Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 411
Filtrar
1.
BMB Rep ; 52(3): 214-219, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30670152

RESUMO

The role of tumor-proximal factors in tumor plasticity during chemoresistance and metastasis following chemotherapy is well studied. However, the role of endothelial cell (EC) derived paracrine factors in tumor plasticity, their effect on chemotherapeutic outcome, and the mechanism by which these paracrine factors modulate the tumor microenvironment are not well understood. In this study, we report a novel mechanism by which endothelial miR-125a and let-7e-mediated regulation of interleukin-6 (IL-6) signaling can manipulate vasculogenic mimicry (VM) formation of MDA-MB-231 breast cancer cells. We found that endothelial IL-6 levels were significantly higher in response to cisplatin treatment, whereas levels of IL-6 upon cisplatin exposure remained unchanged in MDA-MB-231 breast cancer cells. We additionally found an inverse correlation between IL-6 and miR-125a/let-7e expression levels in cisplatin treated ECs. Interestingly, IL-6, IL-6 receptor (IL-6R), and signal transducer and activator of transcription 3 (STAT3) genes in the IL-6 pathway are closely regulated by miR-125a and let-7e, which directly target its 3' untranslated region. Functional analyses revealed that endothelial miR-125a and let-7e inhibit IL-6-induced adhesion of monocytes to ECs. Furthermore, conditioned medium from cisplatin treated ECs induced a significantly higher formation of VM in MDA-MB-231 breast cancer cells as compared to that from intact ECs; this effect of cisplatin treatment was abrogated by concurrent overexpression of miR-125a and let-7e. Overall, this study reveals a novel EC-tumor cell crosstalk mediated by the endothelial miR-125a/let-7e-IL-6 signaling axis, which might improve chemosensitivity and provide potential therapeutic targets for the treatment of cancer. [BMB Reports 2019; 52(3): 214-219].


Assuntos
Neoplasias da Mama/irrigação sanguínea , Interleucina-6/metabolismo , MicroRNAs/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Diferenciação Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Cisplatino/farmacologia , Regulação para Baixo , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Feminino , Células HEK293 , Células Endoteliais da Veia Umbilical Humana , Humanos , Interleucina-6/genética , MicroRNAs/antagonistas & inibidores , MicroRNAs/biossíntese , MicroRNAs/genética , Receptores de Interleucina-7/genética , Receptores de Interleucina-7/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais
2.
J Immunol ; 202(4): 1137-1144, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30651344

RESUMO

Thymus autonomy is the capacity of the thymus to maintain T lymphocyte development and export independently of bone marrow contribution. Prolonging thymus autonomy was shown to be permissive to the development of T cell acute lymphoblastic leukemia (T-ALL), similar to the human disease. In this study, performing thymus transplantation experiments in mice, we report that thymus autonomy can occur in several experimental conditions, and all are permissive to T-ALL. We show that wild type thymi maintain their function of T lymphocyte production upon transplantation into recipients with several genotypes (and corresponding phenotypic differences), i.e., Rag2 - / - γc - / -, γc - / -, Rag2 - / - IL-7rα - / -, and IL-7rα - / - We found that the cellularity of the thymus grafts is influenced exclusively by the genotype of the host, i.e., IL-7rα-/- versus γc -/- Nonetheless, the difference in cellularity detected in thymus autonomy bore no impact on onset, incidence, immunophenotype, or pathologic condition of T-ALL. In all tested conditions, T-ALL reached an incidence of 80%, demonstrating that thymus autonomy bears a high risk of leukemia. We also analyzed the microbiota composition of the recipients and their genetic background, but none of the differences found influenced the development of T-ALL. Taken together, our data support that IL-7 drives cellular turnover non-cell autonomously, which is required for prevention of T-ALL. We found no influence for T-ALL in the specific combination of the genotypic mutations tested (including the developmental block caused by Rag deficiency), in microbiota composition, or minor differences in the genetic background of the strains.


Assuntos
Leucemia-Linfoma Linfoblástico de Células T Precursoras/imunologia , Receptores de Interleucina-7/imunologia , Timo/imunologia , Animais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Receptores de Interleucina-7/deficiência , Receptores de Interleucina-7/genética
3.
Clin Respir J ; 12(4): 1607-1614, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28960939

RESUMO

BACKGROUND: Long non-coding RNAs (lncRNAs) regulate a variety of genes and biological processes. Lnc-IL7R plays a considerable role in the regulation of inflammation, but its prognostic potential in acute respiratory distress syndrome (ARDS) has not been fully explained. In this study, the role of lnc-IL7R as a potential biomarker in ARDS was examined. OBJECTIVE: Role of lnc-IL7R as potential biomarker in ARDS. METHODS: LncRNA-IL7R was isolated from the plasma of patients with ARDS and healthy controls and clinical indexes were obtained within 24 h after admission. The relative expression of lnc-IL7R was obtained by quantitative real-time PCR. The correlations between lnc-IL7R and continuous variables in ARDS were tested using Spearman's coefficients. RESULTS: A total of 85 ARDS patients and 49 healthy controls were included. Plasma lnc-IL7R was significantly down-regulated in ARDS compared with the levels in healthy control individuals, especially in severe ARDS (P < .01). The area under the curve (AUC) of lnc-IL7R for ARDS diagnosis was 0.87 (sensitivity 75.3%, specificity 93.9%). The lnc-IL7R levels were correlated with the severity of ARDS (ρ = -0.31, P = .0215), oxygenation index (ρ = 0.61, P < .001), APACHE II score (ρ = -0.04, P = .0230), CRP (ρ = -0.26, P = .0148) and WBC (ρ = -0.29, P = .0064). Lnc-IL7R relative value ≥ 0.33 showed the lower 28-day mortality in the patients with ARDS(P < .05).The survivors showed higher lnc-IL7R level and lower APACHE II score, SOFA score and length of mechanical ventilation than in the non-survivors (P = .0109, P < .001, P < .001 and P = .017, respectively). CONCLUSIONS: Lnc-IL7R is a novel biomarker for the diagnosis of ARDS and predicts the severity of ARDS and 28-day mortality in this patients cohort. TRIAL REGISTRATION: The study was registered with the Chinese Clinical Trial Registry (ChiCTR-DOD-16008657).


Assuntos
Regulação da Expressão Gênica , RNA Longo não Codificante/sangue , Receptores de Interleucina-7/sangue , Respiração Artificial/métodos , Síndrome do Desconforto Respiratório do Adulto/sangue , Biomarcadores/sangue , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , RNA Longo não Codificante/genética , Curva ROC , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Interleucina-7/genética , Síndrome do Desconforto Respiratório do Adulto/genética , Síndrome do Desconforto Respiratório do Adulto/terapia
4.
PLoS One ; 12(12): e0188112, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29272267

RESUMO

Cross-presentation of apoptotic cell associated antigens by immature dendritic cells prevents the activation of self reactive CD8 T cells. Tolerized self reactive CD8 T cells down-regulate IL-7R expression on their surface. Whether over-expression of IL-7R can reverse their fate and function has not been examined. In this paper, we showed forced expression of IL-7R in OT-I T cells by a transgene enhanced CD8 T cell mediated diabetes in the RIP-mOVA model. Although IL-7R Tg (transgenic) did not completely reverse the deletion of OT-I T cells, it provided a significant survival advantage over w.t OT-I T cells. Furthermore, IL7R Tg OT-I T cells isolated from diabetic pancreata displayed increased production of IFN-γ, higher expression of T-bet, and increased externalization of CD107a. We also found that immature DCs containing apoptotic cells expressed high levels of PDL-1 on their surface. Although IL-7R Tg did not change PD1 expression on activated OT-I cells in vivo, the transgene enabled a significantly lower number of OT-I T cells to induce diabetes in the absence of PDL-1. Our results demonstrated that forced expression of IL-7R not only improved the functionality of tolerized CD8 T cells, it also acted in synergy with PDL-1 deficiency to further promote CD8 T cell cytotoxicity to self antigens.


Assuntos
Autoantígenos/imunologia , Linfócitos T CD8-Positivos/imunologia , Receptores de Interleucina-7/metabolismo , Transferência Adotiva , Animais , Apoptose , Anergia Clonal , Regulação para Baixo , Regulação da Expressão Gênica , Interferon gama/biossíntese , Camundongos , Camundongos Transgênicos , Ovalbumina/imunologia , Receptores de Interleucina-7/genética
5.
Immunol Cell Biol ; 95(10): 933-942, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28890536

RESUMO

Interleukin-7 receptor (IL-7R) signaling is critical for multiple stages of T-cell development, but a role in the establishment of the mature thymic architecture needed for T-cell development and thymocyte selection has not been established. Crosstalk signals between developing thymocytes and thymic epithelial cell (TEC) precursors are critical for their differentiation into cortical TECs (cTECs) and medullary TECs (mTECs). In addition, mTEC-derived factors have been implicated in the recruitment of thymic dendritic cells (DCs) and intrathymic DC development. We therefore examined corticomedullary structure and DC populations in the thymus of Il7r-/- mice. Analysis of TEC phenotype and spatial organization revealed a striking shift in the mTEC to cTEC ratio, accompanied by disorganized corticomedullary structure. Several of the thymic subsets known to have DC potential were nearly absent, accompanied by reductions in DC cell numbers. We also examined chemokine expression in the Il7r-/- thymus, and found a significant decrease in mTEC-derived CCR7 ligand expression, and high levels of cTEC-derived chemokines, including CCL25 and CXCL12. Although splenic DCs were similarly affected, bone marrow (BM) precursors capable of giving rise to DCs were unperturbed. Finally, BM chimeras showed that there was no intrinsic need for IL-7R signaling in the development or recruitment of thymic DCs, but that the provision of wild-type progenitors enhanced reconstitution of thymic DCs from Il7r-/- progenitors. Our results are therefore supportive of a model in which Il7r-dependent cells are required to set up the microenvironments that allow accumulation of thymic DCs.


Assuntos
Células Dendríticas/fisiologia , Células Epiteliais/fisiologia , Receptores de Interleucina-7/metabolismo , Linfócitos T/fisiologia , Timo/imunologia , Animais , Diferenciação Celular , Células Cultivadas , Microambiente Celular , Quimiocina CXCL12/metabolismo , Quimiocinas CC/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores CCR7/metabolismo , Receptores de Interleucina-7/genética
6.
J Immunol ; 199(7): 2366-2376, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28835458

RESUMO

IL-17-producing γδ T (γδT-17) cells have proved to be an important early source of IL-17 in many inflammatory settings and are emerging as an important participant in protumor immune responses. Considering that their peripheral activation depends largely on innate signals rather than TCR ligation, it is important to understand what mechanisms exist to curb unwanted activation. Expression of the high-affinity IL-2R on γδT-17 cells prompted us to investigate a role for this cytokine. We found γδT-17 cells to be enriched, not depleted, in IL-2-deficient mice. The absence of IL-2 also resulted in higher IL-17 production and the emergence of IL-17+IFN-γ+ double producers. Furthermore, the addition of IL-2 to in vitro cultures of sorted γδT-17 cells was able to moderate IL-17 and affect differentiation into polyfunctional cytokine-producing cells. Interestingly, the Vγ6+ subset was more susceptible to the effects of IL-2 than Vγ4+ γδT-17 cells. We also found that unlike other γδ T cells, γδT-17 cells do not produce IL-2, but express Blimp-1, a known transcriptional repressor of IL-2. Although IL-2 was able to induce robust proliferation of γδT-17 cells, it did not sustain viability, negatively impacting their survival via downregulation of the IL-7R. Taken together, these data indicate that IL-2 can augment the γδT-17 response in favor of short-lived effectors with limited plasticity, particularly in the presence of IL-1ß and IL-23. In this way, IL-2 may act to curtail the innate-like response of γδT-17 cells upon arrival of IL-2-producing adaptive immune cells at the site of inflammation.


Assuntos
Interleucina-17/biossíntese , Interleucina-2/imunologia , Interleucina-2/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Linfócitos T/imunologia , Animais , Diferenciação Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citocinas/biossíntese , Citometria de Fluxo , Inflamação , Interferon gama/biossíntese , Interferon gama/imunologia , Interleucina-17/imunologia , Interleucina-2/deficiência , Interleucina-2/genética , Interleucina-23/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fator 1 de Ligação ao Domínio I Regulador Positivo , Receptores de Interleucina-7/genética , Transdução de Sinais , Linfócitos T/efeitos dos fármacos , Linfócitos T/fisiologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
7.
Immunol Cell Biol ; 95(10): 916-924, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28811625

RESUMO

Interleukin-7 (IL-7) is essential for the development of T cells in humans and mice where deficiencies in IL-7 signaling result in severe immunodeficiency. T cells require IL-7 at multiple points during development; however, it is unclear when IL-7 is first necessary. We observed that mice with impaired IL-7 signaling had a large reduction in the number of early thymic progenitors (ETPs) while mice that overexpress IL-7 had greatly increased numbers of ETPs. These results indicated that the development of ETPs is sensitive to IL-7. Bone marrow progenitors of ETP are present in normal numbers in mice with impaired IL-7 signaling (IL-7Rα449F) and were efficiently recruited to the thymus. Furthermore, ETPs and their progenitors from IL-7Rα449F mice did not undergo increased apoptosis and proliferate normally compared to WT cells. Mixed bone marrow chimeras demonstrated that IL-7 signaling has a cell-intrinsic role in ETP development but was not required for development of bone marrow progenitors. We have shown a novel role for IL-7 signaling in the development of ETPs that is distinct from classic mechanisms of IL-7 regulating survival and proliferation.


Assuntos
Células da Medula Óssea/fisiologia , Interleucina-7/metabolismo , Linfócitos T/fisiologia , Timo/imunologia , Animais , Diferenciação Celular , Linhagem da Célula , Proliferação de Células , Sobrevivência Celular , Células Cultivadas , Humanos , Linfopoese , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Interleucina-7/genética , Transdução de Sinais
8.
EMBO Rep ; 18(9): 1604-1617, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28705801

RESUMO

Precursor B lymphocytes expand upon expression of a pre-B cell receptor (pre-BCR), but then transit into a resting state in which immunoglobulin light chain gene recombination is initiated. This bi-phasic sequence is orchestrated by the IL-7 receptor (IL-7R) and pre-BCR signaling, respectively, but little is known about microRNAs fine-tuning these events. Here, we show that pre-B cells lacking miR-15 family functions exhibit prolonged proliferation due to aberrant expression of the target genes cyclin E1 and D3. As a consequence, they fail to trigger the transcriptional reprogramming normally accompanying their differentiation, resulting in a developmental block at the pre-B cell stage. Intriguingly, our data indicate that the miR-15 family is suppressed by both IL-7R and pre-BCR signaling, suggesting it is actively integrated into the regulatory circuits of developing B cells. These findings identify the miR-15 family as a novel element required to promote the switch from pre-B cell proliferation to differentiation.


Assuntos
Diferenciação Celular , Proliferação de Células , MicroRNAs/imunologia , MicroRNAs/metabolismo , Células Precursoras de Linfócitos B/fisiologia , Animais , Linfócitos B/imunologia , Ciclina D3/genética , Ciclina E/genética , Ativação Linfocitária , Linfopoese , Camundongos , MicroRNAs/genética , Proteínas Oncogênicas/genética , Receptores de Antígenos de Linfócitos B/genética , Receptores de Interleucina-7/genética , Transdução de Sinais
9.
Immunity ; 47(1): 171-182.e4, 2017 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-28723549

RESUMO

Interleukin-7 (IL-7) availability determines the size and proliferative state of the resting T cell pool. However, the mechanisms that regulate steady-state IL-7 amounts are unclear. Using experimental lymphopenic mouse models and IL-7-induced homeostatic proliferation to measure IL-7 availability in vivo, we found that radioresistant cells were the source of IL-7 for both CD4+ and CD8+ T cells. Hematopoietic lineage cells, although irrelevant as a source of IL-7, were primarily responsible for limiting IL-7 availability via their expression of IL-7R. Unexpectedly, innate lymphoid cells were found to have a potent influence on IL-7 amounts in the primary and secondary lymphoid tissues. These results demonstrate that IL-7 homeostasis is achieved through consumption by multiple subsets of innate and adaptive immune cells.


Assuntos
Células-Tronco Hematopoéticas/fisiologia , Interleucina-7/metabolismo , Linfócitos/imunologia , Linfopenia/imunologia , Linfócitos T/fisiologia , Imunidade Adaptativa , Animais , Proliferação de Células , Células Cultivadas , Modelos Animais de Doenças , Homeostase , Humanos , Imunidade Inata , Interleucina-7/genética , Interleucina-7/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Tolerância a Radiação , Receptores de Interleucina-7/genética , Receptores de Interleucina-7/metabolismo
10.
PLoS Pathog ; 13(6): e1006425, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28582466

RESUMO

T-cell proliferation and generation of protective memory during chronic infections depend on Interleukin-7 (IL-7) availability and receptivity. Regulation of IL-7 receptor (IL-7R) expression and signalling are key for IL-7-modulated T-cell functions. Aberrant expression of soluble (s) and membrane-associated (m) IL-7R molecules is associated with development of autoimmunity and immune failure in acquired immune deficiency syndrome (AIDS) patients. Here we investigated the role of IL-7/IL-7R on T-cell immunity in human tuberculosis. We performed two independent case-control studies comparing tuberculosis patients and healthy contacts. This was combined with follow-up examinations for a subgroup of tuberculosis patients under therapy and recovery. Blood plasma and T cells were characterised for IL-7/sIL-7R and mIL-7R expression, respectively. IL-7-dependent T-cell functions were determined by analysing STAT5 phosphorylation, antigen-specific cytokine release and by analysing markers of T-cell exhaustion and inflammation. Tuberculosis patients had lower soluble IL-7R (p < 0.001) and higher IL-7 (p < 0.001) plasma concentrations as compared to healthy contacts. Both markers were largely independent and aberrant expression normalised during therapy and recovery. Furthermore, tuberculosis patients had lower levels of mIL-7R in T cells caused by post-transcriptional mechanisms. Functional in vitro tests indicated diminished IL-7-induced STAT5 phosphorylation and impaired IL-7-promoted cytokine release of Mycobacterium tuberculosis-specific CD4+ T cells from tuberculosis patients. Finally, we determined T-cell exhaustion markers PD-1 and SOCS3 and detected increased SOCS3 expression during therapy. Only moderate correlation of PD-1 and SOCS3 with IL-7 expression was observed. We conclude that diminished soluble IL-7R and increased IL-7 plasma concentrations, as well as decreased membrane-associated IL-7R expression in T cells, reflect impaired T-cell sensitivity to IL-7 in tuberculosis patients. These findings show similarities to pathognomonic features of impaired T-cell functions and immune failure described in AIDS patients.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Interleucina-7/sangue , Receptores de Interleucina-7/sangue , Tuberculose/imunologia , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Interleucina-7/genética , Interleucina-7/imunologia , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/fisiologia , Fosforilação , Receptores de Interleucina-7/genética , Receptores de Interleucina-7/imunologia , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/imunologia , Proteína 3 Supressora da Sinalização de Citocinas/genética , Proteína 3 Supressora da Sinalização de Citocinas/imunologia , Tuberculose/microbiologia , Adulto Jovem
11.
Neuroscience ; 355: 9-21, 2017 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-28456715

RESUMO

Neuroinflammation is proposed to be an important component in the development of several central nervous system (CNS) disorders including depression, Alzheimer's disease, Parkinson's disease, and traumatic brain injury. However, exactly how neuroinflammation leads to, or contributes to, these central disorders is unclear. The objective of the study was to examine and compare the expression of mRNAs for interleukin-6 (IL-6), IL-7, IL-10 and the receptors for IL-6 (IL-6R) and IL-7 (IL-7R) using in situ hybridization in discrete brain regions and in the spleen after multiple injections of 3mg/kg lipopolysaccharide (LPS), a model of neuroinflammation. In the spleen, LPS significantly elevated IL-6 mRNA expression, then IL-10 mRNA, with no effect on IL-7 or IL-7R mRNA, while significantly decreasing IL-6R mRNA expression. In the CNS, LPS administration had the greatest effect on IL-6 and IL-6R mRNA. LPS increased IL-6 mRNA expression only in non-neuronal cells throughout the brain, but significantly elevated IL-6R mRNA in neuronal populations, where observed, except the cerebellum. LPS resulted in variable effects on IL-10 mRNA, and had no effect on IL-7 or IL-7R mRNA expression. These studies indicate that LPS-induced neuroinflammation has substantial but variable effects on the regional and cellular patterns of CNS IL-6, IL-7 and IL-10, and for IL-6R and IL-7R mRNA expression. It is apparent that administration of LPS can affect non-neuronal and neuronal cells in the brain. Further research is required to determine how CNS inflammatory changes associated with IL-6, IL-10 and IL-6R could in turn contribute to the development of CNS neurological disorders.


Assuntos
Encéfalo/metabolismo , Interleucinas/metabolismo , RNA Mensageiro/metabolismo , Receptores de Interleucina-6/metabolismo , Receptores de Interleucina-7/metabolismo , Baço/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/metabolismo , Interleucinas/genética , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosfopiruvato Hidratase/metabolismo , Receptores de Interleucina-6/genética , Receptores de Interleucina-7/genética , Baço/efeitos dos fármacos
12.
J Immunol ; 198(10): 3909-3918, 2017 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-28404633

RESUMO

Thymic stromal lymphopoietin (TSLP) and IL-7 are related cytokines that mediate growth and differentiation events in the immune system. They signal through IL-7Rα-containing receptors. Target cells of TSLP in Th2 responses include CD4 T cells and dendritic cells (DCs). Although it has been reported that expression of TSLP receptor (TSLPR) on CD4 T cells is required for OVA-induced lung inflammation, DCs have also been shown to be target cells of TSLP. In this study, we show that murine ex vivo splenic DCs are unresponsive to TSLP, as they fail to phosphorylate STAT5, but in vitro overnight culture, especially in presence of IL-4, renders DCs responsive to both TSLP and IL-7. This induced responsiveness is accompanied by dramatic upregulation of IL-7Rα on DCs with little change in expression of TSLPR or of γc In splenic DCs, the induction of IL-7Rα occurs mainly in CD8- DCs. In vivo, we found that IL-4 has a differential regulatory role on expression of IL-7Rα depending on the cell type; IL-4 decreases IL-7Rα expression on CD4 T cells whereas it upregulates the expression on DCs. Our results indicate that the induction of IL-7Rα expression on DCs is critical for TSLP responsiveness and that IL-4 can upregulate IL-7Rα on DCs.


Assuntos
Citocinas/imunologia , Células Dendríticas/imunologia , Regulação da Expressão Gênica , Receptores de Interleucina-7/genética , Receptores de Interleucina-7/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular , Interleucina-4/genética , Interleucina-4/imunologia , Interleucina-4/farmacologia , Interleucina-7/imunologia , Interleucina-7/farmacologia , Camundongos , Fosforilação , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais , Células Th2/imunologia , Regulação para Cima
13.
Oncotarget ; 8(17): 28395-28407, 2017 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-28415697

RESUMO

Interleukin 7 receptor (IL-7R) has been associated with the pathogenesis of multiple sclerosis (MS), though the mechanisms are not clear. Because myelin expression is highly conserved between zebrafish and mammals, zebrafish have become an ideal model for studying demyelination. We used a transgenic (Tg; mbp:nfsB-egfp) zebrafish line in which oligodendrocytes expressed green fluorescent protein (GFP) from the larval stage to adulthood. Exposing adult transgenic zebrafish to metronidazole induced demyelination that resembled the morphological changes associated with the early stages of MS. The metronidazole-induced demyelination was confirmed by magnetic resonance imaging (MRI) for the first time. Microarray analysis revealed down-regulation of IL-7R during demyelination. Targeted knockdown of IL-7R demonstrated that IL-7R is essential for myelination in embryonic and larval zebrafish. Moreover, IL-7R down-regulation induced signaling via the JAK/STAT pathway leading to apoptosis in oligodendrocytes. These findings contribute to our understanding of the role of IL-7R in demyelination, and provide a rationale for the development of IL-7R-based therapies for MS and other demyelinating diseases.


Assuntos
Doenças do Sistema Nervoso Central/genética , Doenças Desmielinizantes/genética , Regulação da Expressão Gênica , Receptores de Interleucina-7/genética , Animais , Animais Geneticamente Modificados , Doenças do Sistema Nervoso Central/diagnóstico por imagem , Doenças do Sistema Nervoso Central/metabolismo , Doenças do Sistema Nervoso Central/patologia , Doenças Desmielinizantes/diagnóstico por imagem , Doenças Desmielinizantes/metabolismo , Doenças Desmielinizantes/patologia , Modelos Animais de Doenças , Regulação para Baixo , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Genes bcl-2 , Janus Quinases/metabolismo , Receptores de Interleucina-7/metabolismo , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Medula Espinal/metabolismo , Medula Espinal/patologia , Peixe-Zebra
14.
Nat Commun ; 8: 14601, 2017 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-28361874

RESUMO

The signals that maintain tissue-resident innate lymphoid cells (ILC) in different microenvironments are incompletely understood. Here we show that IL-7 receptor (IL-7R) is not strictly required for the development of any ILC subset, as residual cells persist in the small intestinal lamina propria (siLP) of adult and neonatal Il7ra-/- mice. Il7ra-/- ILC2 primarily express an ST2- phenotype, but are not inflammatory ILC2. CCR6+ ILC3, which express higher Bcl-2 than other ILC3, are the most abundant subset in Il7ra-/- siLP. All ILC subsets are functionally competent in vitro, and are sufficient to provide enhanced protection to infection with C. rodentium. IL-15 equally sustains wild-type and Il7ra-/- ILC survival in vitro and compensates for IL-7R deficiency, as residual ILCs are depleted in mice lacking both molecules. Collectively, these data demonstrate that siLP ILCs are not completely IL-7R dependent, but can persist partially through IL-15 signalling.


Assuntos
Interleucina-15/imunologia , Subpopulações de Linfócitos/imunologia , Linfócitos/imunologia , Receptores de Interleucina-7/imunologia , Animais , Feminino , Imunidade Inata , Interleucina-15/genética , Intestino Delgado/imunologia , Células Matadoras Naturais/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Membrana Mucosa/imunologia , Receptores de Interleucina-7/genética , Transdução de Sinais
15.
Mol Cancer Ther ; 16(6): 1068-1079, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28138030

RESUMO

The traditional maximum dose density chemotherapy renders the tumor patients not only the tumor remission but the chemotherapy resistance and more adverse side effects. According to the widely positive expression of Toll-like receptor (TLR)-3 in oral squamous cell carcinoma (OSCC) patients (n = 166), we here provided an alternative strategy involved the orderly treatment of TLR3 agonist polyinosine-polycytidylic acid (PIC) and low-dose cisplatin. The optimal dose of cisplatin, the novel role of PIC and the side effects of the combined chemotherapy were determined in vitro and in distinct human tumor models in vivo The results in vitro indicated that preculture with PIC downregulated drug transporters (e.g., P-gp and MRP-1) and increased the cytoplasmic residence of cisplatin, and dramatically strengthened the low-dose cisplatin-induced cell death in TLR3- and caspase-3-dependent manner. Meanwhile, the spleen immunocytes were activated but the immunosuppressive cancer-associated fibroblasts (CAF) were dampened. These findings were confirmed in human tumor models in vivo Pretreatment with PIC promoted the low-dose cisplatin residence for tumor regression with decreased myeloid-suppressive cells (MDSC), tumor-associated macrophages (TAM) and CAFs, and alleviated adverse side effects in the OSCC model, which was further enhanced by the Cetuximab safely. This strategy also repressed the progression of melanoma and lymphoma. Moreover, TLR3 negatively manipulated the inflammation-related long noncoding RNA lnc-IL7R, which was upregulated during this chemotherapy. Knockdown of lnc-IL7R improved the chemotherapy sensitivity. Overall, this study provided preclinically new instructions for the PIC/cisplatin utilization to target tumor microenvironment and strengthen the low-dose cisplatin-based chemotherapy with reduced side effects. Mol Cancer Ther; 16(6); 1068-79. ©2017 AACR.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Cisplatino/administração & dosagem , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Receptor 3 Toll-Like/agonistas , Animais , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/mortalidade , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/efeitos adversos , Cisplatino/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Masculino , Camundongos , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/mortalidade , Receptores de Interleucina-7/genética , Receptor 3 Toll-Like/genética , Receptor 3 Toll-Like/metabolismo , Carga Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
16.
Mol Med Rep ; 15(3): 1412-1418, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28138707

RESUMO

Rheumatoid arthritis (RA) is an inflammatory and autoimmune disease that affects ~1% of the world's population. Although the precise mechanism of RA has yet to be elucidated, accumulating evidence suggests that fibroblast­like synoviocytes (FLSs) serve critical roles in the initiation and progression of RA. However, the underlying molecular mechanisms of FLS proliferation have yet to be elucidated. Long noncoding­interleukin­7 receptor (lnc­IL7R) has been recently identified, which is activated by lipopolysaccharide (LPS) stimulation and diminishes the LPS­induced inflammatory response. In the present study, gain­ and loss­of­function assays were performed in order to investigate the role of lnc­IL7R in FLS. It is demonstrated, to the best of the authors' knowledge for the first time, that lnc­IL7R promotes cell proliferation, cell cycle progression and inhibits apoptosis in FLS. Further investigation identified that lnc­IL7 interacts with enhancer of zeste homolog 2 (EZH2) and is required for polycomb repressive complex 2 (PRC2)­mediated suppression, including cyclin­dependent kinase inhibitor 1A and cyclin­dependent kinase inhibitor 2A. Lnc­IL7R may be a promising therapeutic target for the treatment of RA.


Assuntos
Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/genética , RNA Longo não Codificante/genética , Receptores de Interleucina-7/genética , Sinoviócitos/metabolismo , Apoptose/genética , Artrite Reumatoide/patologia , Ciclo Celular/genética , Proliferação de Células , Células Cultivadas , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Epigênese Genética , Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Receptores de Interleucina-7/metabolismo
17.
AIDS Rev ; 19(1): 3-15, 2017 Jan-Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28182609

RESUMO

The pathogenic mechanisms of the accelerated progression of liver injury in HIV/HCV coinfection are incompletely understood. The progression of liver disease is variable between individuals having similar risk factors, suggesting that genetic background is an important contributor. The aim of this review is to give a summary of all single nucleotide polymorphisms associated with the severity of liver disease in patients coinfected with HIV and HCV reported in the literature. Therefore, a systematic search for articles published was made, 17 of which were selected for this review. In summary, a large number of single nucleotide polymorphisms have been associated with the severity of liver disease in HIV/HCV-coinfected patients. These genes are involved in different biological processes, including seven that correspond to cytokine genes (IFNL3-4, CXCL9-11, IL15, TNF), two to receptor genes (IL7R, TLR8), and three are genes related to metabolism (PNPLA3, FTO, GSTM1). In addition, two combinations of polymorphisms (cirrhosis risk score and mitochondrial haplogroups) have also been related to severity of liver disease in HIV/HCV-coinfected patients. Although determinants other than genetics, such as environmental and viral factors, may be implicated in liver disease progression, information about genetic variation might be useful in clinical practice, allowing prioritization of patients with a genetic background that predispose to a worse evolution of HCV-related liver disease.


Assuntos
Coinfecção/complicações , Infecções por HIV/complicações , Hepatite C/complicações , Hepatopatias/genética , Polimorfismo de Nucleotídeo Único , Biomarcadores , Quimiocina CXCL9/genética , Progressão da Doença , Humanos , Interleucinas/genética , Hepatopatias/etiologia , Hepatopatias/imunologia , Receptores de Interleucina-7/genética , Receptor 8 Toll-Like/genética
18.
Neurosci Lett ; 642: 174-178, 2017 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-28174058

RESUMO

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) is a neurological disease of the central nervous system (CNS) that causes physical and cognitive impairments. IL-7Ra is a key non-MHC gene associated with MS. IL-7Ra is a likely functional candidate for this complex disease because it is involved in the development, maturation, and homeostasis of T and B cells. Our aim was to evaluate the expression level and controlling role of lnc-IL-7R in the expression of two variants of IL-7Ra in MS patients versus healthy controls and their correlation with certain clinical features. METHODS: Using the real-time PCR method, we analyzed the expression levels of membrane-bound (IL-7RB) and soluble (IL-7RS) isoforms of IL-7R gene and lnc-IL-7R in 36 MS patients versus 30 healthy controls. RESULTS: Our results revealed no significant difference between the expression levels of IL-7RB and IL-7RS isoforms of IL-7R gene and lnc-IL-7R in MS patients versus healthy controls (p=0.7, p=0.6 and p=0.8, respectively). Moreover, we found a significant correlation between the expression levels of IL-7RB with lnc-IL-7R, IL-7RS with lnc-IL-7R and IL-7RB with IL-7RS in both patient and control groups. CONCLUSIONS: We have probably uncovered new evidence for the controlling role of long non-coding RNAs in the expression level of genes and their roles in MS.


Assuntos
Esclerose Múltipla/metabolismo , RNA Longo não Codificante/metabolismo , Receptores de Interleucina-7/metabolismo , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , RNA Longo não Codificante/genética , Receptores de Interleucina-7/genética , Adulto Jovem
19.
Sci Rep ; 7: 42036, 2017 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-28181541

RESUMO

Optimal CD4+ T cell recovery after initiating combination antiretroviral treatment (cART) in HIV infection reduces risk of morbidity and mortality. T-allele homozygosity ('TT') in the single nucleotide polymorphism, rs6897932(C/T), in the IL-7 receptor α (IL-7RA) is associated with faster CD4+ T cell recovery after cART initiation compared to C-allele homozygosity in rs6897932 ('CC'). However, underlying mechanisms are unknown. We aimed to examine potential mechanisms explaining the association between rs6897932 and CD4+ T cell recovery. Ten 'TT' and 10 'CC' HIV-infected individuals matched on gender, age, and nadir and current CD4+ T cell counts were included in a cross-sectional study. 'TT' individuals had higher proportion of CD4+ T cells expressing pSTAT5 compared to 'CC' individuals after stimulating with IL-7, especially when co-stimulated with soluble IL7-RA (sIL-7RA). Furthermore, 'TT' individuals had a higher proportion of proliferating CD4+ T cells after 7 days of culture with IL-7 + sIL-7RA compared to 'CC' individuals. No differences between 'TT' and 'CC' in binding of biotinylated IL-7 were found. In conclusion, increased signal transduction and proliferation in response to IL-7 was found in 'TT' compared to 'CC' HIV-infected individuals providing a mechanistic explanation of the effect of rs6897932 T-allele on CD4+ T cell recovery in HIV infection.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/genética , Infecções por HIV/patologia , Polimorfismo de Nucleotídeo Único , Receptores de Interleucina-7/genética , Receptores de Interleucina-7/metabolismo , Antirretrovirais/uso terapêutico , Estudos Transversais , Infecções por HIV/tratamento farmacológico , Humanos , Resultado do Tratamento
20.
Orphanet J Rare Dis ; 12(1): 6, 2017 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-28077132

RESUMO

Nude severe combined immunodeficiency is a rare inherited disease caused by autosomal recessive loss-of-function mutations in FOXN1. This gene encodes a transcription factor essential for the development of the thymus, the primary lymphoid organ that supports T-cell development and selection. To date nine cases have been reported presenting with the clinical triad of absent thymus resulting in severe T-cell immunodeficiency, congenital alopecia universalis and nail dystrophy. Diagnosis relies on testing for FOXN1 mutations, which allows genetic counselling and guides therapeutic management. Options for treating the underlying immune deficiency include HLA-matched genoidentical haematopoietic cell transplantation containing mature donor T-cells or thymus tissue transplantation. Experience from other severe combined immune deficiency syndromes suggests that early diagnosis, supportive care and definitive management result in better patient outcomes. Without these the prognosis is poor due to early-onset life threatening infections.


Assuntos
Fatores de Transcrição Forkhead/deficiência , Fatores de Transcrição Forkhead/metabolismo , Imunodeficiência Combinada Severa/metabolismo , Alopecia/genética , Alopecia/metabolismo , Alopecia/patologia , Animais , Fatores de Transcrição Forkhead/genética , Camundongos Nus , Camundongos SCID , Mutação/genética , Receptores de Interleucina-7/genética , Receptores de Interleucina-7/metabolismo , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/patologia , Linfócitos T/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA