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1.
Genes Dev ; 33(17-18): 1117-1135, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31481536

RESUMO

T-cell development in mammals is a model for lineage choice and differentiation from multipotent stem cells. Although T-cell fate choice is promoted by signaling in the thymus through one dominant pathway, the Notch pathway, it entails a complex set of gene regulatory network and chromatin state changes even before the cells begin to express their signature feature, the clonal-specific T-cell receptors (TCRs) for antigen. This review distinguishes three developmental modules for T-cell development, which correspond to cell type specification, TCR expression and selection, and the assignment of cells to different effector types. The first is based on transcriptional regulatory network events, the second is dominated by somatic gene rearrangement and mutation and cell selection, and the third corresponds to establishing a poised state of latent regulator priming through an unknown mechanism. Interestingly, in different lineages, the third module can be deployed at variable times relative to the completion of the first two modules. This review focuses on the gene regulatory network and chromatin-based kinetic constraints that determine activities of transcription factors TCF1, GATA3, PU.1, Bcl11b, Runx1, and E proteins in the primary establishment of T-cell identity.


Assuntos
Diferenciação Celular , Regulação da Expressão Gênica no Desenvolvimento , Linfócitos T/citologia , Animais , Diferenciação Celular/genética , Linhagem da Célula , Cromatina/metabolismo , Redes Reguladoras de Genes , Hematopoese , Linfócitos T/metabolismo , Timo/citologia , Timo/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
2.
Int J Mol Sci ; 20(11)2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31151139

RESUMO

Here, we investigate the role of RelB in the regulation of genes which were identified to be induced in an aryl hydrocarbon receptor (AhR)-dependent manner and critically involved in regulation of immune responses. We analyzed the expression of genes of the AhR gene battery, cytokines, and immune regulatory enzymes in bone marrow-derived macrophages (BMM) and thymus of B6 wildtype (wt) mice and RelB knockout (RelB-/-) mice after treatment with various AhR ligands. The 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced expression of indoleamine 2,3-dioxygenase 1 (IDO1) and IDO2 was significantly repressed in thymus of RelB-/- mice but not in BMM derived from RelB-/- mice. Interestingly, the induced and basal expression of the cytokines interleukin (IL)-17A, IL-22, and CCL20 required the functional expression of RelB. The RelB-dependent expression of CCL20 was induced by the AhR ligands TCDD and 6-formylindolo[3,2-b]carbazole (FICZ), whereas indole-3-carbinol (I3C) suppressed CCL20 in lipopolysaccharide (LPS)-activated wt BMM. The LPS-induced expression of IL-6 and IL-10 was enhanced by TCDD and FICZ, whereas I3C significantly suppressed these cytokines in BMM. The exposure to FICZ led to higher increases of IL-17A and IL-22 mRNA compared to the effect of TCDD or I3C in thymus of wt mice. On the other hand, TCDD was the strongest inducer of CYP1A1, AhR Repressor (AhRR), and IDO2. In summary, these findings provide evidence for the important role of RelB in the transcriptional regulation of cytokines and enzymes induced by AhR ligands.


Assuntos
Receptores de Hidrocarboneto Arílico/metabolismo , Fator de Transcrição RelB/metabolismo , Animais , Citocinas/genética , Citocinas/metabolismo , Expressão Gênica , Regulação da Expressão Gênica , Imunomodulação/genética , Ligantes , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Knockout , Ligação Proteica , Receptores de Hidrocarboneto Arílico/genética , Timo/imunologia , Timo/metabolismo , Fator de Transcrição RelB/genética
3.
Electromagn Biol Med ; 38(2): 177-183, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31017814

RESUMO

The study investigated the effect of extremely low-frequency electromagnetic fields (ELF-EMFs) exposure at different magnetic flux densities on genes expression of transcription factor Maf (c-Maf), signal transducer and activator of transcription 6 (STAT6), and retinoid-related orphan receptor alpha (RORα) in the spleen and thymus of rats. Eighty adult male rats were separated into four ELF-EMFs exposed and were exposed to magnetic flux densities of 1, 100, 500, and 2000 µT at a frequency of 50 Hz for 2 h daily for up to 60 d. All rats were intraperitoneally immunized on d 31, 44, and 58 of exposure. The experimental results showed that the expression levels of c-Maf, STAT6, and RORα in the thymus were not significantly changed at different magnetic flux densities. The expression levels of RORα and c-Maf were significantly downregulated at the densities of 1 and 100 µT, while the expression of STAT6 was only significantly decreased at the density of 100 µT. In conclusion, low magnetic flux densities of ELF-EMFs may reduce the expression levels of c-Maf, STAT6, and RORα genes in the spleen.


Assuntos
Campos Eletromagnéticos , Regulação da Expressão Gênica/efeitos da radiação , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Proteínas Proto-Oncogênicas c-maf/genética , Fator de Transcrição STAT6/genética , Baço/efeitos da radiação , Timo/efeitos da radiação , Animais , Relação Dose-Resposta à Radiação , Masculino , Ratos , Ratos Wistar , Baço/metabolismo , Timo/metabolismo
4.
Methods Mol Biol ; 1899: 129-142, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30649770

RESUMO

This review briefly describes the last decades of experimental work on the thymus. Given the histological complexity of this organ, the multiple embryological origins of its cellular components and its role in carefully regulating T lymphocyte maturation and function, methods to dissect and understand this complexity have been developed through the years. The possibility to study ex vivo the thymus organ function has been achieved by developing Fetal Thymus Organ Cultures (FTOC). Subsequently, the combination of organ disaggregation and reaggregation in vitro represented by Reaggregate Thymus Organ cultures (RTOC) allowed mixing cellular components from different genetic backgrounds. Moreover, RTOC allowed dissecting the different stromal and hematological components to study the interactions between Major Histocompatibility Complex (MHC) molecules and the T-cell receptors during thymocytes selection. In more recent years, prospective isolation of stromal cells and thymocytes at different stages of development made it possible to explore and elucidate the molecular and cellular players in both the developing and adult thymus. Finally, the appearance of novel cell sources such as embryonic stem (ES) cells and more recently induced pluripotent stem (iPS) cells has opened new scenarios in modelling thymus development and regeneration strategies. Most of the work described was carried out in rodents and the current challenge is to develop equivalent or even more informative assays and tools in entirely human model systems.


Assuntos
Técnicas de Cultura de Órgãos/métodos , Células Estromais/citologia , Timo/citologia , Animais , Diferenciação Celular/genética , Humanos , Timo/metabolismo
5.
Bull Exp Biol Med ; 166(3): 339-343, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30627913

RESUMO

We studied effects of semaphorin 3A, keratinocyte growth factor (KGF), hepatocyte growth factor (HGF), and their combinations on the proliferative activity of cortical (cTEC1-2) and medullary (mTEC3-10) thymus epithelium cell lines. Semaphorin 3A inhibited the proliferative activity of epithelial cells, while HGF and KGF, in contrast, exerted a stimulating effect. The effect of KGF and semaphorin 3A on different cell lines depended on the expression of receptors for these two factors. When the combination of two factors was used, semaphorin 3A was able to neutralize the stimulating effect of HGF and KGF. It can be assumed that semaphorin 3A synthesized in the thymus stroma, can act as a functional antagonist of HGF and KGF and have an inhibitory effect when these drugs are administered into the body for the therapeutic purpose of restoring thymus functions.


Assuntos
Proliferação de Células/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Fator 7 de Crescimento de Fibroblastos/farmacologia , Fator de Crescimento de Hepatócito/farmacologia , RNA Mensageiro/genética , Semaforina-3A/farmacologia , Animais , Linhagem Celular , Combinação de Medicamentos , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Fator 7 de Crescimento de Fibroblastos/genética , Fator 7 de Crescimento de Fibroblastos/metabolismo , Regulação da Expressão Gênica , Fator de Crescimento de Hepatócito/genética , Fator de Crescimento de Hepatócito/metabolismo , Camundongos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neuropilina-1/genética , Neuropilina-1/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , RNA Mensageiro/metabolismo , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Semaforina-3A/genética , Semaforina-3A/metabolismo , Transdução de Sinais , Timo/citologia , Timo/metabolismo
6.
Toxicol Lett ; 304: 30-38, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30605750

RESUMO

Clinical study showed that smoking during pregnancy deceased the thymus size in newborns. However, the long-term effect remains unclear. This study was aimed to observe the effects of prenatal nicotine exposure (PNE) on the development of thymus and the T-lymphocyte subpopulation in mice offspring from the neonatal to adulthood. Both the thymus weight and cytometry data indicated that PNE caused persistent thymic hypoplasia in male offspring from neonatal to adult period and transient changes in female offspring from neonatal to prepuberal period. Flow cytometry analysis disclosed a permanent decreased proportion and number of mature CD4 single-positive (SP) T cells in thymus of both sex. In addition, the PNE male offspring showed a more serious thymus atrophy in the ovalbumin (OVA)-sensitized model. Moreover, increased autophagic vacuole and elevated mRNA expression of Beclin 1 were noted in PNE fetal thymus. In conclusion, PNE offspring showed thymus atrophy and CD 4 SP T cell reduction at different life stages. Mechanically, PNE induced excessive autophagy in fetal thymocytes might be involved in these changes. All the results provided evidence for elucidating the PNE-induced programmed immune diseases.


Assuntos
Linfócitos T CD4-Positivos/efeitos dos fármacos , Doenças do Sistema Imunitário/induzido quimicamente , Nicotina/toxicidade , Agonistas Nicotínicos/toxicidade , Efeitos Tardios da Exposição Pré-Natal , Timócitos/efeitos dos fármacos , Timo/efeitos dos fármacos , Fatores Etários , Animais , Animais Recém-Nascidos , Autofagia/efeitos dos fármacos , Proteína Beclina-1/genética , Proteína Beclina-1/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Feminino , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/metabolismo , Doenças do Sistema Imunitário/patologia , Masculino , Exposição Materna , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia , Fenótipo , Gravidez , Timócitos/imunologia , Timócitos/metabolismo , Timócitos/patologia , Timo/imunologia , Timo/metabolismo , Timo/patologia
7.
PLoS Pathog ; 15(1): e1007456, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30608984

RESUMO

Innate CD8+ T cells express a memory-like phenotype and demonstrate a strong cytotoxic capacity that is critical during the early phase of the host response to certain bacterial and viral infections. These cells arise in the thymus and depend on IL-4 and IL-15 for their development. Even though innate CD8+ T cells exist in the thymus of WT mice in low numbers, they are highly enriched in KO mice that lack certain kinases, leading to an increase in IL-4 production by thymic NKT cells. Our work describes that in C57BL/6 WT mice undergoing a Th1 biased infectious disease, the thymus experiences an enrichment of single positive CD8 (SP8) thymocytes that share all the established phenotypical and functional characteristics of innate CD8+ T cells. Moreover, through in vivo experiments, we demonstrate a significant increase in survival and a lower parasitemia in mice adoptively transferred with SP8 thymocytes from OT I-T. cruzi-infected mice, demonstrating that innate CD8+ thymocytes are able to protect against a lethal T. cruzi infection in an Ag-independent manner. Interestingly, we obtained similar results when using thymocytes from systemic IL-12 + IL-18-treated mice. This data indicates that cytokines triggered during the acute stage of a Th1 infectious process induce thymic production of IL-4 along with IL-15 expression resulting in an adequate niche for development of innate CD8+ T cells as early as the double positive (DP) stage. Our data demonstrate that the thymus can sense systemic inflammatory situations and alter its conventional CD8 developmental pathway when a rapid innate immune response is required to control different types of pathogens.


Assuntos
Interleucina-15/metabolismo , Interleucina-4/metabolismo , Timo/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular/imunologia , Citocinas/metabolismo , Feminino , Imunidade Inata/genética , Interleucina-12/metabolismo , Interleucina-15/genética , Interleucina-18/metabolismo , Interleucina-4/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células T Matadoras Naturais/imunologia , Transdução de Sinais , Células Th1/imunologia , Timócitos/metabolismo , Timo/metabolismo , Timo/patologia
8.
Food Chem Toxicol ; 125: 62-70, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30597219

RESUMO

Effects of Maillard reaction products derived from 1 to 3 kDa soybean peptides (MRPF3) on aging ICR mice were investigated. Seven animal groups were established for 5 weeks, including one normal group and six D-galactose (1000 mg kg-1/day) treated groups. Aging control was D-galactose + saline solution, and positive controls were D-galactose + ascorbic acid (Vc) (400 mg kg-1/day) and oligofructose (400 mg kg-1/day), respectively, while the test groups are D-galactose + high (800 mg kg-1/day), medium (400 mg kg-1/day) and low (200 mg kg-1/day) doses of MRPF3. Compared with the aging controls, food intake, body weights and organ indexes returned to normal after feeding with MRPF3, and the color of feces as well as the fluorescence intensity of urine increased. The content of malondialdehyde (MDA) in the liver significantly decreased with the intake of MRPF3, and the activities of SOD and GSH-Px and the total antioxidant capacity of serum significantly increased. The abundance ratio of Bacteroidetes and Firmicutes significantly decreased in MRPF3 groups, and the abundance of Lactobacillus significantly increased, while potentially pathogenic bacteria such as Porphyromonadaceae significantly decreased. Our results showed that MRPF3 might offer a potent retardation potential for aging.


Assuntos
Envelhecimento/metabolismo , Reação de Maillard , Proteínas de Plantas/farmacologia , Soja/química , Animais , Antioxidantes/farmacologia , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Glutationa Peroxidase/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Proteínas de Plantas/química , Baço/efeitos dos fármacos , Baço/metabolismo , Superóxido Dismutase/metabolismo , Timo/efeitos dos fármacos , Timo/metabolismo
9.
Mech Ageing Dev ; 177: 88-90, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29490231

RESUMO

Cellular senescence, an age-related process in response to damage and stress, also occurs during normal development and adult life. The thymus is a central lymphoepithelial organ of the immune system that exhibits age-related changes termed thymic involution. Since the mechanisms regulating thymic involution are still not well elucidated, we questioned whether cellular senescence is implicated in this process. We demonstrate, for the first time in situ, that cellular senescence occurs during human thymic involution using SenTraGor™, a novel chemical compound that is applicable in archival tissue material, providing thus further insights in thymus histophysiology.


Assuntos
Senescência Celular/fisiologia , Células Epiteliais/metabolismo , Timo/metabolismo , Células Epiteliais/citologia , Humanos , Timo/citologia
10.
Biol Trace Elem Res ; 189(1): 209-223, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30094741

RESUMO

The objective of this study is to construct a digital gene expression tag profile to identify genes potentially related to immune response in the ostrich. Exposure to boron leads to an immune response in the ostrich, although the underlying mechanism remains obscure. Thus, a dire need of biological resource in the form of transcriptomic data for ostriches arises to key out genes and to gain insights into the function of boron on the immune response of thymus. For this purpose, RNA-Seq analysis was performed using the Illumina technique to investigate differentially expressed genes in ostrich thymuses treated with different boric acid concentrations (0, 80, and 640 mg/L). Compared with the control group, we identified 309 upregulated and 593 downregulated genes in the 80 mg/L treated sample and 228 upregulated and 1816 downregulated genes in 640 mg/L treated sample, respectively. Trend analysis of these differentially expressed genes uncovers three statistically significant trends. Functional annotation analysis of the differentially expressed genes verifies multiple functions associated with immune response. When ostrich thymuses were treated with boron, expression changes were observed in genes predominantly associated with MAPK and calcium signaling pathways. The results of this study provide all-inclusive information on gene expression at the transcriptional level that further enhances our apprehension for the molecular mechanisms of boron on the ostrich immune system. The calcium and MAPK signaling pathways might play a pivotal role in regulating the immune response of boron-treated ostriches.


Assuntos
Boro/farmacologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Timo/efeitos dos fármacos , Timo/imunologia , Timo/metabolismo , Animais , Perfilação da Expressão Gênica , Transdução de Sinais/efeitos dos fármacos , Struthioniformes , Transcriptoma/efeitos dos fármacos , Transcriptoma/genética
11.
Stress ; 22(1): 36-43, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29932814

RESUMO

Stress can impair T cell-mediated immunity. To determine if infants with high stress responses had deficits in T-cell mediated immunity, we examined the association of pain-induced cortisol responsiveness with thymic function and vaccine responses in infants. This study was performed among 306 (male = 153 and female = 153) participants of a randomized, controlled trial examining the effect of neonatal vitamin A supplementation on immune function in Bangladesh (NCT01583972). Salivary cortisol was measured before and 20 min after a needle stick (vaccination) at 6 weeks of age. The thymic index (TI) was determined by ultrasonography at 1, 6, 10 and 15 weeks. T-cell receptor excision circle and blood T-cell concentrations were measured at 6 and 15 weeks. Responses to Bacillus Calmette-Guérin (BCG), tetanus toxoid, hepatitis B virus and oral poliovirus vaccination were assayed at 6 and 15 weeks. Cortisol responsiveness was negatively associated with TI at all ages (p < .01) in boys only, was negatively associated with naïve helper T-cell concentrations in both sexes at both 6 (p = .0035) and 15 weeks (p = .0083), and was negatively associated with the delayed-type hypersensitivity (DTH) skin test response to BCG vaccination at 15 weeks (p = .034) in both sexes. Infants with a higher cortisol response to pain have differences in the T-cell compartment and a lower DTH response to vaccination. Sex differences in the immune system were seen as early as 6 weeks of age in these healthy infants.


Assuntos
Vacina BCG/administração & dosagem , Hidrocortisona/metabolismo , Vacina Antipólio Oral/administração & dosagem , Estresse Psicológico/metabolismo , Toxoide Tetânico/administração & dosagem , Timo/metabolismo , Vitamina A/administração & dosagem , Suplementos Nutricionais , Método Duplo-Cego , Feminino , Humanos , Hidrocortisona/imunologia , Lactente , Recém-Nascido , Masculino , Estresse Psicológico/imunologia , Linfócitos T/imunologia , Timo/imunologia , Vitamina A/imunologia
12.
FASEB J ; 33(1): 239-253, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29975569

RESUMO

Reduced fetal nutrition and rapid postnatal growth accelerates the aging phenotype in many organ systems; however, effects on the immune system are unclear. We addressed this by studying the thymus from a rat model of developmental programming. The recuperated group was generated by in utero protein restriction, followed by cross-fostering to control-fed mothers, and were then compared with controls. Fat infiltration and adipocyte size increased with age ( P < 0.001) and in recuperated thymi ( P < 0.05). Cortex/medulla ratio decreased with age ( P < 0.001) and decreased ( P < 0.05) in 12-mo recuperated thymi. Age-associated decreases in thymic-epithelial cell ( P < 0.01) and thymocyte markers ( P < 0.01) were observed in both groups and was decreased ( P < 0.05) in recuperated thymi. These data demonstrate effects of developmental programming upon thymic involution. The recuperated group had longer thymic telomeres than controls ( P < 0.001) at 22 d and at 3 mo, which was associated with increased expression of telomere-length maintenance molecules [telomerase RNA component ( Terc; P < 0.01), P23 ( P = 0.02), and Ku70 and Ku80 ( P < 0.01)]. By 12 mo, recuperated offspring had shorter thymic telomeres than controls had ( P < 0.001) and reduced DNA damage-response markers [( DNA-PKcs, Mre11 ( P < 0.01), Xrcc4 ( P = 0.02), and γ-H2ax ( P < 0.001], suggesting failure of earlier compensatory responses. Our results suggest that low birth weight with rapid postnatal growth results in premature thymic maturation, resulting in accelerated thymic aging. This could lead to increased age-associated vulnerability to infection.-Tarry-Adkins, J. L., Aiken, C. E., Ashmore, T. J., Fernandez-Twinn, D. S., Chen, J.-H., Ozanne, S. E. A suboptimal maternal diet combined with accelerated postnatal growth results in an altered aging profile in the thymus of male rats.


Assuntos
Envelhecimento/patologia , Senescência Celular , Dieta , Desnutrição/fisiopatologia , Fenômenos Fisiológicos da Nutrição Materna , Encurtamento do Telômero , Timo/patologia , Envelhecimento/metabolismo , Animais , Biomarcadores , Dano ao DNA , Feminino , Masculino , Estresse Oxidativo , Ratos , Ratos Wistar , Timo/metabolismo
13.
Immunogenetics ; 71(3): 217-221, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30324237

RESUMO

Positive selection of T cells in the thymus is induced by low-affinity TCR recognition of self-peptide-MHC complexes expressed by cortical thymic epithelial cells (cTECs). cTECs express a specialized type of proteasomes, the thymoproteasome, which generates a unique spectrum of MHC class I-associated peptides and plays a critical role in thymic positive selection of CD8+ T cells. However, it remains unclear how the thymoproteasome contributes to the thymic positive selection. More than 30 years ago, the "peptidic self" hypothesis proposed that TCRs recognize MHC-presented peptides only, without interacting with MHC molecules, which turned out to be incorrect. Interestingly, however, by implying that a set of MHC-associated peptides forms immunological self, this hypothesis also predicted that positive selection in the thymus is the primary immune response to "foreign epitope" peptides during T cell development. The thymoproteasome-dependent unique self-peptides may create those foreign epitope peptides displayed in the thymus for positive selection of T cells.


Assuntos
Apresentação do Antígeno/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Fragmentos de Peptídeos/imunologia , Complexo de Endopeptidases do Proteassoma/imunologia , Linfócitos T/imunologia , Timo/imunologia , Animais , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Fragmentos de Peptídeos/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Linfócitos T/metabolismo , Timo/metabolismo
14.
Fish Physiol Biochem ; 45(1): 133-144, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30056593

RESUMO

Interferon regulatory factors (IRFs) are transcription factors of the interferon (IFN)-inducible signaling pathway essential for host immunity against antimicrobial infection by virus and bacteria. Interferon regulatory factor 3 (IRF3) regulates the expression of IFNs and IFN-stimulated genes by binding to the IFN stimulatory response element (ISRE). In this study, we analyze the thymus transcriptome of the mandarin fish Siniperca chuatsi and report the functional analysis of Irf3 from the thymus as an emerging model of antiviral approaches. The predicted S. chuatsi IRF3 (Sc-Irf3) protein has 465 amino acid residues and evolutionarily conserved domains and is clustered in the IRF3 subfamily on a phylogenetic tree. Sc-Irf3 upon transgenic expression was mainly found in the cytoplasm through Western blot analysis and microscopy, but it translocated to the nucleus after polyinosinic:polycytidylic acid (ploly I:C) treatment. Endogenous Sc-irf3 RNA expression was detected in all eight adult organs examined. Importantly, Sc-irf3 RNA expression was significantly upregulated by ploly(I:C) treatment in the adult organs. Concurrently, reporter assays revealed that Sc-Irf3 increased the transcriptional activity of the ifnß promoter, a minimal ISRE-containing promoter, and ifn promoter of mandarin fish. Therefore, Sc-Irf3 plays a major role in the IFN immune defense system against virus infection.


Assuntos
Regulação da Expressão Gênica/fisiologia , Fator Regulador 3 de Interferon/metabolismo , Interferons/metabolismo , Perciformes/fisiologia , Timo/metabolismo , Animais , Fator Regulador 3 de Interferon/genética , Interferons/genética
15.
PLoS One ; 13(12): e0209364, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30557320

RESUMO

Myocilin is an extracellular glycoprotein with a poorly understood biological function and typically known because of its association with glaucoma. In this study, we analyzed the expression and biological activity of human myocilin in some non-ocular tissues. Western immunoblot showed the presence of myocilin in blood plasma as well as in liver and lymphoid tissues (thymus and lymph node). Quantitative PCR confirmed the expression of MYOC in these lymphoid organs and revealed that its mRNA is also present in T-lymphocytes and leukocytes. In addition, detection of 30 kDa C-terminal myocilin fragments in thymus and liver suggested that myocilin undergoes an in vivo proteolytic processing that might regulate its biological activity. The presence of myocilin in blood was further corroborated by peptide mass fingerprinting of the HPLC-isolated protein, and gross estimation of its concentration by Western immunoblot indicated that it is a medium-abundance serum protein with an approximate concentration of 0.85 mg/ml (15.5 µM). Finally, in vitro analyses indicated that myocilin acts as an anti-adhesive protein for human circulating leukocytes incubated with endothelial cell monolayers. Altogether, these data provide insightful information on new biological properties of myocilin and suggest its putative role as a blood matricellular protein.


Assuntos
Proteínas Sanguíneas/fisiologia , Adesão Celular , Proteínas do Citoesqueleto/fisiologia , Proteínas do Olho/fisiologia , Glicoproteínas/fisiologia , Células Endoteliais da Veia Umbilical Humana/fisiologia , Leucócitos/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas Sanguíneas/análise , Western Blotting , Proteínas do Citoesqueleto/sangue , Proteínas do Olho/sangue , Feminino , Glicoproteínas/sangue , Células HEK293 , Voluntários Saudáveis , Humanos , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Proteólise , RNA Mensageiro/análise , Reação em Cadeia da Polimerase em Tempo Real , Timo/metabolismo
16.
Pol J Vet Sci ; 21(3): 589-597, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30468342

RESUMO

OBJECTIVE: This study aimed to investigate developmental changes of the thymus and intra- thymic IL-1ß, IL-6 and TNF-α expression in weaned Sprague-Dawley rats induced by lipopolysac- charide. METHODS: Forty healthy weaned rats aged 26 days and weighing 83±4 g were randomly and equally divided into two groups. The lipopolysaccharide group was treated daily with a single injection of lipopolysaccharide for 10 consecutive days, and the saline group was treated with an equal volume of sterilized saline. On the 1st, 4th, 7th and 10th day, histological changes and distribu- tion of IL-1ß-, IL-6- and TNF-α-positive cells were detected in the thymus by hematoxylin-eosin and immunohistochemistry staining, respectively. Subsequently, the expression levels of IL-1ß, IL-6 and TNF-α were evaluated in the thymus by the ELISA method. RESULTS: Thymus weight and index were significantly smaller in lipopolysaccharide-treated rats than in saline-treated rats (p⟨0.05), but no substantial changes were found in the thymus microstructure after lipopolysaccharide induction. Moreover, a large number of IL-1ß-, IL-6- and TNF-α-positive cells were observed with brownish-yellow color and mainly distributed in the thy- mus parenchyma, both integrated optical density and average optical density increased signifi- cantly in lipopolysaccharide-treated rats than those in saline-treated rats. Compared with the saline group, most of the thymic homogenates had higher levels of IL-1ß, IL-6 and TNF-α in the lipopolysaccharide group on different days. CONCLUSION: These findings indicate that the thymus atrophied after lipopolysaccharide induction in weaned Sprague-Dawley rats, and excessive production of intrathymic IL-1ß, IL-6 and TNF-α was probably involved in the atrophic process.


Assuntos
Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos/toxicidade , Timo/efeitos dos fármacos , Timo/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Interleucina-1beta/genética , Interleucina-6/genética , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/genética
17.
Int J Mol Sci ; 19(12)2018 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-30469505

RESUMO

Innate immunity is an essential line of defense against pathogen invasion which is gained at birth, and the mechanism involved is mainly to identify pathogen-associated molecular patterns through pattern recognition receptors. STING (stimulator of interferon genes) is a signal junction molecule that hosts the perception of viral nucleic acids and produces type I interferon response, which plays a crucial role in innate immunity. However, relatively few studies have investigated the molecular characterization, tissue distribution, and potential function of STING in chickens. In this study, we cloned the full-length cDNA of chicken STING that is composed of 1341 bp. Sequence analyses revealed that STING contains a 1140-bp open-reading frame that probably encodes a 379-amino acid protein. Multiple sequence alignments showed that the similarity of the chicken STING gene to other birds is higher than that of mammals. Real-time polymerase chain reaction (PCR) assays revealed that STING is highly expressed in the spleen, thymus and bursa of fabricious in chickens. Furthermore, we observed that STING expression was significantly upregulated both in vitro and in vivo following infection with Newcastle disease virus (NDV). STING expression was also significantly upregulated in chicken embryo fibroblasts upon stimulation with poly(I:C) or poly(dA:dT). Taken together, these findings suggest that STING plays an important role in antiviral signaling pathways in chickens.


Assuntos
Proteínas Aviárias/genética , Proteínas de Membrana/genética , Animais , Proteínas Aviárias/química , Proteínas Aviárias/metabolismo , Células Cultivadas , Embrião de Galinha , Galinhas , Clonagem Molecular , Interferons/genética , Interferons/metabolismo , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Doença de Newcastle/imunologia , Fases de Leitura Aberta , Doenças das Aves Domésticas/imunologia , Baço/metabolismo , Timo/metabolismo , Regulação para Cima
18.
Int J Med Sci ; 15(13): 1555-1563, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30443178

RESUMO

Atherosclerosis is one kind of chronic inflammatory disease, in which multiple types of immune cells or factors are involved. Data from experimental and clinical studies on atherosclerosis have confirmed the key roles of immune cells and inflammation in such process. The thymus as a key organ in T lymphocyte ontogenesis has an important role in optimizing immune system function throughout the life, and dysfunction of thymus has been proved to be associated with severity of atherosclerosis. Based on previous research, we begin with the hypothesis that low density lipoprotein or cholesterol reduces the expression of the thymus transcription factor Foxn1 via low density lipoprotein receptors on the membrane surface and low density lipoprotein receptor related proteins on the cell surface, which cause the thymus function decline or degradation. The imbalance of T cell subgroups and the decrease of naive T cells due to thymus dysfunction cause the increase or decrease in the secretion of various inflammatory factors, which in turn aggravates or inhibits atherosclerosis progression and cardiovascular events. Hence, thymus may be the pivotal role in coronary heart disease mediated by atherosclerosis and cardiovascular events and it can imply a novel treatment strategy for the clinical management of patients with atherosclerosis in addition to different commercial drugs. Modulation of immune system by inducing thymus function may be a therapeutic approach for the prevention of atherosclerosis. Purpose of this review is to summarize and discuss the recent advances about the impact of thymus function on atherosclerosis by the data from animal or human studies and the potential mechanisms.


Assuntos
Aterosclerose/metabolismo , Inflamação/metabolismo , Timo/metabolismo , Envelhecimento/genética , Envelhecimento/fisiologia , Animais , Aterosclerose/imunologia , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Humanos , Inflamação/imunologia , Timo/fisiologia
19.
EMBO Rep ; 19(12)2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30361393

RESUMO

T cells play a crucial role in the adaptive immune system, and their maturation process is tightly regulated. Adenosine deaminase acting on RNA 1 (ADAR1) is the enzyme responsible for adenosine-to-inosine RNA editing in dsRNAs, and loss of ADAR1 activates the innate immune sensing response via melanoma differentiation-associated protein 5 (MDA5), which interprets unedited dsRNA as non-self. Although ADAR1 is highly expressed in the thymus, its role in the adaptive immune system, especially in T cells, remains elusive. Here, we demonstrate that T cell-specific deletion of Adar1 in mice causes abnormal thymic T cell maturation including impaired negative selection and autoimmunity such as spontaneous colitis. This is caused by excessive expression of interferon-stimulated genes, which reduces T cell receptor (TCR) signal transduction, due to a failure of RNA editing in ADAR1-deficient thymocytes. Intriguingly, concurrent deletion of MDA5 restores thymocyte maturation and prevents colitis. These findings suggest that prevention of MDA5 sensing of endogenous dsRNA by ADAR1-mediated RNA editing is required for preventing both innate immune responses and T cell-mediated autoimmunity.


Assuntos
Adenosina Desaminase/metabolismo , Autoimunidade , Edição de RNA , Tolerância a Antígenos Próprios , Timo/metabolismo , Adenosina Desaminase/deficiência , Animais , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/metabolismo , Diferenciação Celular/genética , Colite/imunologia , Colite/patologia , Deleção de Genes , Inflamação/imunologia , Inflamação/patologia , Helicase IFIH1 Induzida por Interferon/metabolismo , Interferons/metabolismo , Ativação Linfocitária/imunologia , Camundongos Knockout , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Timócitos/metabolismo , Regulação para Cima/genética
20.
Front Immunol ; 9: 2335, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30369926

RESUMO

Multiple sclerosis (MS) is a chronic, immune-mediated, demyelinating disease that affects the neurons of the central nervous system. Activated T cells, specific for myelin epitopes, cross the brain barriers, and react against the myelin sheath, leading to demyelination. Since T cells are generated within the thymus, here we explored, in mice, the alterations occurring in this organ throughout the different phases of the disease. We induced experimental autoimmune encephalomyelitis (EAE) in C57BL/6 females and sacrifice them at the onset (day 16) and chronic phases of disease (day 23), along with non-induced controls. We observed thymic atrophy in EAE mice at the onset that remained until the chronic phase of disease. This atrophy was associated with a preferential loss of the CD4+CD8+ double positive thymocytes, an intermediate population between the more immature CD4-CD8- double negative and the most mature single positive thymocytes. This was accompanied by an increase in the thymic medullary/cortical ratio and by an altered expression levels of genes important for T cell survival. During the chronic phase, the thymi remained atrophic, but reacquired the normal proportion of the main four thymocyte populations and the normal medullary/cortical ratio. Importantly, at the onset phase, and accompanying these thymic alterations, EAE animals presented an increased percentage of demyelinating lesion area in the cerebellum, and an increased expression of interferon gamma (Ifng), interleukin (Il) 12a, and Il17a. This study suggests dynamic thymic alterations occurring in response to EAE, from the induction to the chronic phase, that might help to elucidate the MS pathophysiology.


Assuntos
Autoimunidade , Imunidade , Glicoproteína Mielina-Oligodendrócito/imunologia , Timo/imunologia , Animais , Atrofia , Biomarcadores , Diferenciação Celular/imunologia , Cerebelo/imunologia , Cerebelo/metabolismo , Cerebelo/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/imunologia , Feminino , Expressão Gênica , Imunofenotipagem , Mediadores da Inflamação/metabolismo , Camundongos , Esclerose Múltipla/imunologia , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Timócitos/imunologia , Timócitos/metabolismo , Timo/metabolismo , Timo/patologia
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