fármacos
5.
J Virol ; 82(15): 7666-76, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18508882

RESUMO

Many viruses escape the cellular immune response by downregulating cell surface expression of major histocompatibility complex (MHC) class I molecules. However, infection of cells with flaviviruses can upregulate the expression of these molecules. In this study we analyzed the expression of MHC class I in K562 and THP-1 human cell lines that were stably transfected with self-replicating subgenomic dengue virus RNA (replicons) and express all the dengue virus nonstructural proteins together. We show that MHC class I expression is upregulated in the dengue virus replicon-expressing cells and that the binding of natural killer (NK) inhibitory receptors to these cells is augmented. This upregulation results in reduced susceptibility of the dengue virus replicon-expressing cells to NK lysis, indicating a possible mechanism for evasion of the dengue virus from NK cell recognition. Visualizing MHC class I expression in replicon-containing K562 and THP-1 cells by confocal microscopy demonstrated aggregation of MHC class I molecules on the cell surface. Finally, replicon-expressing K562 cells manifested increased TAP (transporter associated with antigen processing) and LMP (low-molecular-mass protein) gene transcription, while replicon-expressing THP-1 cells manifested increased NF-kappaB activity and MHC class I transcription. We suggest that expression of dengue virus nonstructural proteins is sufficient to induce MHC class I upregulation through both TAP-dependent and -independent mechanisms. Additionally, aggregation of MHC class I molecules on the cell membrane also contributes to significantly higher binding of low-affinity NK inhibitory receptors, resulting in lower sensitivity to lysis by NK cells.


Assuntos
Citotoxicidade Imunológica , Vírus da Dengue/imunologia , Antígenos de Histocompatibilidade Classe I/biossíntese , Células Matadoras Naturais/imunologia , Proteínas não Estruturais Virais/imunologia , Transportadores de Cassetes de Ligação de ATP/biossíntese , Linhagem Celular , Membrana Celular/química , Testes Imunológicos de Citotoxicidade , Humanos , Microscopia Confocal , NF-kappa B/metabolismo
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