Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 26
Filtrar
Filtros adicionais











Intervalo de ano
1.
J Immunol ; 199(8): 2745-2757, 2017 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-28904129

RESUMO

The control of lymphoid homeostasis is the result of a very fine balance between lymphocyte production, proliferation, and apoptosis. In this study, we focused on the role of T cells in the maintenance/survival of the mature naive peripheral B cell population. We show that naive B and T cells interact via the signaling lymphocyte activation molecule (SLAM) family receptor, SLAMF6. This interaction induces cell type-specific signals in both cell types, mediated by the SLAM-associated protein (SAP) family of adaptors. This signaling results in an upregulation of the expression of the cytokine migration inhibitory factor in the T cells and augmented expression of its receptor CD74 on the B cell counterparts, consequently enhancing B cell survival. Furthermore, in X-linked lymphoproliferative disease patients, SAP deficiency reduces CD74 expression, resulting in the perturbation of B cell maintenance from the naive stage. Thus, naive T cells regulate B cell survival in a SLAMF6- and SAP-dependent manner.


Assuntos
Subpopulações de Linfócitos B/fisiologia , Linfócitos B/fisiologia , Células Sanguíneas/fisiologia , Transtornos Linfoproliferativos/imunologia , Proteína Associada à Molécula de Sinalização da Ativação Linfocitária/metabolismo , Família de Moléculas de Sinalização da Ativação Linfocitária/metabolismo , Linfócitos T/fisiologia , Animais , Anticorpos Bloqueadores/administração & dosagem , Comunicação Celular , Diferenciação Celular , Proliferação de Células , Sobrevivência Celular , Células Cultivadas , Homeostase , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA Interferente Pequeno/genética , Proteína Associada à Molécula de Sinalização da Ativação Linfocitária/genética , Família de Moléculas de Sinalização da Ativação Linfocitária/genética
2.
J Immunol ; 198(12): 4659-4671, 2017 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-28507030

RESUMO

Chemokines and chemokine receptors establish a complex network modulating immune cell migration and localization. These molecules were also suggested to mediate the differentiation of leukocytes; however, their intrinsic, direct regulation of lymphocyte fate remained unclear. CCR2 is the main chemokine receptor inducing macrophage and monocyte recruitment to sites of inflammation, and it is also expressed on T cells. To assess whether CCR2 directly regulates T cell responses, we followed the fates of CCR2-/- T cells in T cell-specific inflammatory models. Our in vitro and in vivo results show that CCR2 intrinsically mediates the expression of inflammatory T cell cytokines, and its absence on T cells results in attenuated colitis progression. Moreover, CCR2 deficiency in T cells promoted a program inducing the accumulation of Foxp3+ regulatory T cells, while decreasing the levels of Th17 cells in vivo, indicating that CCR2 regulates the immune response by modulating the effector/regulatory T ratio.


Assuntos
Imunidade Celular , Receptores CCR2/metabolismo , Linfócitos T Reguladores/imunologia , Animais , Movimento Celular , Colite/imunologia , Citocinas/genética , Citocinas/imunologia , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica , Macrófagos/imunologia , Camundongos , Receptores CCR2/deficiência , Receptores CCR2/genética , Receptores CCR2/imunologia , Receptores CCR5/imunologia , Receptores CCR5/metabolismo , Células Th17/imunologia , Células Th17/fisiologia
3.
Eur J Immunol ; 47(2): 225-235, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28054344

RESUMO

T cells are highly influenced by nutrient uptake from their environment, and changes in overall nutritional status, such as malnutrition or obesity, can result in altered T-cell metabolism and behavior. In states of severe malnutrition or starvation, T-cell survival, proliferation, and inflammatory cytokine production are all decreased, as is T-cell glucose uptake and metabolism. The altered T-cell function and metabolism seen in malnutrition is associated with altered adipokine levels, most particularly decreased leptin. Circulating leptin levels are low in malnutrition, and leptin has been shown to be a key link between nutrition and immunity. The current view is that leptin signaling is required to upregulate activated T-cell glucose metabolism and thereby fuel T-cell activation. In the setting of obesity, T cells have been found to have a key role in promoting the recruitment of inflammatory macrophages to adipose depots along with the production of inflammatory cytokines that promote the development of insulin resistance leading to diabetes. Deletion of T cells, key T-cell transcription factors, or pro-inflammatory T-cell cytokines prevents insulin resistance in obesity and underscores the importance of T cells in obesity-associated inflammation and metabolic disease. Altogether, T cells have a critical role in nutritional immunometabolism.


Assuntos
Alimentos , Inflamação/imunologia , Leptina/metabolismo , Desnutrição/imunologia , Estado Nutricional/imunologia , Obesidade/imunologia , Linfócitos T/metabolismo , Animais , Citocinas/metabolismo , Glucose/metabolismo , Humanos , Resistência à Insulina , Ativação Linfocitária , Transdução de Sinais/imunologia
4.
J Basic Clin Physiol Pharmacol ; 28(2): 167-170, 2017 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-27831921

RESUMO

BACKGROUND: Smoking has a thermogenic effect and is associated with low physical performance. Nevertheless, a direct, quantitative effect of acute smoking on exercise heat tolerance has not been reported. METHODS: Sixteen healthy young male volunteers, eight cigarette smokers, and eight non-smokers participated in the study. All subjects performed a maximal oxygen consumption test (VO2max) and a standardized heat tolerance test (HTT) after at least 12 h without smoking under the following conditions: no nicotine exposure, 10 min after nicotine exposure (2 mg nicotine lozenge), and 10 min after smoking two cigarettes (0.8 mg nicotine in each cigarette, smokers only). RESULTS: There was no significant effect of nicotine exposure on physiological performance and heat tolerance in the non-smokers group. In the smokers group, cigarette smoking, but not nicotine ingestion, resulted with higher heart rate (by 9±9 bpm) at the end of the HTT (p<0.05). Moreover, both smoking and nicotine ingestion increased smokers' rectal temperature at the end of the HTT (by 0.24±0.16°C and 0.21±0.26°C, respectively, p<0.05) and were associated with higher sweat rate during the HTT (by 0.08±0.07 g/h and 0.06±0.08 g/h, respectively, p<0.05). Heart rate variability (HRV) analysis also revealed a higher LF/HF (low frequency/high frequency) ratio after exposure to nicotine and smoking in the smokers group compared with no exposure (2.13±2.57 and 2.48±2.76, respectively, p<0.05), indicating a higher sympathetic tone. CONCLUSIONS: According to this preliminary study, cigarette smoking and nicotine ingestion increase the physiological strain during a HTT in smokers. Acute smoking may, therefore, increase heat intolerance and the risk to heat injuries.


Assuntos
Exercício/fisiologia , Nicotina/efeitos adversos , Fumar/efeitos adversos , Termotolerância/efeitos dos fármacos , Termotolerância/fisiologia , Adulto , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Humanos , Masculino , Nicotina/administração & dosagem , Distribuição Aleatória , Adulto Jovem
5.
Nat Immunol ; 17(12): 1459-1466, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27695003

RESUMO

CD4+ effector T cells (Teff cells) and regulatory T cells (Treg cells) undergo metabolic reprogramming to support proliferation and immunological function. Although signaling via the lipid kinase PI(3)K (phosphatidylinositol-3-OH kinase), the serine-threonine kinase Akt and the metabolic checkpoint kinase complex mTORC1 induces both expression of the glucose transporter Glut1 and aerobic glycolysis for Teff cell proliferation and inflammatory function, the mechanisms that regulate Treg cell metabolism and function remain unclear. We found that Toll-like receptor (TLR) signals that promote Treg cell proliferation increased PI(3)K-Akt-mTORC1 signaling, glycolysis and expression of Glut1. However, TLR-induced mTORC1 signaling also impaired Treg cell suppressive capacity. Conversely, the transcription factor Foxp3 opposed PI(3)K-Akt-mTORC1 signaling to diminish glycolysis and anabolic metabolism while increasing oxidative and catabolic metabolism. Notably, Glut1 expression was sufficient to increase the number of Treg cells, but it reduced their suppressive capacity and Foxp3 expression. Thus, inflammatory signals and Foxp3 balance mTORC1 signaling and glucose metabolism to control the proliferation and suppressive function of Treg cells.


Assuntos
Fatores de Transcrição Forkhead/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia , Receptores Toll-Like/metabolismo , Animais , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Transportador de Glucose Tipo 1/genética , Glicólise , Tolerância Imunológica , Alvo Mecanístico do Complexo 1 de Rapamicina , Metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Complexos Multiproteicos/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
6.
Immunity ; 45(3): 540-554, 2016 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-27637146

RESUMO

Follicular helper T (Tfh) cells are crucial for germinal center (GC) formation and humoral adaptive immunity. Mechanisms underlying Tfh cell differentiation in peripheral and mucosal lymphoid organs are incompletely understood. We report here that mTOR kinase complexes 1 and 2 (mTORC1 and mTORC2) are essential for Tfh cell differentiation and GC reaction under steady state and after antigen immunization and viral infection. Loss of mTORC1 and mTORC2 in T cells exerted distinct effects on Tfh cell signature gene expression, whereas increased mTOR activity promoted Tfh responses. Deficiency of mTORC2 impaired CD4(+) T cell accumulation and immunoglobulin A production and aberrantly induced the transcription factor Foxo1. Mechanistically, the costimulatory molecule ICOS activated mTORC1 and mTORC2 to drive glycolysis and lipogenesis, and glucose transporter 1-mediated glucose metabolism promoted Tfh cell responses. Altogether, mTOR acts as a central node in Tfh cells by linking immune signals to anabolic metabolism and transcriptional activity.


Assuntos
Diferenciação Celular/imunologia , Glucose/metabolismo , Complexos Multiproteicos/metabolismo , Transdução de Sinais/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Células Cultivadas , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Imunidade Humoral/imunologia , Ativação Linfocitária/imunologia , Alvo Mecanístico do Complexo 1 de Rapamicina , Alvo Mecanístico do Complexo 2 de Rapamicina , Camundongos , Camundongos Endogâmicos C57BL , Complexos Multiproteicos/imunologia , Serina-Treonina Quinases TOR/imunologia
7.
J Immunol ; 197(6): 2532-40, 2016 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-27511728

RESUMO

Leukemia can promote T cell dysfunction and exhaustion that contributes to increased susceptibility to infection and mortality. The treatment-independent mechanisms that mediate leukemia-associated T cell impairments are poorly understood, but metabolism tightly regulates T cell function and may contribute. In this study, we show that B cell leukemia causes T cells to become activated and hyporesponsive with increased PD-1 and TIM3 expression similar to exhausted T cells and that T cells from leukemic hosts become metabolically impaired. Metabolic defects included reduced Akt/mammalian target of rapamycin complex 1 (mTORC1) signaling, decreased expression of the glucose transporter Glut1 and hexokinase 2, and reduced glucose uptake. These metabolic changes correlated with increased regulatory T cell frequency and expression of PD-L1 and Gal-9 on both leukemic and stromal cells in the leukemic microenvironment. PD-1, however, was not sufficient to drive T cell impairment, as in vivo and in vitro anti-PD-1 blockade on its own only modestly improved T cell function. Importantly, impaired T cell metabolism directly contributed to dysfunction, as a rescue of T cell metabolism by genetically increasing Akt/mTORC1 signaling or expression of Glut1 partially restored T cell function. Enforced Akt/mTORC1 signaling also decreased expression of inhibitory receptors TIM3 and PD-1, as well as partially improved antileukemia immunity. Similar findings were obtained in T cells from patients with acute or chronic B cell leukemia, which were also metabolically exhausted and had defective Akt/mTORC1 signaling, reduced expression of Glut1 and hexokinase 2, and decreased glucose metabolism. Thus, B cell leukemia-induced inhibition of T cell Akt/mTORC1 signaling and glucose metabolism drives T cell dysfunction.


Assuntos
Transportador de Glucose Tipo 1/antagonistas & inibidores , Glucose/metabolismo , Leucemia Linfocítica Crônica de Células B/imunologia , Complexos Multiproteicos/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Linfócitos T/imunologia , Serina-Treonina Quinases TOR/metabolismo , Animais , Metabolismo dos Carboidratos , Linhagem Celular Tumoral , Glucose/antagonistas & inibidores , Transportador de Glucose Tipo 1/genética , Glicólise , Humanos , Ativação Linfocitária , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Baço/citologia , Baço/imunologia
8.
Cell Metab ; 23(4): 649-62, 2016 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-27076078

RESUMO

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy associated with Notch pathway mutations. While both normal activated and leukemic T cells can utilize aerobic glycolysis to support proliferation, it is unclear to what extent these cell populations are metabolically similar and if differences reveal T-ALL vulnerabilities. Here we show that aerobic glycolysis is surprisingly less active in T-ALL cells than proliferating normal T cells and that T-ALL cells are metabolically distinct. Oncogenic Notch promoted glycolysis but also induced metabolic stress that activated 5' AMP-activated kinase (AMPK). Unlike stimulated T cells, AMPK actively restrained aerobic glycolysis in T-ALL cells through inhibition of mTORC1 while promoting oxidative metabolism and mitochondrial Complex I activity. Importantly, AMPK deficiency or inhibition of Complex I led to T-ALL cell death and reduced disease burden. Thus, AMPK simultaneously inhibits anabolic growth signaling and is essential to promote mitochondrial pathways that mitigate metabolic stress and apoptosis in T-ALL.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Glicólise , Mitocôndrias/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Animais , Linhagem Celular Tumoral , Sobrevivência Celular , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos Endogâmicos C57BL , Mitocôndrias/patologia , Complexos Multiproteicos/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Receptores Notch/metabolismo , Transdução de Sinais , Estresse Fisiológico , Linfócitos T/metabolismo , Linfócitos T/patologia , Serina-Treonina Quinases TOR/metabolismo
9.
Inflamm Bowel Dis ; 22(2): 257-67, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26529559

RESUMO

The continuous recirculation of mature lymphocytes and their entry into the peripheral lymph nodes are crucial for the development of an immune response to foreign antigens. Occasionally, the entry and the subsequent response of T lymphocytes in these sites lead to severe inflammation and pathological conditions. Here, we characterized the tetraspanin molecule, CD151, as a regulator of T cell motility in health and in models of inflammatory bowel disease. CD151 formed a cell surface complex with VLA-4 and LFA-1 integrins, and its activation led to enhanced migration of T cells. Picomolar levels of CCL2 that were previously shown to inhibit T-cell migration to lymph nodes suppressed CD151 expression and dissociated CD151-integrin complexes in T lymphocytes, resulting in attenuated migration toward T-cell attractant chemokines. To directly inhibit CD151 function, a truncated CD151 peptide fragment mimicking of the CD151 extracellular loop was designed. CD151 extracellular loop inhibited T-cell migration in vitro and in vivo and attenuated the development of dextrane sulfate sodium-induced colitis. Thus, CD151 is a key orchestrator of T cell motility; interference with its proper function results in attenuated progression of inflammatory bowel disease.


Assuntos
Movimento Celular/imunologia , Colite Ulcerativa/imunologia , Doença de Crohn/imunologia , Inflamação/imunologia , Linfócitos T/imunologia , Tetraspanina 24/fisiologia , Animais , Estudos de Casos e Controles , Movimento Celular/fisiologia , Seguimentos , Proteínas de Homeodomínio/fisiologia , Humanos , Antígenos Comuns de Leucócito/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Prognóstico , Receptores CCR2/fisiologia
10.
Br J Pharmacol ; 171(4): 888-95, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24111754

RESUMO

UNLABELLED: In healthy individuals, the pool of peripheral lymphocytes is constant in size. The control of lymphoid homeostasis is the result of a very fine balance between lymphocyte production, survival and proliferation. Survival factors have been shown to play a critical role in maintaining the correct size of lymphocyte populations. Midkine, a heparin-binding cytokine was recently shown to be involved in cell proliferation, differentiation and apoptosis in various cell types including normal and malignant B cells. This review focuses on the role of midkine in the regulation of peripheral B cell survival in health and disease. LINKED ARTICLES: This article is part of a themed section on Midkine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-4.


Assuntos
Linfócitos B/imunologia , Citocinas/imunologia , Animais , Linfócitos B/citologia , Diferenciação Celular , Sobrevivência Celular , Citocinas/metabolismo , Humanos , Midkina , Neoplasias/imunologia , Neoplasias/metabolismo
11.
Clin Radiol ; 68(12): 1212-9, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23937823

RESUMO

AIM: To report the computed tomography (CT) findings of acute and complicated appendicitis in adults with incidental midgut malrotation. MATERIALS AND METHODS: The medical records and CT studies of eight patients with appendicitis and incidental midgut malrotation who presented to two medical centres between 1998 and 2009 were reviewed. RESULTS: All patients presented with 1-5 days of acute abdominal pain, which was diffuse in two, left-sided in two, lower abdominal in two, and in the right lower quadrant in two patients. The inflamed appendix was right-sided in three, left-sided in three, and in the midline in two patients. Three cases were complicated by a peri-appendicular abscess, and one patient also had a small bowel obstruction. All patients had a complete non-rotation with right-sided duodenum and jejunum, and left-sided colon. All eight patients had an abnormal superior mesenteric artery-superior mesenteric vein (SMA/SMV) relationship and a dysplastic uncinate process of the pancreas. Urgent surgery was performed in six patients and the remaining two were treated conservatively. CONCLUSION: Altered anatomy in malrotation affects the typical clinical and CT findings of acute appendicitis, therefore delaying diagnosis. When CT shows focal inflammation anywhere within the abdomen, along with an abnormal SMA/SMV relationship, the position of the caecum should be ascertained and acute appendicitis ruled out.


Assuntos
Apendicite/diagnóstico por imagem , Anormalidades do Sistema Digestório/diagnóstico por imagem , Volvo Intestinal/diagnóstico por imagem , Dor Abdominal/diagnóstico por imagem , Dor Abdominal/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Apendicite/complicações , Anormalidades do Sistema Digestório/complicações , Feminino , Humanos , Achados Incidentais , Volvo Intestinal/complicações , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tomografia Computadorizada por Raios X
12.
J Allergy Clin Immunol ; 131(2): 477-85.e1, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23374270

RESUMO

BACKGROUND: Profound combined immunodeficiency can present with normal numbers of T and B cells, and therefore the functional defect of the cellular and humoral immune response is often not recognized until the first severe clinical manifestation. Here we report a patient of consanguineous descent presenting at 13 months of age with hypogammaglobulinemia, Pneumocystis jirovecii pneumonia, and a suggestive family history. OBJECTIVE: We sought to identify the genetic alteration in a patient with combined immunodeficiency and characterize human caspase recruitment domain family, member 11 (CARD11), deficiency. METHODS: Molecular, immunologic, and functional assays were performed. RESULTS: The immunologic characterization revealed only subtle changes in the T-cell and natural killer cell compartment, whereas B-cell differentiation, although normal in number, was distinctively blocked at the transitional stage. Genetic evaluation revealed a homozygous deletion of exon 21 in CARD11 as the underlying defect. This deletion abrogated protein expression and activation of the canonical nuclear factor κB (NF-κB) pathway in lymphocytes after antigen receptor or phorbol 12-myristate 13-acetate stimulation, whereas CD40 signaling in B cells was preserved. The abrogated activation of the canonical NF-κB pathway was associated with severely impaired upregulation of inducible T-cell costimulator, OX40, cytokine production, proliferation of T cells, and B cell-activating factor receptor expression on B cells. CONCLUSION: Thus in patients with CARD11 deficiency, the combination of impaired activation and especially upregulation of inducible T-cell costimulator on T cells, together with severely disturbed peripheral B-cell differentiation, apparently leads to a defective T-cell/B-cell cooperation and probably germinal center formation and clinically results in severe immunodeficiency. This report discloses the crucial and nonredundant role of canonical NF-κB activation and specifically CARD11 in the antigen-specific immune response in human subjects.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/deficiência , Guanilato Ciclase/deficiência , Síndromes de Imunodeficiência/enzimologia , Deleção de Sequência , Agamaglobulinemia/enzimologia , Agamaglobulinemia/genética , Agamaglobulinemia/imunologia , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/imunologia , Feminino , Guanilato Ciclase/genética , Guanilato Ciclase/imunologia , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Lactente
13.
Biochim Biophys Acta ; 1833(5): 1104-13, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23313050

RESUMO

The NIMA-related kinases (NRK or Nek) are emerging as conserved and crucial regulators of mitosis and cilia formation. The microtubule (MT) network has long been suspected as a major target of the Neks. However, the underlying mechanism remains unclear. Using the PlusTipTracker software, recently developed by the Danuser group, we followed the consequences of alterations in Nek7 levels on MT dynamic instability. siRNA-mediated downregulation of Nek7 in HeLa cells resulted in lower speeds of MT growth and catastrophe, reduction of the relative time spent in catastrophe, and considerably lowered the overall MT dynamicity. Co-expression of Nek7 with the siRNA treatment rescued the MT phenotypes, while ectopic overexpression of Nek7 yielded inverse characteristics compared to Nek7 downregulation. MT dynamics in mouse embryonic fibroblasts derived from targeted null mutants for Nek7 recapitulated the siRNA downregulation phenotypes. Precise MT dynamic instability is critical for accurate shaping of the mitotic spindle and for cilium formation, and higher MT dynamicity is associated with tumorigenicity. Thus, our results can supply a mechanistic explanation for Nek involvement in these processes.


Assuntos
Cílios , Microtúbulos , Proteínas Serina-Treonina Quinases , Fuso Acromático/genética , Animais , Centrossomo/metabolismo , Cílios/genética , Cílios/metabolismo , Regulação para Baixo , Fibroblastos/citologia , Fibroblastos/metabolismo , Células HeLa , Humanos , Camundongos , Microtúbulos/genética , Microtúbulos/metabolismo , Mitose , Quinases Relacionadas a NIMA , Proteínas Serina-Treonina Quinases/genética , RNA Interferente Pequeno
14.
Cytokine ; 60(1): 13-22, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22784632

RESUMO

Adaptive immunity depends on the production and maintenance of a pool of mature peripheral lymphocytes throughout life. The signals regulating the survival of mature splenic B cells have become a major focus in recent studies of B cell immunology. Lasting B cell persistence in the periphery is dependent on survival signals that are transduced by cell surface receptors. Cytokines have been shown to play a critical role in maintaining lymphocyte homeostasis. This review focuses on the role of cytokines and their receptors in the regulation of peripheral B cell survival, with an emphasis on those that have received relatively less attention in the literature.


Assuntos
Linfócitos B/imunologia , Proliferação de Células , Citocinas/imunologia , Receptores de Citocinas/imunologia , Linfócitos B/metabolismo , Sobrevivência Celular/imunologia , Citocinas/metabolismo , Homeostase/imunologia , Humanos , Modelos Imunológicos , Receptores de Citocinas/metabolismo , Baço/imunologia , Baço/metabolismo
15.
FEBS Lett ; 586(18): 2906-10, 2012 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-22841548

RESUMO

Chronic lymphocytic leukemia (CLL), the most common adult leukemia in the Western world, is characterized by the progressive accumulation of small mature CD5(+)B lymphocytes in the peripheral blood, lymphoid organs, and bone marrow (BM). The main feature of the disease is decreased apoptosis, resulting in the pathologic accumulation of these malignant cells. Appropriate cellular responses to changes in oxygen tension during normal development or pathological processes, such as cardiovascular disease and cancer, are ultimately regulated by the transcription factor, hypoxia-inducible factor (HIF). Unlike their normal counterparts, CLL cells express HIF-1α even under normoxia. In addition, overexpression of HIF-1α has been observed in leukemic cells in BM specimens from CLL patients. The HIF transcription factor has been implicated in controlling the expression of a wide variety of genes implicated in apoptosis, angiogenesis, invasion, and metastasis. This review describes pathways regulating CLL survival with a focus on HIF-1α and its target genes, MIF and Midkine (MK), and the potential cross-talk between these factors.


Assuntos
Fator 1 Induzível por Hipóxia/fisiologia , Leucemia Linfocítica Crônica de Células B/patologia , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/metabolismo
16.
J Immunol ; 188(1): 259-69, 2012 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-22140262

RESUMO

Lasting B cell persistence depends on survival signals that are transduced by cell surface receptors. In this study, we describe a novel biological mechanism essential for survival and homeostasis of normal peripheral mature B cells and chronic lymphocytic leukemia cells, regulated by the heparin-binding cytokine, midkine (MK), and its proteoglycan receptor, the receptor-type tyrosine phosphatase ζ (RPTPζ). We demonstrate that MK initiates a signaling cascade leading to B cell survival by binding to RPTPζ. In mice lacking PTPRZ, the proportion and number of the mature B cell population are reduced. Our results emphasize a unique and critical function for MK signaling in the previously described MIF/CD74-induced survival pathway. Stimulation of CD74 with MIF leads to c-Met activation, resulting in elevation of MK expression in both normal mouse splenic B and chronic lymphocytic leukemia cells. Our results indicate that MK and RPTPζ are important regulators of the B cell repertoire. These findings could pave the way toward understanding the mechanisms shaping B cell survival and suggest novel therapeutic strategies based on the blockade of the MK/RPTPζ-dependent survival pathway.


Assuntos
Antígenos de Diferenciação de Linfócitos B/imunologia , Linfócitos B/imunologia , Citocinas/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Glicoproteínas de Membrana/imunologia , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/imunologia , Receptores de Fatores de Crescimento/imunologia , Transdução de Sinais/imunologia , Animais , Antígenos de Diferenciação de Linfócitos B/genética , Antígenos de Diferenciação de Linfócitos B/metabolismo , Linfócitos B/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Sobrevivência Celular/imunologia , Citocinas/genética , Citocinas/metabolismo , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/imunologia , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Midkina , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/imunologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/genética , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/metabolismo , Receptores de Fatores de Crescimento/genética , Receptores de Fatores de Crescimento/metabolismo , Transdução de Sinais/genética , Baço/imunologia , Baço/metabolismo
17.
Transplantation ; 91(4): 398-405, 2011 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-21192322

RESUMO

BACKGROUND: Xenogeneic embryonic pancreatic tissue can provide an attractive alternative for organ replacement therapy. However, immunological rejection represents a major obstacle. This study examines the potential of regulatory T cells (Tregs) in the prevention of E42 pancreas rejection. METHODS: To develop new approaches to combat rejection, we evaluated engraftment, growth, and development of E42 pig pancreatic tissue in mice treated with ex vivo expanded Tregs in combination with T-cell debulking and the conventional immunosuppressive drugs, rapamycin and FTY720. RESULTS: Transplantation of E42 pig pancreas into C57BL/6 mice immunosuppressed by this protocol resulted in complete rejection within less than 6 weeks. In contrast, additional treatment with a single infusion of ex vivo expanded third-party Tregs markedly delayed the onset of graft rejection to 10 weeks. The infusion of Tregs was associated with a significant reduction in CD4 and CD8 expansion in the lymph nodes and other peripheral organs at the priming stages after implantation. Freezing and thawing of the Tregs did not affect their efficacy, indicating the potential of Tregs banking. CONCLUSION: Considering the technical difficulties encountered in the generation of Tregs from patients or from specific donors, our results demonstrate the feasibility of using "off-the-shelf" fresh or frozen third-party Tregs to control rejection in organ transplantation.


Assuntos
Diabetes Mellitus/cirurgia , Transplante de Pâncreas/imunologia , Suínos/imunologia , Linfócitos T Reguladores/imunologia , Tolerância ao Transplante , Transplante Heterólogo/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Embrião de Mamíferos/imunologia , Cloridrato de Fingolimode , Sobrevivência de Enxerto/imunologia , Imunossupressores/uso terapêutico , Insulina/sangue , Camundongos , Camundongos Endogâmicos C57BL , Propilenoglicóis/uso terapêutico , Sirolimo/uso terapêutico , Esfingosina/análogos & derivados , Esfingosina/uso terapêutico , Suínos/embriologia
18.
World J Gastroenterol ; 16(26): 3258-66, 2010 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-20614481

RESUMO

AIM: To investigate the expression and function of CD74 in normal murine colon epithelial cells (CEC) and colon carcinoma cells. METHODS: Expression of CD74 mRNA and protein were measured by reverse transcriptase-polymerase chain reaction (RT-PCR), Western blotting and fluorescence-activated cell sorter (FACS). The effect of migration inhibitory factor (MIF) on the survival of normal CEC from C57BL/6, NOD/SCID, and CD74 deficient mice both in vitro and in vivo, and on the CT26 carcinoma cell line was analyzed by (quantitative) qRT-PCR, RT-PCR, Western blotting and FACS. RESULTS: CD74 was found to be expressed on normal CEC. Stimulation of CD74 by MIF induced a signaling cascade leading to up-regulation of Bcl-2 expression, resulting in a significant increased survival of CEC. CD74 was also expressed on the CT26 colon carcinoma cell line and its stimulation by MIF resulted in enhanced cell survival, up-regulation of Akt phosphorylation and Bcl-2 expression. CONCLUSION: CD74 is expressed on CEC and colon carcinoma cells and serves as a survival receptor in these cells. These results may have implications on colorectal cancer research.


Assuntos
Antígenos de Diferenciação de Linfócitos B/genética , Antígenos de Diferenciação de Linfócitos B/metabolismo , Colo/citologia , Colo/imunologia , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/metabolismo , Animais , Sequência de Bases , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Colo/efeitos dos fármacos , Colo/metabolismo , Neoplasias do Colo/genética , Neoplasias do Colo/imunologia , Neoplasias do Colo/metabolismo , Primers do DNA/genética , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Técnicas In Vitro , Fatores Inibidores da Migração de Macrófagos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Proteínas Recombinantes/farmacologia
19.
J Immunol ; 185(4): 2020-31, 2010 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-20639480

RESUMO

The signals regulating the survival of mature splenic B cells have become a major focus in recent studies of B cell immunology. Durable B cell persistence in the periphery is dependent on survival signals that are transduced by cell surface receptors. In this study, we describe a novel biological mechanism involved in mature B cell homeostasis, the hepatocyte growth factor/scatter factor (HGF)/c-Met pathway. We demonstrate that c-Met activation by HGF leads to a survival cascade, whereas its blockade results in induction of mature B cell death. Our results emphasize a unique and critical function for c-Met signaling in the previously described macrophage migration inhibitory factor/CD74-induced survival pathway. Macrophage migration inhibitory factor recruits c-Met to the CD74/CD44 complex and thereby enables the induction of a signaling cascade within the cell. This signal results in HGF secretion, which stimulates the survival of the mature B cell population in an autocrine manner. Thus, the CD74-HGF/c-Met axis defines a novel physiologic survival pathway in mature B cells, resulting in the control of the humoral immune response.


Assuntos
Antígenos de Diferenciação de Linfócitos B/metabolismo , Linfócitos B/metabolismo , Fator de Crescimento de Hepatócito/metabolismo , Antígenos de Histocompatibilidade Classe II/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Animais , Antígenos de Diferenciação de Linfócitos B/genética , Apoptose/efeitos dos fármacos , Linfócitos B/citologia , Western Blotting , Membrana Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Citometria de Fluxo , Fator de Crescimento de Hepatócito/genética , Fator de Crescimento de Hepatócito/farmacologia , Antígenos de Histocompatibilidade Classe II/genética , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/metabolismo , Fatores Inibidores da Migração de Macrófagos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ligação Proteica , Proteínas Proto-Oncogênicas c-met/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos
20.
Transplantation ; 89(10): 1198-207, 2010 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-20195218

RESUMO

BACKGROUND: We recently defined the optimal gestational time windows for the transplantation of several embryonic tissues. We showed that the liver and kidney obtained from E28 pig embryos can grow and differentiate normally after transplantation, whereas 1 week earlier in gestation, these tissues develop into teratoma-like structures or fibrotic mass. In this study, we investigated whether cotransplantation of E28 with E21 tissue could control its tumorogenic potential, or alternatively whether the stem cells derived from the earlier tissue contribute to the growth of the more committed one. METHODS: Pig embryonic precursors from E21 and E28 gestational age were transplanted alone or together, into nonobese diabetic/severe combined immunodeficiency mice, and their growth and differentiation was evaluated by immunohistology. In situ analysis, based on sex disparity between the E21 and E28 tissues, was used to identify the tissue source. In some experiments, mouse embryonic fibroblasts (MEF) were cotransplanted with E28 liver, and their effect was evaluated. RESULTS: E28 tissues could not abrogate the propensity of the cells within the undifferentiated tissue to form teratoma-like structures. However, E21 kidney or liver tissue markedly enhanced the growth and function of E28 kidney, liver, and heart grafts. Moreover, similar growth enhancement was observed on coimplantation of E28 liver tissue with MEF or on infusion of MEF culture medium, indicating that this enhancement is likely mediated through soluble factors secreted by the fibroblasts. CONCLUSION: Our results suggest a novel approach for the enhancement of growth and differentiation of transplanted embryonic tissues by the use of soluble factors secreted by embryonic fibroblasts.


Assuntos
Fibroblastos/transplante , Suínos/embriologia , Transplante de Tecidos/métodos , Animais , Diferenciação Celular , Feminino , Fibroblastos/citologia , Idade Gestacional , Transplante de Coração/patologia , Transplante de Coração/fisiologia , Rim/embriologia , Transplante de Rim/patologia , Transplante de Rim/fisiologia , Fígado/embriologia , Fígado/crescimento & desenvolvimento , Transplante de Fígado/patologia , Transplante de Fígado/fisiologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Gravidez , Transplante de Células-Tronco/métodos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA