RESUMEN
Regulatory T cells (Tregs), characterized by the expression of Forkhead Box P3 (FOXP3), constitute a distinct subset of T cells crucial for immune regulation. Tregs can exert direct and indirect control over immune homeostasis by releasing inhibitory factors or differentiating into Th-like Treg (Th-Treg), thereby actively contributing to the prevention and treatment of autoimmune diseases. The epigenetic regulation of FOXP3, encompassing DNA methylation, histone modifications, and post-translational modifications, governs the development and optimal suppressive function of Tregs. In addition, Tregs can also possess the ability to maintain homeostasis in diverse microenvironments through non-suppressive mechanisms. In this review, we primarily focus on elucidating the epigenetic regulation of Tregs as well as their multifaceted roles within diverse physiological contexts while looking forward to potential strategies involving augmentation or suppression of Tregs activity for disease management, particularly in light of the ongoing global COVID-19 pandemic.
Asunto(s)
COVID-19 , Epigénesis Genética , Factores de Transcripción Forkhead , Homeostasis , Linfocitos T Reguladores , Humanos , Linfocitos T Reguladores/inmunología , Factores de Transcripción Forkhead/metabolismo , Factores de Transcripción Forkhead/genética , COVID-19/inmunología , Metilación de ADN , SARS-CoV-2/inmunología , SARS-CoV-2/fisiologíaRESUMEN
Histone deacetylases 1 and 2 play a major role in the transcriptional regulation of T-regulatory (Treg) cells via interactions with a myriad of coregulatory factors. Sin3a has been well established as a Hdac1/2 cofactor, while its role within Tregs has not been established. In this study, the effects of conditional deletion of Sin3a within Foxp3+ Tregs were evaluated. Developmental deletion of Sin3a from Foxp3+ Tregs resulted in the rapid onset of fatal autoimmunity. Treg numbers were greatly reduced, while residual Tregs had impaired suppressive function. Mice also showed effector T-cell activation, autoantibody production, and widespread tissue injury. Mechanistically, Sin3a deletion resulted in decreased transcription of Foxp3 with a complete lack of CNS2 CpG demethylation. In addition, Foxp3 protein stability was impaired with an increased ex-Treg population. Thus, Sin3a plays a critical role in the maintenance of Treg identity and function and is essential for the expression and stability of Foxp3.
Asunto(s)
Factores de Transcripción Forkhead , Complejo Correpresor Histona Desacetilasa y Sin3 , Linfocitos T Reguladores , Factores de Transcripción Forkhead/metabolismo , Factores de Transcripción Forkhead/genética , Animales , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Complejo Correpresor Histona Desacetilasa y Sin3/genética , Ratones , Ratones Noqueados , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Regulación de la Expresión Génica , Autoinmunidad , Ratones Endogámicos C57BL , Activación de Linfocitos/inmunologíaRESUMEN
FOXO transcription factors modulate aging-related pathways and influence longevity in multiple species, but the transcriptional targets that mediate these effects remain largely unknown. Here, we identify an evolutionarily conserved FOXO target gene, Oxidative stress-responsive serine-rich protein 1 (OSER1), whose overexpression extends lifespan in silkworms, nematodes, and flies, while its depletion correspondingly shortens lifespan. In flies, overexpression of OSER1 increases resistance to oxidative stress, starvation, and heat shock, while OSER1-depleted flies are more vulnerable to these stressors. In silkworms, hydrogen peroxide both induces and is scavenged by OSER1 in vitro and in vivo. Knockdown of OSER1 in Caenorhabditis elegans leads to increased ROS production and shorter lifespan, mitochondrial fragmentation, decreased ATP production, and altered transcription of mitochondrial genes. Human proteomic analysis suggests that OSER1 plays roles in oxidative stress response, cellular senescence, and reproduction, which is consistent with the data and suggests that OSER1 could play a role in fertility in silkworms and nematodes. Human studies demonstrate that polymorphic variants in OSER1 are associated with human longevity. In summary, OSER1 is an evolutionarily conserved FOXO-regulated protein that improves resistance to oxidative stress, maintains mitochondrial functional integrity, and increases lifespan in multiple species. Additional studies will clarify the role of OSER1 as a critical effector of healthy aging.
Asunto(s)
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Proteínas de Drosophila , Factores de Transcripción Forkhead , Longevidad , Estrés Oxidativo , Animales , Longevidad/genética , Caenorhabditis elegans/genética , Caenorhabditis elegans/fisiología , Caenorhabditis elegans/metabolismo , Humanos , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Factores de Transcripción Forkhead/metabolismo , Factores de Transcripción Forkhead/genética , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Bombyx/genética , Bombyx/metabolismo , Bombyx/fisiología , Drosophila melanogaster/genética , Mitocondrias/metabolismo , Mitocondrias/genética , Especies Reactivas de Oxígeno/metabolismo , Regulación de la Expresión GénicaRESUMEN
Transforming growth factor-ß (TGFß) and FoxP3 regulatory T cells (Treg) are involved in human breast carcinogenesis. This topic is not well documented in canine mammary tumors (CMT). In this work, the tumoral TGFß expression was assessed by immunohistochemistry in 67 malignant CMT and its correlation to previously determined FoxP3, VEGF, and CD31 markers and other clinicopathologic parameters was evaluated. The high levels of TGFß were statistically significantly associated with skin ulceration, tumor necrosis, high histological grade of malignancy (HGM), presence of neoplastic intravascular emboli and presence of lymph node metastases. The observed levels of TGFß were positively correlated with intratumoral FoxP3 (strong correlation), VEGF (weak correlation) and CD31 (moderate correlation). Tumors that presented a concurrent high expression of TGFß/FoxP3, TGFß/VEGF, and TGFß/CD31 markers were statistically significantly associated with parameters of tumor malignancy (high HGM, presence of vascular emboli and nodal metastasis). Additionally, shorter overall survival (OS) time was statistically significantly associated with tumors with an abundant TGFß expression and with concurrent high expression of TGFß/FoxP3, TGFß/VEGF, and TGFß/CD31. The presence of lymph node metastasis increased 11 times the risk of disease-related death, arising as an independent predictor of poor prognosis in the multivariable analysis. In conclusion, TGFß and Treg cells seem involved in tumor progression emerging as potential therapeutic targets for future immunotherapy studies.
Asunto(s)
Enfermedades de los Perros , Neoplasias Mamarias Animales , Neovascularización Patológica , Factor de Crecimiento Transformador beta , Perros , Animales , Enfermedades de los Perros/inmunología , Femenino , Neoplasias Mamarias Animales/inmunología , Neoplasias Mamarias Animales/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Pronóstico , Neovascularización Patológica/veterinaria , Factores de Transcripción Forkhead/metabolismo , Biomarcadores de Tumor , Linfocitos T Reguladores/inmunología , Inmunohistoquímica/veterinaria , Factor A de Crecimiento Endotelial Vascular/metabolismo , AngiogénesisRESUMEN
BACKGROUND: Lymphatic valves are specialized structures in collecting lymphatic vessels and are crucial for preventing retrograde lymph flow. Mutations in valve-forming genes have been clinically implicated in the pathology of congenital lymphedema. Lymphatic valves form when oscillatory shear stress from lymph flow signals through the PI3K/AKT pathway to promote the transcription of valve-forming genes that trigger the growth and maintenance of lymphatic valves. Conventionally, in many cell types, AKT is phosphorylated at Ser473 by the mTORC2 (mammalian target of rapamycin complex 2). However, mTORC2 has not yet been implicated in lymphatic valve formation. METHODS: In vivo and in vitro techniques were used to investigate the role of Rictor, a critical component of mTORC2, in lymphatic endothelium. RESULTS: Here, we showed that embryonic and postnatal lymphatic deletion of Rictor, a critical component of mTORC2, led to a significant decrease in lymphatic valves and prevented the maturation of collecting lymphatic vessels. RICTOR knockdown in human dermal lymphatic endothelial cells not only reduced the level of activated AKT and the expression of valve-forming genes under no-flow conditions but also abolished the upregulation of AKT activity and valve-forming genes in response to oscillatory shear stress. We further showed that the AKT target, FOXO1 (forkhead box protein O1), a repressor of lymphatic valve formation, had increased nuclear activity in Rictor knockout mesenteric lymphatic endothelial cells in vivo. Deletion of Foxo1 in Rictor knockout mice restored the number of valves to control levels in lymphatic vessels of the ear and mesentery. CONCLUSIONS: Our work identifies a novel role for RICTOR in the mechanotransduction signaling pathway, wherein it activates AKT and prevents the nuclear accumulation of the valve repressor, FOXO1, which ultimately enables the formation and maintenance of lymphatic valves.
Asunto(s)
Proteínas Portadoras , Proteína Forkhead Box O1 , Linfangiogénesis , Vasos Linfáticos , Diana Mecanicista del Complejo 2 de la Rapamicina , Mecanotransducción Celular , Ratones Noqueados , Proteínas Proto-Oncogénicas c-akt , Proteína Asociada al mTOR Insensible a la Rapamicina , Transducción de Señal , Animales , Proteína Asociada al mTOR Insensible a la Rapamicina/metabolismo , Proteína Asociada al mTOR Insensible a la Rapamicina/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteína Forkhead Box O1/metabolismo , Proteína Forkhead Box O1/genética , Vasos Linfáticos/metabolismo , Diana Mecanicista del Complejo 2 de la Rapamicina/metabolismo , Diana Mecanicista del Complejo 2 de la Rapamicina/genética , Humanos , Proteínas Portadoras/metabolismo , Proteínas Portadoras/genética , Células Endoteliales/metabolismo , Células Cultivadas , Serina-Treonina Quinasas TOR/metabolismo , Fosforilación , Factores de Transcripción Forkhead/metabolismo , Factores de Transcripción Forkhead/genética , Ratones , Complejos Multiproteicos/metabolismo , Complejos Multiproteicos/genética , Ratones Endogámicos C57BL , Interferencia de ARN , TransfecciónRESUMEN
In Saccharomyces cerevisiae, the forkhead (Fkh) transcription factor Fkh1 (forkhead homolog) enhances the activity of many DNA replication origins that act in early S-phase (early origins). Current models posit that Fkh1 acts directly to promote these origins' activity by binding to origin-adjacent Fkh1 binding sites (FKH sites). However, the post-DNA binding functions that Fkh1 uses to promote early origin activity are poorly understood. Fkh1 contains a conserved FHA (forkhead associated) domain, a protein-binding module with specificity for phosphothreonine (pT)-containing partner proteins. At a small subset of yeast origins, the Fkh1-FHA domain enhances the ORC (origin recognition complex)-origin binding step, the G1-phase event that initiates the origin cycle. However, the importance of the Fkh1-FHA domain to either chromosomal replication or ORC-origin interactions at genome scale is unclear. Here, S-phase SortSeq experiments were used to compare genome replication in proliferating FKH1 and fkh1-R80A mutant cells. The Fkh1-FHA domain promoted the activity of ≈ 100 origins that act in early to mid- S-phase, including the majority of centromere-associated origins, while simultaneously inhibiting ≈ 100 late origins. Thus, in the absence of a functional Fkh1-FHA domain, the temporal landscape of the yeast genome was flattened. Origins are associated with a positioned nucleosome array that frames a nucleosome depleted region (NDR) over the origin, and ORC-origin binding is necessary but not sufficient for this chromatin organization. To ask whether the Fkh1-FHA domain had an impact on this chromatin architecture at origins, ORC ChIPSeq data generated from proliferating cells and MNaseSeq data generated from G1-arrested and proliferating cell populations were assessed. Origin groups that were differentially regulated by the Fkh1-FHA domain were characterized by distinct effects of this domain on ORC-origin binding and G1-phase chromatin. Thus, the Fkh1-FHA domain controlled the distinct chromatin architecture at early origins in G1-phase and regulated origin activity in S-phase.
Asunto(s)
Cromatina , Replicación del ADN , Fase G1 , Complejo de Reconocimiento del Origen , Origen de Réplica , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae , Origen de Réplica/genética , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Replicación del ADN/genética , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Cromatina/genética , Cromatina/metabolismo , Complejo de Reconocimiento del Origen/genética , Complejo de Reconocimiento del Origen/metabolismo , Fase G1/genética , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Fase S/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Dominios Proteicos/genética , Sitios de Unión , Unión Proteica , Cromosomas Fúngicos/genética , Cromosomas Fúngicos/metabolismo , Nucleosomas/metabolismo , Nucleosomas/genéticaRESUMEN
Regulatory T cells (Treg) are critical players of immune tolerance that develop in the thymus via two distinct developmental pathways involving CD25+Foxp3- and CD25-Foxp3lo precursors. However, the mechanisms regulating the recently identified Foxp3lo precursor pathway remain unclear. Here, we find that the membrane-bound lymphotoxin α1ß2 (LTα1ß2) heterocomplex is upregulated during Treg development upon TCR/CD28 and IL-2 stimulation. We show that Lta expression limits the maturational development of Treg from Foxp3lo precursors by regulating their proliferation, survival, and metabolic profile. Transgenic reporter mice and transcriptomic analyses further reveal that medullary thymic epithelial cells (mTEC) constitute an unexpected source of IL-4. We demonstrate that LTα1ß2-lymphotoxin ß receptor-mediated interactions with mTEC limit Treg development by down-regulating IL-4 expression in mTEC. Collectively, our findings identify the lymphotoxin axis as the first inhibitory checkpoint of thymic Treg development that fine-tunes the Foxp3lo Treg precursor pathway by limiting IL-4 availability.
Asunto(s)
Factores de Transcripción Forkhead , Interleucina-4 , Receptor beta de Linfotoxina , Linfotoxina-alfa , Transducción de Señal , Linfocitos T Reguladores , Animales , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Factores de Transcripción Forkhead/metabolismo , Factores de Transcripción Forkhead/genética , Interleucina-4/metabolismo , Ratones , Linfotoxina-alfa/metabolismo , Linfotoxina-alfa/genética , Receptor beta de Linfotoxina/metabolismo , Receptor beta de Linfotoxina/genética , Timo/inmunología , Timo/citología , Timo/metabolismo , Células Epiteliales/metabolismo , Ratones Endogámicos C57BL , Diferenciación Celular , Ratones Transgénicos , Interleucina-2/metabolismo , Proliferación Celular , Heterotrímero de Linfotoxina alfa1 y beta2/metabolismo , Heterotrímero de Linfotoxina alfa1 y beta2/genéticaRESUMEN
We previously demonstrated that glycyrrhizin (GL) suppressed inflammation and carcinogenesis in an azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced murine model of colorectal cancer (CC). In this study, we found an accumulation of regulatory T cells (Tregs) in the spleen and suppression by GL in model mice. ICR mice were divided into four groups: Control, GL, CC, and GL-treated CC (CC+GL), and were sacrificed 20 weeks after AOM/DSS treatment. We measured spleen weight, areas of white and red pulp, and CD8+ T cells (cytotoxic T lymphocytes, CTL), and CD11c-positive cells (dendritic cells) in splenic tissues and forkhead box protein 3 (FoxP3)-positive cells (Tregs) in colorectal and splenic tissues. In all cases, the CC group showed a significant increase compared with those in Control group, and GL administration significantly attenuated this increase. These results indicate that Tregs accumulated in the spleen may participate in inflammation-related carcinogenesis by suppressing CTL. We also suggest that GL which binds to high-mobility group box 1 (HMGB1), suppresses carcinogenesis with decreasing Tregs in the spleen. Furthermore, there was an expression of FoxP3 in cancer cells, indicating that it may be involved in the malignant transformation of cancer cells.
Asunto(s)
Azoximetano , Neoplasias Colorrectales , Sulfato de Dextran , Factores de Transcripción Forkhead , Ácido Glicirrínico , Bazo , Linfocitos T Reguladores , Animales , Ácido Glicirrínico/farmacología , Factores de Transcripción Forkhead/metabolismo , Bazo/metabolismo , Bazo/patología , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/inducido químicamente , Neoplasias Colorrectales/tratamiento farmacológico , Ratones , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Ratones Endogámicos ICR , Masculino , Inmunohistoquímica , Proteína HMGB1/metabolismoRESUMEN
In C. elegans mechanisms by which peripheral organs relay internal state information to the nervous system remain unknown, although strong evidence suggests that such signals do exist. Here we report the discovery of a peptide of the ancestral insulin superfamily called INS-7 that functions as an enteroendocrine peptide and is secreted from specialized cells of the intestine. INS-7 secretion is stimulated by food withdrawal, increases during fasting and acts as a bona fide gut-to-brain peptide that attenuates the release of a neuropeptide that drives fat loss in the periphery. Thus, INS-7 functions as a homeostatic signal from the intestine that gates the neuronal drive to stimulate fat loss during food shortage. Mechanistically, INS-7 functions as an antagonist at the canonical DAF-2 receptor and functions via FOXO and AMPK signaling in ASI neurons. Phylogenetic analysis suggests that INS-7 bears greater resemblance to members of the broad insulin/relaxin superfamily than to conventional mammalian insulin and IGF peptides. The discovery of an endogenous insulin antagonist secreted by specialized intestinal cells with enteroendocrine functions suggests unexpected and important properties of the intestine and its role in directing neuronal functions.
Asunto(s)
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Homeostasis , Insulina , Neuronas , Animales , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Insulina/metabolismo , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Receptor de Insulina/metabolismo , Receptor de Insulina/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Neuropéptidos/metabolismo , Factores de Transcripción Forkhead/metabolismo , Factores de Transcripción Forkhead/genética , Intestinos , Filogenia , Ayuno , Mucosa Intestinal/metabolismoRESUMEN
Amid global climate change featuring erratic temperature fluctuations, insects adapt via seasonal polyphenism, essential for population sustainability and reproductive success. Cacopsylla chinensis, influenced by environment variations, displays a distinct summer form and winter form distinguished by significant morphological variations. Previous studies have highlighted the role of temperature receptor CcTPRM in orchestrating the transition in response to 10 °C temperature. Nevertheless, the contribution of the transcription factor FoxO in this process has remained ambiguous. Here, we aimed to explore the correlation between C. chinensis FoxO (CcFoxO) and cold stress responses, while identifying potential energetic substances for monitoring physiological shifts during this transition from summer to winter form under cold stress by using RNAi. Initially, CcFoxO emerges as responsive to low temperatures (10 °C) and is regulated by CcTRPM. Subsequent investigations reveal that CcFoxO facilitates the accumulation of triglycerides and glycogen, thereby influencing the transition from summer form to winter form by affecting cuticle pigment content, cuticle chitin levels, and cuticle thickness. Thus, the knockdown of CcFoxO led to high mortality and failed transition. Overall, our findings demonstrate that CcFoxO governs seasonal polyphenism by regulating energy storage. These insights not only enhance our comprehension of FoxO functionality but also offer avenues for environmentally friendly management strategies for C. chinensis.
Asunto(s)
Estaciones del Año , Animales , Proteínas de Insectos/metabolismo , Proteínas de Insectos/genética , Factores de Transcripción Forkhead/metabolismo , Factores de Transcripción Forkhead/genética , Respuesta al Choque por Frío , Heterópteros/metabolismo , Heterópteros/genética , Heterópteros/fisiologíaRESUMEN
BACKGROUND: Increased activity of the transcription factor FOXC1 leads to elevated transcription of target genes, ultimately facilitating the progression of various cancer types. However, there are currently no literature reports on the role of FOXC1 in renal cell carcinoma. METHODS: By using RT-qPCR, immunohistochemistry and Western blotting, FOXC1 mRNA and protein expression was evaluated. Gain of function experiments were utilized to assess the proliferation and metastasis ability of cells. A nude mouse model was created for transplanting tumors and establishing a lung metastasis model to observe cell proliferation and spread in a living organism. Various techniques including biological analysis, CHIP assay, luciferase assay, RT-qRCR and Western blotting experiments were utilized to investigate how FOXC1 contributes to the transcription of ABHD5 on a molecular level. FOXC1 was assessed by Western blot for its impact on AMPK/mTOR signaling pathway. RESULTS: FOXC1 is down-regulated in RCC, causing unfavorable prognosis of patients with RCC. Further experiments showed that forced FOXC1 expression significantly restrains RCC cell growth and cell metastasis. Mechanically, FOXC1 promotes the transcription of ABHD5 to activate AMPK signal pathway to inhibit mTOR signal pathway. Finally, knockdown of ABHD5 recovered the inhibitory role of FOXC1 overexpression induced cell growth and metastasis suppression. CONCLUSION: In general, our study demonstrates that FOXC1 exerts its tumor suppressor role by promoting ABHD5 transcription to regulating AMPK/mTOR signal pathway. FOXC1 could serve as both a diagnostic indicator and potential treatment focus for RCC.
Asunto(s)
1-Acilglicerol-3-Fosfato O-Aciltransferasa , Proteínas Quinasas Activadas por AMP , Carcinoma de Células Renales , Proliferación Celular , Factores de Transcripción Forkhead , Neoplasias Renales , Ratones Desnudos , Transducción de Señal , Serina-Treonina Quinasas TOR , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/patología , Humanos , Animales , Factores de Transcripción Forkhead/metabolismo , Factores de Transcripción Forkhead/genética , Neoplasias Renales/genética , Neoplasias Renales/patología , Neoplasias Renales/metabolismo , Línea Celular Tumoral , Serina-Treonina Quinasas TOR/metabolismo , Serina-Treonina Quinasas TOR/genética , Proliferación Celular/genética , Ratones , Proteínas Quinasas Activadas por AMP/metabolismo , Proteínas Quinasas Activadas por AMP/genética , 1-Acilglicerol-3-Fosfato O-Aciltransferasa/metabolismo , 1-Acilglicerol-3-Fosfato O-Aciltransferasa/genética , Regulación Neoplásica de la Expresión Génica , Progresión de la Enfermedad , Masculino , Femenino , Ratones Endogámicos BALB CRESUMEN
BACKGROUND: Chronic idiopathic thrombocytopenic purpura (ITP) is an autoimmune disease characterized by a breakdown of immune tolerance; in ITP, the body's immune system mistakenly attacks and destroys platelets. This study aims to investigate the role and underlying mechanisms of FOXP3 in chronic ITP. METHODS: Flow cytometry was used to detect the proportion of CD4+CD25+FOXP3+ regulatory T cells (Tregs) in CD4+CD25+ T lymphocytes from 20 patients with chronic ITP (CITP), 20 acute ITP (AITP) controls, and 20 healthy individuals.CD4+CD25+ Treg cells were isolated from peripheral blood of patients with CITP using magnetic beads and then treated with phosphate-buffered saline solution or decitabine (a methylation inhibitor) for 48 h. The levels of interleukin-2 (IL-2), IL-10, and transforming growth factor-beta1 (TGF-ß1) in the plasma and CD4+CD25+ Treg cells were assessed by Enzyme-linked-immunosorbent serologic assay and quantitative real-time polymerase chain reaction (qRT-PCR). FOXP3 level was measured by qRT-PCR and Western blot analysis. Methylation-specific PCR (MS-PCR) was adopted to detect the status of FOXP3 methylation. RESULTS: The number of Treg cells and the contents of IL-2, IL-10, and TGF-ß1 decreased in patients with CITP, compared to the AITP control group and normal group. FOXP3 expression was reduced and FOXP3 methylation increased in patients with CITP, compared to the AITP control group and normal group. Hypermethylation of FOXP3 promoter led to decrease in FOXP3 level in Treg cells. Inhibition of FOXP3 promoter hypermethylation promoted the secretion of IL-2, IL-10, and TGF-ß1 in Treg cells. CONCLUSION: The number of Treg cells in CITP patients decreased, and the hypermethylation of FOXP3 promoter led to reduction of its expression in Treg cells, thus affecting the immune functioning of Treg cells.
Asunto(s)
Metilación de ADN , Factores de Transcripción Forkhead , Púrpura Trombocitopénica Idiopática , Linfocitos T Reguladores , Humanos , Linfocitos T Reguladores/inmunología , Púrpura Trombocitopénica Idiopática/inmunología , Púrpura Trombocitopénica Idiopática/genética , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Masculino , Femenino , Adulto , Persona de Mediana Edad , Enfermedad Crónica , Interleucina-2 , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta1/sangre , Adulto Joven , Decitabina/farmacología , Células Cultivadas , Interleucina-10/genética , Interleucina-10/metabolismo , AncianoRESUMEN
Regulatory T cells (Tregs) play a crucial and complex role in balancing the immune response to viral infection. Primarily, they serve to regulate the immune response by limiting the expression of proinflammatory cytokines, reducing inflammation in infected tissue, and limiting virus-specific T cell responses. But excessive activity of Tregs can also be detrimental and hinder the ability to effectively clear viral infection, leading to prolonged disease and potential worsening of disease severity. Not much is known about the impact of Tregs during severe influenza. In the present study, we show that CD4+/CD25+FoxP3+ Tregs are strongly involved in disease progression during influenza A virus (IAV) infection in mice. By comparing sublethal with lethal dose infection in vivo, we found that not the viral load but an increased number of CD4+/CD25+FoxP3+ Tregs may impair the immune response by suppressing virus specific CD8+ T cells and favors disease progression. Moreover, the transfer of induced Tregs into mice with mild disease symptoms had a negative and prolonged effect on disease outcome, emphasizing their importance for pathogenesis. Furthermore, treatment with MEK-inhibitors resulted in a significant reduction of induced Tregs in vitro and in vivo and positively influenced the progression of the disease. Our results demonstrate that CD4+/CD25+FoxP3+ Tregs are involved in the pathogenesis of severe influenza and indicate the potential of the MEK-inhibitor zapnometinib to modulate CD4+/CD25+FoxP3+ Tregs. Thus, making MEK-inhibitors even more promising for the treatment of severe influenza virus infections.
Asunto(s)
Virus de la Influenza A , Infecciones por Orthomyxoviridae , Linfocitos T Reguladores , Animales , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Infecciones por Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/tratamiento farmacológico , Ratones , Virus de la Influenza A/inmunología , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Femenino , Ratones Endogámicos C57BL , Factores de Transcripción Forkhead/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Carga Viral/efectos de los fármacos , Modelos Animales de EnfermedadRESUMEN
Osteosarcoma is an aggressive form of bone cancer and affects the health in children and adolescents. Although conventional treatment improves the osteosarcoma survival, some patients have metastasis and drug resistance, leading to a worse prognosis. Therefore, it is necessary to explore the molecular mechanism of osteosarcoma occurrence and progression, which could discover the novel treatment for osteosarcoma. Long noncoding RNAs (lncRNAs) have been reported to regulate osteosarcoma occurrence and malignant progression. LncRNA HOXA-AS3 facilitates the tumorigenesis and progression in a variety of human cancers. However, the underlying mechanism of lncRNA HOXA-AS3-induced oncogenesis is poorly determined in osteosarcoma. To address this point, we utilized several cellular biological strategies and molecular approaches to explore the biological functions and mechanisms of lncRNA HOXA-AS3 in osteosarcoma cells. We found that lncRNA HOXA-AS3 facilitates cell proliferation and invasion via targeting miR-218-5p/FOXP1 axis in osteosarcoma. In conclusion, lncRNA HOXA-AS3 could be a promising target for osteosarcoma treatment.
Asunto(s)
Neoplasias Óseas , Proliferación Celular , Factores de Transcripción Forkhead , Regulación Neoplásica de la Expresión Génica , MicroARNs , Osteosarcoma , ARN Largo no Codificante , Proteínas Represoras , Osteosarcoma/genética , Osteosarcoma/patología , Osteosarcoma/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Humanos , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Proliferación Celular/genética , Línea Celular Tumoral , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Neoplasias Óseas/genética , Neoplasias Óseas/patología , Neoplasias Óseas/metabolismo , Invasividad Neoplásica , Movimiento Celular/genéticaRESUMEN
The skin, as the largest organ of the body, is constantly exposed to environmental threats, including: injuries and oxidative stress. The thioredoxin system is one of the skin antioxidant systems , which protects cells against oxidative stress, regulates cell migration, proliferation and apoptosis, and also participates in signal transmission by regulating the activity of transcription factors. Recent studies have shown a correlation between the epidermal transcription factor Foxn1 and the thioredoxin system in mouse skin. Mass spectrometry analysis, followed by in vitro and in vivo experiments, showed that Foxn1 in keratinocytes regulates elements of the electron transport chain as well as the thioredoxin system (Txn2, Txnrd3), especially under hypoxic condition. High levels of Txnrd3 mRNA were detected for the first time in the injured skin of Foxn1+/+ mice compared to Foxn1-/- mice, and also showed that Foxn1 in keratinocytes upregulates Txnrd3 protein expression. Moreover, in silico analyzes indicated possible binding sites of the transcription factor Foxn1 in the Txn system. In conclusion, the data presented in this review identify Foxn1 as a novel component of the skin antioxidant system.
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Antioxidantes , Factores de Transcripción Forkhead , Piel , Animales , Factores de Transcripción Forkhead/metabolismo , Antioxidantes/metabolismo , Piel/metabolismo , Humanos , Ratones , Queratinocitos/metabolismo , Estrés Oxidativo/fisiología , Tiorredoxinas/metabolismoRESUMEN
Sepsis-induced acute kidney injury (S-AKI) is a severe and frequent complication that occurs during sepsis. This study aimed to understand the role of FOXQ1 in S-AKI and its potential upstream and downstream regulatory mechanisms. A cecal ligation and puncture induced S-AKI mouse model in vivo and an LPS-induced HK-2 cell model in vitro were used. FOXQ1 was significantly upregulated in CLP mice and downregulated in the LPS-induced HK-2 cells. Upregulation of FOXQ1 improved kidney injury and dysfunction in CLP mice. Overexpression of FOXQ1 remarkably suppressed the apoptosis and inflammatory response via down-regulating oxidative stress indicators and pro-inflammatory factors (IL-1ß, IL-6, and TNF-α), both in vivo and in vitro. From online analysis, the CREB5/NF-κB axis was identified as the downstream target of FOXQ1. FOXQ1 transcriptionally activated CREB5, upregulating its expression. Overexpression of FOXQ1 suppressed the phosphorylation level and nucleus transport of p65. Rescue experiments showed that CREB5 mediates the protective role of FOXQ1 on S-AKI. Furthermore, FOXQ1 was identified as a substrate of USP10, a deubiquitinating enzyme. Ectopic expression of USP10 reduced the ubiquitination of FOXQ1, promoting its protein stability. USP10 upregulation alleviated LPS-induced cell apoptosis and inflammatory response, while suppression of FOXQ1 augmented these trends. Collectively, our results suggest that FOXQ1, deubiquitinated by USP10, plays a protective role in S-AKI induced inflammation and apoptosis by targeting CREB5/NF-κB axis.
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Lesión Renal Aguda , Proteína de Unión a Elemento de Respuesta al AMP Cíclico , Factores de Transcripción Forkhead , FN-kappa B , Sepsis , Transducción de Señal , Ubiquitina Tiolesterasa , Ubiquitinación , Animales , Sepsis/metabolismo , Sepsis/complicaciones , Sepsis/patología , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/patología , Lesión Renal Aguda/genética , Ubiquitina Tiolesterasa/metabolismo , Ubiquitina Tiolesterasa/genética , Ratones , Factores de Transcripción Forkhead/metabolismo , Factores de Transcripción Forkhead/genética , Humanos , FN-kappa B/metabolismo , Masculino , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Apoptosis , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Línea Celular , Lipopolisacáridos , Inflamación/metabolismo , Inflamación/patologíaRESUMEN
BACKGROUND: Mitral valve (MV) disease including myxomatous degeneration is the most common form of valvular heart disease with an age-dependent frequency. Genetic evidence indicates that mutations of the human transcription factor FOXC1 are associated with MV defects, including MV regurgitation. In this study, we sought to determine whether murine Foxc1 and its closely related factor, Foxc2, are required in valvular endothelial cells (VECs) for the maintenance of MV leaflets, including VEC junctions and the stratified trilaminar ECM (extracellular matrix). METHODS: Adult mice carrying tamoxifen-inducible, vascular endothelial cell (EC), and lymphatic EC-specific, compound Foxc1;Foxc2 mutations (ie, EC-Foxc-DKO and lymphatic EC-Foxc-DKO mice, respectively) were used to study the function of Foxc1 and Foxc2 in the maintenance of MVs. The EC and lymphatic EC mutations of Foxc1/c2 were induced at 7 to 8 weeks of age by tamoxifen treatment, and abnormalities in the MVs of these mutant mice were assessed via whole-mount immunostaining, immunohistochemistry/RNAscope, Movat pentachrome/Masson Trichrome staining, and Evans blue injection. RESULTS: EC deletions of Foxc1 and Foxc2 in mice resulted in abnormally extended and thicker MVs by causing defects in the regulation of ECM organization with increased proteoglycan and decreased collagen. Notably, reticular adherens junctions were found in VECs of control MV leaflets, and these reticular structures were severely disrupted in EC-Foxc-DKO mice. PROX1 (prospero homeobox protein 1), a key regulator in a subset of VECs on the fibrosa side of MVs, was downregulated in EC-Foxc1/c2 mutant VECs. Furthermore, we determined the precise location of lymphatic vessels in murine MVs, and these lymphatic vessels were aberrantly expanded and dysfunctional in EC-Foxc1/c2 mutant MVs. Lymphatic EC deletion of Foxc1/c2 also resulted in similar structural/ECM abnormalities as seen in EC-Foxc1/c2 mutant MVs. CONCLUSIONS: Our results indicate that Foxc1 and Foxc2 are required for maintaining the integrity of the MV, including VEC junctions, ECM organization, and lymphatic vessel formation/function to prevent myxomatous MV degeneration.
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Modelos Animales de Enfermedad , Células Endoteliales , Factores de Transcripción Forkhead , Linfangiogénesis , Vasos Linfáticos , Ratones Noqueados , Animales , Factores de Transcripción Forkhead/metabolismo , Factores de Transcripción Forkhead/genética , Células Endoteliales/metabolismo , Células Endoteliales/patología , Vasos Linfáticos/metabolismo , Vasos Linfáticos/patología , Válvula Mitral/metabolismo , Válvula Mitral/patología , Mutación , Ratones , Uniones Intercelulares/metabolismo , Uniones Intercelulares/patología , Enfermedades de las Válvulas Cardíacas/metabolismo , Enfermedades de las Válvulas Cardíacas/patología , Enfermedades de las Válvulas Cardíacas/genética , Fenotipo , Ratones Endogámicos C57BL , Prolapso de la Válvula Mitral/metabolismo , Prolapso de la Válvula Mitral/genética , Prolapso de la Válvula Mitral/patología , Matriz Extracelular/metabolismo , Matriz Extracelular/patologíaRESUMEN
Imiqualines are analogues of the immunomodulatory drug imiquimod. EAPB02303, the lead of the second-generation imiqualines, is characterized by significant anti-tumor effects with IC50s in the nanomolar range. We used Caenorhabditis elegans transgenic and mutant strains of two key signaling pathways (PI3K-Akt and Ras-MAPK) disrupted in human cancers to investigate the mode of action of EAPB02303. The ability of this imiqualine to inhibit the insulin/IGF1 signaling (IIS) pathway via the PI3K-Akt kinase cascade was explored through assessing the lifespan of wild-type worms. Micromolar doses of EAPB02303 significantly enhanced longevity of N2 strain and led to the nuclear translocation and subsequent activation of transcription factor DAF-16, the only forkhead box transcription factor class O (Fox O) homolog in C. elegans. Moreover, EAPB02303 significantly reduced the multivulva phenotype in let-60/Ras mutant strains MT2124 and MT4698, indicative of its mode of action through the Ras pathway. In summary, we showed that EAPB02303 potently reduced the activity of IIS and Ras-MAPK signaling in C. elegans. Our results revealed the mechanism of action of EAPB02303 against human cancers associated with hyperactivated IIS pathway and oncogenic Ras mutations.
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Antineoplásicos , Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Factores de Transcripción Forkhead , Quinoxalinas , Transducción de Señal , Caenorhabditis elegans/efectos de los fármacos , Caenorhabditis elegans/genética , Animales , Quinoxalinas/farmacología , Quinoxalinas/química , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Antineoplásicos/farmacología , Antineoplásicos/química , Transducción de Señal/efectos de los fármacos , Factores de Transcripción Forkhead/metabolismo , Factores de Transcripción Forkhead/genética , Longevidad/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Humanos , Imidazoles/farmacología , Imidazoles/química , Animales Modificados GenéticamenteRESUMEN
PURPOSE: Tumor initiating cells (TICs) or cancer stem cells (CSCs) are considered to be the main culprit of hepatocellular carcinoma (HCC) initiation and progression, nevertheless the mechanism by which tumor microenvironment maintains the HCC 'stemness' is not fully understood. This study aims to investigate the effect of regulatory T cells (Tregs) on the TICs characteristics of HCC. METHODS: Immunocytochemistry, flow cytometry, real-time PCR, western blot, in vitro sphere-formation, and in vivo tumorigenesis assay were used to detect HCC 'stemness'. Additionally, after forced expression or inhibition of FoxP3, ß-catenin expression and HCC 'stemness' were investigated. RESULTS: Tregs enhanced the 'stemness' of HCC cells by upregulating TIC-related markers CD133, Oct3/4, Sox2, c-Myc, Klf4, Nanog, CD13, EpCAM, and inducting epithelial to mesenchymal transition (EMT), increasing TICs ratio, as well as promoting tumorigenic ability. Moreover, ß-catenin and c-Myc were upregulated in HCC cells after co-cultured with Tregs. HCC 'stemness' was inhibited after treatment with Wnt/ß-catenin pathway inhibitor. Furthermore, forced expression of FoxP3 resulted in increased GSK3ß, decreased ß-catenin and TIC ratio in HCC. In contrast, FoxP3 interference reduced GSK3ß, enhanced ß-catenin and TIC ratio of HCC. CONCLUSION: This study, for the first time, demonstrated that Tregs increased the population of TICs in HCC by inhibiting FoxP3 as well as promoting ß-catenin expression.
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Carcinoma Hepatocelular , Factores de Transcripción Forkhead , Factor 4 Similar a Kruppel , Neoplasias Hepáticas , Células Madre Neoplásicas , Linfocitos T Reguladores , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/metabolismo , Humanos , Células Madre Neoplásicas/patología , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/inmunología , Factores de Transcripción Forkhead/metabolismo , Linfocitos T Reguladores/inmunología , Factor 4 Similar a Kruppel/metabolismo , Ratones , Animales , Línea Celular Tumoral , Microambiente Tumoral/inmunología , Transición Epitelial-Mesenquimal , beta Catenina/metabolismo , Ratones Desnudos , Vía de Señalización Wnt , Ratones Endogámicos BALB CRESUMEN
Regulatory T (Treg) cells play a key role in maintaining immune tolerance and tissue homeostasis. However, in some disease microenvironments, Treg cells exhibit fragility, which manifests as preserved FoxP3 expression accompanied by inflammation and loss of immunosuppression. Fragile Treg cells are formatively, phenotypically and functionally diverse in various diseases, further complicating the role of Treg cells in the immunotherapeutic response and offering novel targets for disease treatment by modulating specific Treg subsets. In this review, we summarize findings on fragile Treg cells to provide a framework for characterizing the formation and role of fragile Treg cells in different diseases, and we discuss how this information may guide the development of more specific Treg-targeted immunotherapies.