RESUMO
The dysregulated long non-coding RNA A1BG antisense RNA 1 (A1BG-AS1) has been implicated in the oncogenicity of hepatocellular carcinoma. Using reverse transcription quantitative polymerase chain reaction in this study, we detected A1BG-AS1 expression in breast cancer and elucidated the regulatory functions and exact mechanisms of A1BG-AS1 in breast cancer cells. The regulatory functions of A1BG-AS1 were examined in vitro using the Cell Counting Kit-8 assay, flow cytometric, and Transwell migration and invasion assays and in vivo through tumor xenograft experiments. In addition, we performed bioinformatics analysis, luciferase reporter assay, RNA immunoprecipitation, and rescue experiments to verify the interaction among A1BG-AS1, microRNA-485-5p (miR-485-5p), and flotillin-1 (FLOT1) in breast cancer. We found A1BG-AS1 to be highly expressed in breast cancer tissues and cell lines. In terms of function, depleted A1BG-AS1 markedly suppressed cell proliferation, accelerated cell apoptosis, and hindered cell migration and invasion in breast cancer. Furthermore, A1BG-AS1 interference reduced tumor growth in vivo. Mechanistic investigations confirmed that A1BG-AS1 directly interacted with miR-485-5p as a molecular sponge. We demonstrated that FLOT1 is a direct target of miR-485-5p, which could be positively regulated by A1BG-AS1 by competing for miR-485-5p. Rescue experiments clearly showed that the downregulation of miR-485-5p and upregulation of FLOT1 were capable of reversing the anticancer activities of A1BG-AS1 deficiency in terms of breast cancer cell malignancy. A1BG-AS1 acts as a miR-485-5p sponge and subsequently increases FLOT1 expression in breast cancer cells, ultimately facilitating cancer progression. Hence, the A1BG-AS1/miR-485-5p/FLOT1 pathway might offer a novel therapeutic perspective for breast cancer.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Carcinogênese/genética , Regulação Neoplásica da Expressão Gênica/genética , Glicoproteínas/fisiologia , Imunoglobulinas/fisiologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Longo não Codificante/fisiologia , Neoplasias da Mama/terapia , Linhagem Celular Tumoral , Movimento Celular/genética , Feminino , Glicoproteínas/genética , Humanos , Imunoglobulinas/genética , Terapia de Alvo Molecular , Invasividade Neoplásica/genética , RNA Longo não Codificante/genética , Transdução de Sinais/genética , Transdução de Sinais/fisiologiaRESUMO
Rationale: Siglec15 is an emerging target for normalization cancer immunotherapy. However, pan-cancer anti-Siglec15 treatment is not yet validated and the potential role of Siglec15 in bladder cancer (BLCA) remains elusive. Methods: We comprehensively evaluated the expression pattern and immunological role of Siglec15 using pan-cancer analysis based on RNA sequencing data obtained from The Cancer Genome Atlas. We then systematically correlated Siglec15 with immunological characteristics in the BLCA tumor microenvironment (TME), including immunomodulators, cancer immunity cycles, tumor-infiltrating immune cells (TIICs), immune checkpoints, and T cell inflamed score. We also analyzed the role of Siglec15 in predicting the molecular subtype and the response to several treatment options in BLCA. Our results were validated in several public cohorts as well as our BLCA tumor microarray cohort, the Xiangya cohort. We developed an immune risk score (IRS), validated it, and tested its ability to predict the prognosis and response to cancer immunotherapy. Results: We found that Siglec15 was specifically overexpressed in the TME of various cancers. We hypothesize that Siglec15 designs a non-inflamed TME in BLCA based on the evidence that Siglec15 negatively correlated with immunomodulators, TIICs, cancer immunity cycles, immune checkpoints, and T cell inflamed score. Bladder cancer with high Siglec15 expression was not sensitive to cancer immunotherapy, but exhibited a higher incidence of hyperprogression. High Siglec15 levels indicated a luminal subtype of BLCA characterized by lower immune infiltration, lower response to cancer immunotherapy and neoadjuvant chemotherapy, but higher response to anti-angiogenic therapy and targeted therapies such as blocking Siglec15, ß-catenin, PPAR-γ, and FGFR3 pathways. Notably, a combination of anti-Siglec15 and cancer immunotherapy may be a more effective strategy than monotherapy. IRS can accurately predict the prognosis and response to cancer immunotherapy. Conclusions: Anti-Siglec15 immunotherapy might be suitable for BLCA treatment as Siglec15 correlates with a non-inflamed TME in BLCA. Siglec15 could also predict the molecular subtype and the response to several treatment options.
Assuntos
Imunoglobulinas/metabolismo , Proteínas de Membrana/metabolismo , Neoplasias da Bexiga Urinária/metabolismo , Biomarcadores Tumorais/genética , China , Biologia Computacional/métodos , Bases de Dados Genéticas , Progressão da Doença , Expressão Gênica/genética , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Imunoglobulinas/fisiologia , Imunoterapia , Proteínas de Membrana/fisiologia , Prognóstico , Análise de Sequência de RNA/métodos , Microambiente Tumoral/imunologia , Neoplasias da Bexiga Urinária/patologiaRESUMO
La función de las amígdalas siempre ha sido discutida, desde afirmar que no tenían funcionalidad, hasta la actualidad que se plantea un papel inmunológico, con actividad linfocitaria de defensa, debido a la localización de linfocitos en el tejido de las amígdalas. Este artículo de actualización pretende describir desde la embriología, histología, fisiología, patología y estomatología, el rol que desempeñan las mismas en su papel inmunológico ante la acción de agentes patógenos. Se destaca la acción conjunta de las amígdalas palatinas, amígdalas faríngeas o adenoides, amígdalas peritubarias, amígdalas linguales y todo el resto de tejido linfático que conforman el anillo linfático faríngeo o anillo de Waldeyer, ya que cumplen un rol determinante en la defensa del organismo (AU)
The function of the tonsils has always been debated, from stating that they had no functionality, to the present day that an immunological role is proposed, with lymphocyte defense activity, due to the location of lymphocytes in the tissue of the tonsils. This update article aims to describe from embryology, histology, physiology, pathology and stomatology, the role they play in their immunological role against the action of pathogens. The joint action of the palatine tonsils, pharyngeal or adenoid tonsils, peritubal tonsils, lingual tonsils and all the rest of the lymphatic tissue that make up the pharyngeal lymphatic ring or Waldeyer's ring is highlighted, since they play a decisive role in the defense of the organism (AU)
Assuntos
Humanos , Tonsila Palatina/imunologia , Tonsila Faríngea/imunologia , Tecido Linfoide , Imunoglobulinas/fisiologia , Linfócitos/fisiologia , Doenças da Boca/imunologiaRESUMO
PNAd and MAdCAM-1 addressins on venules are of importance in T-cell homing and potential therapeutic targets in ulcerative colitis (UC). Normally, PNAd+ high endothelial venules (HEVs) are only present in lymphoid organs, whereas small numbers of MAdCAM-1+ venules can be seen in non-lymphoid tissue. We aimed to study their presence in the intestinal mucosa of UC patients at diagnosis and during follow-up, and their correlation with disease activity. Colonic biopsy specimens of 378 UC patients were analyzed by immunohistochemistry for CD3, CD20, ERG, MECA-79 (PNAd) and MECA-376 (MAdCAM-1) and compared to healthy controls (HC). The proportion of PNAd+HEVs in UC at diagnosis was 4.9% (IQR 2.0%-8.3%), while none were detected in HC. During follow-up, PNAd+HEVs completely disappeared in remission (n = 93), whereas the proportion in active disease was similar to baseline (n = 285, p = 0.39). The proportion of MAdCAM-1+venules in UC at baseline was 5.8% (IQR 2.6-10.0). During follow-up, the proportion in remission was comparable to diagnosis, but upregulated (7.5% (IQR 4.4-10.9), p = 0.001) in active disease. In conclusion, PNAd+HEVs appear in UC during active inflammation which could thus serve as a marker for disease activity, whereas MAdCAM-1+venules remain present after inflammation is resolved and increase after subsequent flares, reflecting chronicity and potentially serving as a therapeutic target.
Assuntos
Colite Ulcerativa/imunologia , Imunoglobulinas/fisiologia , Mucosa Intestinal/fisiopatologia , Vênulas/fisiopatologia , Adulto , Colite Ulcerativa/patologia , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
CONTEXT: The X-linked immunoglobulin superfamily, member 1 (IGSF1), gene is highly expressed in the hypothalamus and in pituitary cells of the POU1F1 lineage. Human loss-of-function mutations in IGSF1 cause central hypothyroidism, hypoprolactinemia, and macroorchidism. Additionally, most affected adults exhibit higher than average IGF-1 levels and anecdotal reports describe acromegaloid features in older subjects. However, somatotrope function has not yet been formally evaluated in this condition. OBJECTIVE: We aimed to evaluate the role of IGSF1 in human and murine somatotrope function. PATIENTS, DESIGN, AND SETTING: We evaluated 21 adult males harboring hemizygous IGSF1 loss-of-function mutations for features of GH excess, in an academic clinical setting. MAIN OUTCOME MEASURES: We compared biochemical and tissue markers of GH excess in patients and controls, including 24-hour GH profile studies in 7 patients. Parallel studies were undertaken in male Igsf1-deficient mice and wild-type littermates. RESULTS: IGSF1-deficient adult male patients demonstrated acromegaloid facial features with increased head circumference as well as increased finger soft-tissue thickness. Median serum IGF-1 concentrations were elevated, and 24-hour GH profile studies confirmed 2- to 3-fold increased median basal, pulsatile, and total GH secretion. Male Igsf1-deficient mice also demonstrated features of GH excess with increased lean mass, organ size, and skeletal dimensions and elevated mean circulating IGF-1 and pituitary GH levels. CONCLUSIONS: We demonstrate somatotrope neurosecretory hyperfunction in IGSF1-deficient humans and mice. These observations define a hitherto uncharacterized role for IGSF1 in somatotropes and indicate that patients with IGSF1 mutations should be evaluated for long-term consequences of increased GH exposure.
Assuntos
Imunoglobulinas/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Proteínas de Membrana/fisiologia , Neurossecreção/fisiologia , Somatotrofos/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Hormônio do Crescimento/biossíntese , Humanos , Imunoglobulinas/deficiência , Fator de Crescimento Insulin-Like I/análise , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Masculino , Proteínas de Membrana/deficiência , Camundongos , Pessoa de Meia-IdadeRESUMO
Cancer-associated fibroblasts (CAF) constitute a major component of the tumor microenvironment. Recent observations in genetically engineered mouse models and clinical studies have suggested that there may exist at least two functionally different populations of CAFs, that is, cancer-promoting CAFs (pCAF) and cancer-restraining CAFs (rCAF). Although various pCAF markers have been identified, the identity of rCAFs remains unknown because of the lack of rCAF-specific marker(s). In this study, we found that Meflin, a glycosylphosphatidylinositol-anchored protein that is a marker of mesenchymal stromal/stem cells and maintains their undifferentiated state, is expressed by pancreatic stellate cells that are a source of CAFs in pancreatic ductal adenocarcinoma (PDAC). In situ hybridization analysis of 71 human PDAC tissues revealed that the infiltration of Meflin-positive CAFs correlated with favorable patient outcome. Consistent herewith, Meflin deficiency led to significant tumor progression with poorly differentiated histology in a PDAC mouse model. Similarly, genetic ablation of Meflin-positive CAFs resulted in poor differentiation of tumors in a syngeneic transplantation model. Conversely, delivery of a Meflin-expressing lentivirus into the tumor stroma or overexpression of Meflin in CAFs suppressed the growth of xenograft tumors. Lineage tracing revealed that Meflin-positive cells gave rise to α-smooth muscle actin-positive CAFs that are positive or negative for Meflin, suggesting a mechanism for generating CAF heterogeneity. Meflin deficiency or low expression resulted in straightened stromal collagen fibers, which represent a signature for aggressive tumors, in mouse or human PDAC tissues, respectively. Together, the data suggest that Meflin is a marker of rCAFs that suppress PDAC progression. SIGNIFICANCE: Meflin marks and functionally contributes to a subset of cancer-associated fibroblasts that exert antitumoral effects.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/20/5367/F1.large.jpg.
Assuntos
Carcinoma Ductal Pancreático/patologia , Fibroblastos/patologia , Imunoglobulinas/fisiologia , Neoplasias Pancreáticas/patologia , Animais , Biomarcadores Tumorais , Carcinogênese , Carcinoma Ductal Pancreático/química , Diferenciação Celular , Linhagem Celular Tumoral , Progressão da Doença , Fibroblastos/química , Regulação Neoplásica da Expressão Gênica , Genes Sintéticos , Xenoenxertos , Humanos , Imunoglobulinas/análise , Imunoglobulinas/deficiência , Imunoglobulinas/genética , Células-Tronco Mesenquimais/patologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Transplante de Neoplasias , Neoplasias Pancreáticas/química , Prognóstico , Proteínas Recombinantes de Fusão/metabolismo , Células Estromais/metabolismo , Células Estromais/patologia , Vitamina D/fisiologiaRESUMO
The host evolves redundant mechanisms to preserve physiological processing and homeostasis. These functions range from sensing internal and external threats, creating a memory of the insult and generating reflexes, which aim to resolve inflammation. Impairment in such functioning leads to chronic inflammatory diseases. By interacting through a common language of ligands and receptors, the immune and sensory nervous systems work in concert to accomplish such protective functions. Whilst this bidirectional communication helps to protect from danger, it can contribute to disease pathophysiology. Thus, the somatosensory nervous system is anatomically positioned within primary and secondary lymphoid tissues and mucosa to modulate immunity directly. Upstream of this interplay, neurons detect danger, which prompts the release of neuropeptides initiating (i) defensive reflexes (ranging from withdrawal response to coughing) and (ii) chemotaxis, adhesion and local infiltration of immune cells. The resulting outcome of such neuro-immune interplay is still ill-defined, but consensual findings start to emerge and support neuropeptides not only as blockers of TH 1-mediated immunity but also as drivers of TH 2 immune responses. However, the modalities detected by nociceptors revealed broader than mechanical pressure and temperature sensing and include signals as various as cytokines and pathogens to immunoglobulins and even microRNAs. Along these lines, we aggregated various dorsal root ganglion sensory neuron expression profiling datasets supporting such wide-ranging sensing capabilities to help identifying new danger detection modalities of these cells. Thus, revealing unexpected aspects of nociceptor neuron biology might prompt the identification of novel drivers of immunity, means to resolve inflammation and strategies to safeguard homeostasis.
Assuntos
Nociceptores/fisiologia , Sistema Nervoso Periférico/fisiologia , Células Receptoras Sensoriais/fisiologia , Citocinas/fisiologia , Hipersensibilidade a Drogas/imunologia , Exossomos/fisiologia , Proteína HMGB1/fisiologia , Humanos , Imunidade Inata/fisiologia , Imunoglobulinas/fisiologia , Infecções/imunologia , Mediadores da Inflamação/fisiologia , Neoplasias/fisiopatologia , Neuroimunomodulação/fisiologia , Nervos Periféricos/fisiologia , Tempo de Reação/fisiologia , Estresse Mecânico , Termorreceptores/fisiologia , Receptor 2 Toll-Like/fisiologia , Receptor 4 Toll-Like/fisiologia , Microambiente Tumoral/fisiologiaRESUMO
Ovarian cancer is the highest mortality rate of all female reproductive malignancies. Drug resistance is a major cause of treatment failure in malignant tumors. Hepatitis B X-interacting protein acts as an oncoprotein, regulates cell proliferation, and migration in breast cancer. We aimed to investigate the effects and mechanisms of hepatitis B X-interacting protein on resistance to cisplatin in human ovarian cancer cell lines. The mRNA and protein levels of hepatitis B X-interacting protein were detected using RT-PCR and Western blotting in cisplatin-resistant and cisplatin-sensitive tissues, cisplatin-resistant cell lines A2780/CP and SKOV3/CP, and cisplatin-sensitive cell lines A2780 and SKOV3. Cell viability and apoptosis were measured to evaluate cellular sensitivity to cisplatin in A2780/CP cells. Luciferase reporter gene assay was used to determine the relationship between hepatitis B X-interacting protein and CD147. The in vivo function of hepatitis B X-interacting protein on tumor burden was assessed in cisplatin-resistant xenograft models. The results showed that hepatitis B X-interacting protein was highly expressed in ovarian cancer of cisplatin-resistant tissues and cells. Notably, knockdown of hepatitis B X-interacting protein significantly reduced cell viability in A2780/CP compared with cisplatin treatment alone. Hepatitis B X-interacting protein and cisplatin cooperated to induce apoptosis and increase the expression of c-caspase 3 as well as the Bax/Bcl-2 ratio. We confirmed that hepatitis B X-interacting protein up-regulated CD147 at the protein expression and transcriptional levels. Moreover, we found that hepatitis B X-interacting protein was able to activate the CD147 promoter through Sp1. In vivo, depletion of hepatitis B X-interacting protein decreased the tumor volume and weight induced by cisplatin. Taken together, these results indicate that hepatitis B X-interacting protein promotes cisplatin resistance and regulated CD147 via Sp1 in ovarian cancer cell lines. Impact statement We found that hepatitis B X-interacting protein (HBXIP) was able to activate the CD147 promoter through Sp1. In vivo, depletion of HBXIP decreased the tumor volume and weight induced by CP. Taken together, these results indicate that HBXIP promotes cisplatin resistance and regulated CD147 via Sp1 in ovarian cancer cell lines.
Assuntos
Antineoplásicos/uso terapêutico , Basigina/fisiologia , Cisplatino/uso terapêutico , Imunoglobulinas/fisiologia , Proteínas Nucleares/fisiologia , Neoplasias Ovarianas/tratamento farmacológico , Transativadores/fisiologia , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Caspase 3/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/fisiologia , Feminino , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Major histocompatibility complex class II (MHC II) expression is tightly regulated, being subjected to cell type-specific mechanisms that closely control its levels at the cell surface. Ubiquitination by the E3 ubiquitin ligase MARCH 1 regulates MHC II expression in dendritic cells and B cells. In this study, we demonstrate that the related ligase MARCH 8 is responsible for regulating surface MHC II in thymic epithelial cells (TECs). March8(-/-) mice have elevated MHC II at the surface of cortical TECs and autoimmune regulator (AIRE)(-) medullary TECs (mTECs), but not AIRE(+) mTECs. Despite this, thymic and splenic CD4(+) T cell numbers and repertoires remained unaltered in March8(-/-) mice. Notably, the ubiquitination of MHC II by MARCH 8 is controlled by CD83. Mice expressing a mutated form of CD83 (Cd83(anu/anu) mice) have impaired CD4(+) T cell selection, but deleting March8 in Cd83(anu/anu) mice restored CD4(+) T cell selection to normal levels. Therefore, orchestrated regulation of MHC II surface expression in TECs by MARCH 8 and CD83 plays a major role in CD4(+) T cell selection. Our results also highlight the specialized use of ubiquitinating machinery in distinct antigen-presenting cell types, with important functional consequences and implications for therapeutic manipulation.
Assuntos
Antígenos CD/fisiologia , Linfócitos T CD4-Positivos/imunologia , Células Epiteliais/imunologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Imunoglobulinas/fisiologia , Glicoproteínas de Membrana/fisiologia , Timo/diagnóstico por imagem , Ubiquitina-Proteína Ligases/fisiologia , Animais , Camundongos , Camundongos Endogâmicos C57BL , Timo/imunologia , Ubiquitinação , Antígeno CD83RESUMO
Deficiency of CD83 in thymic epithelial cells (TECs) dramatically impairs thymic CD4 T cell selection. CD83 can exert cell-intrinsic and -extrinsic functions through discrete protein domains, but it remains unclear how CD83's capacity to operate through these alternative functional modules relates to its crucial role in TECs. In this study, using viral reconstitution of gene function in TECs, we found that CD83's transmembrane domain is necessary and sufficient for thymic CD4 T cell selection. Moreover, a ubiquitination-resistant MHCII variant restored CD4 T cell selection in Cd83(-/-) mice. Although during dendritic cell maturation CD83 is known to stabilize MHCII through opposing the ubiquitin ligase March1, regulation of March1 did not account for CD83's TEC-intrinsic role. Instead, we provide evidence that MHCII in cortical TECs (cTECs) is targeted by March8, an E3 ligase of as yet unknown physiological substrate specificity. Ablating March8 in Cd83(-/-) mice restored CD4 T cell development. Our results identify CD83-mediated MHCII stabilization through antagonism of March8 as a novel functional adaptation of cTECs for T cell selection. Furthermore, these findings suggest an intriguing division of labor between March1 and March8 in controlling inducible versus constitutive MHCII expression in hematopoietic antigen-presenting cells versus TECs.
Assuntos
Antígenos CD/fisiologia , Linfócitos T CD4-Positivos/imunologia , Células Epiteliais/imunologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Imunoglobulinas/fisiologia , Glicoproteínas de Membrana/fisiologia , Timo/imunologia , Ubiquitina-Proteína Ligases/fisiologia , Animais , Células Dendríticas/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Ubiquitinação , Antígeno CD83RESUMO
The cleft is an integral part of synapses, yet its macromolecular organization remains unclear. We show here that the cleft of excitatory synapses exhibits a distinct density profile as measured by cryoelectron tomography (cryo-ET). Aiming for molecular insights, we analyzed the synapse-organizing proteins Synaptic Cell Adhesion Molecule 1 (SynCAM 1) and EphB2. Cryo-ET of SynCAM 1 knockout and overexpressor synapses showed that this immunoglobulin protein shapes the cleft's edge. SynCAM 1 delineates the postsynaptic perimeter as determined by immunoelectron microscopy and super-resolution imaging. In contrast, the EphB2 receptor tyrosine kinase is enriched deeper within the postsynaptic area. Unexpectedly, SynCAM 1 can form ensembles proximal to postsynaptic densities, and synapses containing these ensembles were larger. Postsynaptic SynCAM 1 surface puncta were not static but became enlarged after a long-term depression paradigm. These results support that the synaptic cleft is organized on a nanoscale into sub-compartments marked by distinct trans-synaptic complexes.
Assuntos
Moléculas de Adesão Celular/fisiologia , Moléculas de Adesão Celular/ultraestrutura , Imunoglobulinas/fisiologia , Imunoglobulinas/ultraestrutura , Sinapses/fisiologia , Sinapses/ultraestrutura , Animais , Molécula 1 de Adesão Celular , Moléculas de Adesão Celular Neuronais/fisiologia , Moléculas de Adesão Celular Neuronais/ultraestrutura , Células Cultivadas , Hipocampo/fisiologia , Hipocampo/ultraestrutura , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Microscopia Imunoeletrônica , Neurônios/fisiologia , Neurônios/ultraestruturaRESUMO
Abnormal expression of thymic stromal lymphopoietin (TSLP) and its receptor (TSLPR) was found in patients with acute coronary syndrome. Ticagrelor, an oral platelet ADP P2Y12 receptor antagonist, is widely used in these patients. The aim of this study was to verify whether different doses of ticagrelor regulated plaque progression and platelet activity by modulating TSLP/TSLPR. Seventy-five ApoE-/- mice were randomly divided into five groups: (1) high-cholesterol diet (HCD, n = 15); (2) HCD plus ticagrelor 25 mg/kg/d (T1, n = 15); (3) HCD plus ticagrelor 50 mg/kg/d (T2, n = 15); (4) HCD plus ticagrelor 100 mg/kg/d (T3, n = 15); and (5) a normal diet group (ND, n = 15). At day 0 and at week 16, blood lipids and serum TSLP levels, expression of TSLPR, CD62, and CD63, platelet aggregation, platelet ATP release, PI3K/Akt signaling pathway, and plaque morphology were assessed. HCD increased TSLPR expression and atherosclerosis progression but high-dose ticagrelor (100 mg/kg) moderated this trend. TSLPR was positively correlated with Akt1, platelet aggregation, corrected plaque area, and vulnerability index in the T3 group (P<0.01). In conclusion, low-dose ticagrelor only inhibited platelet activity. Besides this inhibition, high-dose ticagrelor modulated platelet activity and atherosclerosis mediated by TSLPR, potentially through the PI3K/Akt signal pathway.
Assuntos
Adenosina/análogos & derivados , Aterosclerose/tratamento farmacológico , Citocinas/fisiologia , Imunoglobulinas/efeitos dos fármacos , Inibidores da Agregação Plaquetária/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Receptores de Citocinas/efeitos dos fármacos , Adenosina/administração & dosagem , Adenosina/farmacologia , Animais , Aorta/metabolismo , Aorta/patologia , Apolipoproteínas E/deficiência , Aterosclerose/sangue , Aterosclerose/prevenção & controle , Colesterol na Dieta/toxicidade , Citocinas/sangue , Relação Dose-Resposta a Droga , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/complicações , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Imunoglobulinas/biossíntese , Imunoglobulinas/fisiologia , Lipídeos/sangue , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Selectina-P/análise , Fosfatidilinositol 3-Quinases/fisiologia , Inibidores da Agregação Plaquetária/administração & dosagem , Proteínas Proto-Oncogênicas c-akt/biossíntese , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/fisiologia , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Distribuição Aleatória , Receptores de Citocinas/biossíntese , Receptores de Citocinas/fisiologia , Transdução de Sinais/efeitos dos fármacos , Tetraspanina 30/sangue , Ticagrelor , Linfopoietina do Estroma do TimoRESUMO
Increasing evidence has demonstrated that cell adhesion molecule 1/tumor suppressor in lung cancer 1 (CADM1/TSLC1) is crucially implicated in various biological processes, including proliferation, apoptosis, and invasion during tumorigenesis and development. However, the mechanism underlying its suppression of tumor growth and metastasis in melanoma remains elusive. The aim of the present study was to examine if CADM1/TSLC1 was able to induce growth suppression in melanoma. The plasmid pcDNA3.1CADM1/TSLC1 was transfected into A375 cells (a human melanoma cell line). The expression of CADM1/TSLC1 in the transfected cells was determined by RTPCR and western blotting analysis. Cell growth was measured by an 3(4,5dimethylthiazol2yl)2,5diphenyltetrazolium bromide assay and cell apoptosis was determined by flow cytometry, while a transwell assay was utilized to measure the ability of invasion. The expression of MMP2 and MMP9 in the transfected cells was determined by western blotting analysis. RTPCR and western blotting revealed that in pcDNA3.1CADM1/TSLC1 the protein expression of CADM1/TSLC1 protein was higher than in the pcDNA3.1 and A375 cells. The expression of MMP2 and MMP9 was lower in the pcDNA3.1CADM1/TSLC1 than that in the pcDNA3.1 and A375 cells. The growth of CADM1/TSLC1transfected cells was significantly suppressed in vitro and the ability of invasion was also reduced, CADM1/TSLC1 was able to induce cell apoptosis. Furthermore, CADM1/TSLC1 was an antiinvasive gene, the overexpression of which inhibited the invasion of A375 cells. This inhibition may be due to the suppression of the MMP2 and MMP9 expression, which is relative to tumor metastasis and progression.
Assuntos
Moléculas de Adesão Celular/fisiologia , Imunoglobulinas/fisiologia , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Apoptose , Molécula 1 de Adesão Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Humanos , MelanomaRESUMO
V-domain Ig suppressor of T cell activation (VISTA) is a potent negative regulator of T-cell function that is expressed on hematopoietic cells. VISTA levels are heightened within the tumor microenvironment, in which its blockade can enhance antitumor immune responses in mice. In humans, blockade of the related programmed cell death 1 (PD-1) pathway has shown great potential in clinical immunotherapy trials. Here, we report the structure of human VISTA and examine its function in lymphocyte negative regulation in cancer. VISTA is expressed predominantly within the hematopoietic compartment with highest expression within the myeloid lineage. VISTA-Ig suppressed proliferation of T cells but not B cells and blunted the production of T-cell cytokines and activation markers. Our results establish VISTA as a negative checkpoint regulator that suppresses T-cell activation, induces Foxp3 expression, and is highly expressed within the tumor microenvironment. By analogy to PD-1 and PD-L1 blockade, VISTA blockade may offer an immunotherapeutic strategy for human cancer.
Assuntos
Antígenos B7/fisiologia , Imunoglobulinas/fisiologia , Ativação Linfocitária , Linfócitos T/imunologia , Animais , Antígenos B7/química , Antígeno B7-H1 , Feminino , Humanos , Imunoglobulinas/química , Camundongos , Camundongos Endogâmicos C57BLRESUMO
V-domain Ig suppressor of T-cell activation (VISTA) is a novel negative checkpoint ligand that is homologous to PD-L1 and suppresses T-cell activation. This study demonstrates the multiple mechanisms whereby VISTA relieves negative regulation by hematopoietic cells and enhances protective antitumor immunity. VISTA is highly expressed on myeloid cells and Foxp3(+)CD4(+) regulatory cells, but not on tumor cells within the tumor microenvironment (TME). VISTA monoclonal antibody (mAb) treatment increased the number of tumor-specific T cells in the periphery and enhanced the infiltration, proliferation, and effector function of tumor-reactive T cells within the TME. VISTA blockade altered the suppressive feature of the TME by decreasing the presence of monocytic myeloid-derived suppressor cells and increasing the presence of activated dendritic cells within the tumor microenvironment. In addition, VISTA blockade impaired the suppressive function and reduced the emergence of tumor-specific Foxp3(+)CD4(+) regulatory T cells. Consequently, VISTA mAb administration as a monotherapy significantly suppressed the growth of both transplantable and inducible melanoma. Initial studies explored a combinatorial regimen using VISTA blockade and a peptide-based cancer vaccine with TLR agonists as adjuvants. VISTA blockade synergized with the vaccine to effectively impair the growth of established tumors. Our study therefore establishes a foundation for designing VISTA-targeted approaches either as a monotherapy or in combination with additional immune-targeted strategies for cancer immunotherapy.
Assuntos
Antígenos B7/fisiologia , Imunoglobulinas/fisiologia , Ativação Linfocitária , Neoplasias/imunologia , Linfócitos T/imunologia , Animais , Anticorpos Monoclonais/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias/tratamento farmacológico , Linfócitos T Reguladores/imunologia , Microambiente TumoralRESUMO
UNLABELLED: The liver is a tolerogenic environment exploited by persistent infections, such as hepatitis B (HBV) and C (HCV) viruses. In a murine model of intravenous hepatotropic adenovirus infection, liver-primed antiviral CD8(+) T cells fail to produce proinflammatory cytokines and do not display cytolytic activity characteristic of effector CD8(+) T cells generated by infection at an extrahepatic, that is, subcutaneous, site. Importantly, liver-generated CD8(+) T cells also appear to have a T-regulatory (Treg) cell function exemplified by their ability to limit proliferation of antigen-specific T-effector (Teff ) cells in vitro and in vivo via T-cell immunoglobulin and mucin 3 (Tim-3) expressed by the CD8(+) Treg cells. Regulatory activity did not require recognition of the canonical Tim-3 ligand, galectin-9, but was dependent on CD8(+) Treg cell-surface Tim-3 binding to the alarmin, high-mobility group box 1 (HMGB-1). CONCLUSION: Virus-specific Tim-3(+) CD8(+) T cells operating through HMGB-1 recognition in the setting of acute and chronic viral infections of the liver may act to dampen hepatic T-cell responses in the liver microenvironment and, as a consequence, limit immune-mediated tissue injury or promote the establishment of persistent infections.
Assuntos
Imunidade Adaptativa/fisiologia , Infecções por Adenoviridae/imunologia , Infecções por Adenoviridae/fisiopatologia , Linfócitos T CD8-Positivos/fisiologia , Galectinas/fisiologia , Proteína HMGB1/fisiologia , Mucina-3/fisiologia , Adenoviridae/fisiologia , Infecções por Adenoviridae/patologia , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Proliferação de Células , Microambiente Celular , Modelos Animais de Doenças , Imunoglobulinas/fisiologia , Técnicas In Vitro , Fígado/patologia , Fígado/fisiopatologia , Fígado/virologia , Camundongos , Camundongos Endogâmicos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologiaRESUMO
INTRODUCTION: The discovery of IL-7 and thymic stromal lymphopoietin (TSLP) has been a major step in the understanding of arthritis. IL-7 amplifies the inflammation induced by other cytokines, primarily TNF. In animal models of arthritis, inhibition of IL-7 limits inflammation and joint erosion. TSLP is an IL-7-like cytokine that triggers dendritic cell-mediated Th2-type inflammatory responses and is considered as a master switch for allergic inflammation. TSLP is a downstream molecule of TNF-α and as such may be involved in the pathophysiology of inflammatory arthritis. AREAS COVERED: This review summarizes current knowledge of the role of IL-7 and TSLP derived from both animal models and studies in patients with rheumatoid arthritis (RA). The emergence of IL-7 blockade as a future therapy in RA is highlighted, along with the potential goals and limitations of this therapeutic approach. The write-up also highlights the functional capacities of TSLP in arthritis. EXPERT OPINION: Evidences suggest important roles for IL-7 and TSLP in the pathogenesis of RA and can be viewed as potential therapeutic targets. Regulation of these at genetic level is a promising investigational area. Given the difficulty in reconstituting T cells in patients with RA, therapeutic approaches that minimize the elimination of T cells are likely to be more desirable.
Assuntos
Antirreumáticos/farmacologia , Artrite Reumatoide/tratamento farmacológico , Citocinas/antagonistas & inibidores , Interleucina-7/antagonistas & inibidores , Terapia de Alvo Molecular , Animais , Antirreumáticos/uso terapêutico , Artrite Reumatoide/fisiopatologia , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Citocinas/genética , Citocinas/fisiologia , Avaliação Pré-Clínica de Medicamentos , Regulação da Expressão Gênica , Humanos , Imunoglobulinas/fisiologia , Interleucina-7/deficiência , Interleucina-7/genética , Interleucina-7/farmacologia , Interleucina-7/fisiologia , Macrófagos/imunologia , Camundongos , Camundongos Knockout , Receptores de Citocinas/fisiologia , Receptores de Interleucina-7/fisiologia , Selênio/farmacologia , Selênio/uso terapêutico , Líquido Sinovial/metabolismo , Linfopoietina do Estroma do TimoRESUMO
The CD200:CD200R1 inhibitory signaling pathway has been implicated in playing a prominent role in limiting inflammation in a wide range of inflammatory diseases. CD200R1 signaling inhibits the expression of proinflammatory molecules including tumor necrosis factor, interferons, and inducible nitric oxide synthase in response to selected stimuli. Unsurprisingly, due to the regulatory role that CD200R1 plays in multiple inflammatory pathways, an increasing number of parasitic, bacterial, and viral pathogens exploit this pathway to suppress host defenses. A complete understanding of the pathways regulated by CD200R1 signaling and the diverse mechanisms that pathogens have evolved to manipulate the CD200:CD200R1 pathway can help identify clinical situations where targeting this interaction can be of therapeutic benefit. In this review, we compare CD200R1 to other pathogen-targeted inhibitory receptors and highlight how this signaling pathway is utilized by a diverse number of pathogens and, therefore, may represent a novel targeting strategy for the treatment of infectious diseases.
Assuntos
Antígenos CD/fisiologia , Antígenos de Superfície/fisiologia , Interações Hospedeiro-Patógeno/imunologia , Receptores de Superfície Celular/fisiologia , Transdução de Sinais/imunologia , Animais , Líquido Extracelular/imunologia , Líquido Extracelular/microbiologia , Líquido Extracelular/virologia , Interações Hospedeiro-Patógeno/genética , Humanos , Imunoglobulinas/fisiologia , Inflamação/genética , Inflamação/microbiologia , Inflamação/virologia , Influenza Humana/genética , Influenza Humana/imunologia , Influenza Humana/virologia , Lectinas Tipo C/fisiologia , Camundongos , Receptores de Orexina , Infecções por Orthomyxoviridae/genética , Infecções por Orthomyxoviridae/imunologia , Receptores de Superfície Celular/deficiência , Receptores KIR/administração & dosagem , Receptores KIR/genética , Transdução de Sinais/genéticaRESUMO
Establishment of synaptic connections in the neuropils of the developing nervous system requires the coordination of specific neurite-neurite interactions (i.e., axon-axon, dendrite-dendrite and axon-dendrite interactions). The molecular mechanisms underlying coordination of neurite-neurite interactions for circuit assembly are incompletely understood. In this report, we identify a novel Ig superfamily transmembrane protein that we named Borderless (Bdl), as a novel regulator of neurite-neurite interactions in Drosophila. Bdl induces homotypic cell-cell adhesion in vitro and mediates neurite-neurite interactions in the developing visual system. Bdl interacts physically and genetically with the Ig transmembrane protein Turtle, a key regulator of axonal tiling. Our results also show that the receptor tyrosine phosphatase leukocyte common antigen-related protein (LAR) negatively regulates Bdl to control synaptic-layer selection. We propose that precise regulation of Bdl action coordinates neurite-neurite interactions for circuit formation in Drosophila.
Assuntos
Comunicação Celular/genética , Proteínas de Drosophila/fisiologia , Proteínas de Membrana/fisiologia , Rede Nervosa/fisiologia , Vias Visuais/fisiologia , Animais , Regulação para Baixo/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/enzimologia , Drosophila melanogaster/genética , Feminino , Subunidades de Imunoglobulinas/genética , Imunoglobulinas/genética , Imunoglobulinas/fisiologia , Masculino , Proteínas de Membrana/genética , Mutação/genética , Rede Nervosa/enzimologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/fisiologia , Neuritos/fisiologia , Proteínas Tirosina Fosfatases Semelhantes a Receptores/genética , Proteínas Tirosina Fosfatases Semelhantes a Receptores/fisiologia , Vias Visuais/enzimologiaRESUMO
Autonomic neurons innervate pancreatic islets of Langerhans and maintain blood glucose homeostasis by regulating hormone levels. We previously showed that cell adhesion molecule 1 (CADM1) mediated the attachment and interaction between nerves and aggregated pancreatic islet α cells. In this study, we cocultured αTC6 cells, a murine α cell line, with mouse superior cervical ganglion (SCG) neurons. The oscillation of intracellular Ca(2+) concentration ([Ca(2+)]i) was observed in 27% and 14% of αTC6 and CADM1-knockdown αTC6 cells (αTC6(siRNA-CADM1) cells) in aggregates, respectively, within 1min after specific SCG nerve stimulation with scorpion venom. In αTC6(siRNA-CADM1) cells, the responding rate during 3min after SCG nerve stimulation significantly increased compared with that within 1min, whereas the increase in the responding rate was not significantly different in αTC6 cells. This indicated that the response of αTC6 cells according to nerve stimulation occurred more rapidly and effectively than that of αTC6(siRNA-CADM1) cells, suggesting CADM1 involvement in promoting the interaction between nerves and α cells and among α cells. In addition, because we found that neurokinin (NK)-1 receptors, which are neuropeptide substance P receptors, were expressed to a similar extent by both cells, we investigated the effect of substance P on nerve-α cell interaction. Pretreatment with CP99,994 (0.1µg/ml), an NK-1 receptor antagonist, reduced the responding rate of both cells, suggesting that substance P released from stimulated neurites was a mediator to activate αTC6 cells. In addition, α cells that were attached to neurites in a CADM1-mediated manner appeared to respond effectively to neurite activation via substance P/NK-1 receptors.