RESUMEN
Salmonella spp. are gram-negative flagellated bacteria that can cause food- and waterborne gastroenteritis and typhoid fever in humans. We now report that flagellin from Salmonella spp. is recognized in mouse intestine by Toll-like receptor 11 (TLR11). Absence of TLR11 renders mice more susceptible to infection by S. Typhimurium, with increased dissemination of the bacteria and enhanced lethality. Unlike S. Typhimurium, S. Typhi, a human obligatory pathogen that causes typhoid fever, is normally unable to infect mice. TLR11 is expressed in mice, but not in humans, and remarkably, we find that tlr11(-/-) mice are efficiently infected with orally administered S. Typhi. We also find that tlr11(-/-) mice can be immunized against S. Typhi. Therefore, tlr11(-/-) mice represent a small-animal model for the study of the immune response to S. Typhi and for the development of vaccines against this important human pathogen.
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Modelos Animales de Enfermedad , Interacciones Huésped-Patógeno , Ratones , Salmonella typhi , Fiebre Tifoidea/inmunología , Fiebre Tifoidea/microbiología , Animales , Flagelina/metabolismo , Humanos , Ratones Endogámicos C57BL , Ratones Noqueados , Especificidad de la Especie , Receptores Toll-Like/genética , Receptores Toll-Like/inmunología , Receptores Toll-Like/metabolismoRESUMEN
BACKGROUND: Toll-like receptors (TLRs) are the key sensors of innate immunity for triggering immune responses against infections. TLRs are well known to be expressed and activated in innate immune cells, such as macrophage and dendritic cells, but we and others have found that some TLRs are also functional in epithelial cells. However, the role of an epithelial TLR in prostate cancer remains elusive. METHODS: TLR5 expression in messenger RNA and protein level in prostate cancer was determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC). The activation of TLR5 signaling in epithelial cells was detected upon nuclear factor-κB activation by luciferase assay and western blot analysis, and proinflammatory cytokine activation by RT-qPCR. Distinguishing between the TLR5 and NLRC4 pathways, both recognizing flagellin, is determined by small interfering RNA and proinflammatory cytokine activation. The role of TLR5 in prostate cancer was analyzed by IHC and bioinformatics using a general and single-cell database. RESULTS: In the present study, we show that TLR5, among other TLRs, is exceedingly expressed in human prostate cancer cells. This cancer epithelial cell TLR5 functions to activate the TLR5 signaling pathway in human prostate cancer cells, as it does with innate immune cell TLR5. The bacterial protein flagellin induces a robust immune response in prostate cancer cells in a TLR5-dependent but NLRC4-independent manner. TLR5 is highly expressed in prostate cancer patient specimens, and high TLR5 expression in prostate cancer patients indicates a favorable prognosis. CONCLUSIONS: TLR5, as an innate immunity receptor, is a functional TLR in human prostate cancer epithelial cells. TLR5 plays an important role in prostate cancer development and is a new potential prognosis biomarker. TLR5 may represent a novel immunotherapy target against prostate cancer.
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Neoplasias de la Próstata , Receptor Toll-Like 5 , Masculino , Humanos , Receptor Toll-Like 5/genética , Receptor Toll-Like 5/metabolismo , Flagelina/genética , Flagelina/metabolismo , Regulación hacia Arriba , Receptores Toll-Like/genética , Citocinas/metabolismo , Neoplasias de la Próstata/genética , PronósticoRESUMEN
Multiprotein bridging factor 1 (MBF1) is an ancient family of transcription coactivators that play a crucial role in the response of plants to abiotic stress. In this study, we analyzed the genomic data of five Solanaceae plants and identified a total of 21 MBF1 genes. The expansion of MBF1a and MBF1b subfamilies was attributed to whole-genome duplication (WGD), and the expansion of the MBF1c subfamily occurred through transposed duplication (TRD). Collinearity analysis within Solanaceae species revealed collinearity between members of the MBF1a and MBF1b subfamilies, whereas the MBF1c subfamily showed relative independence. The gene expression of SlER24 was induced by sodium chloride (NaCl), polyethylene glycol (PEG), ABA (abscisic acid), and ethrel treatments, with the highest expression observed under NaCl treatment. The overexpression of SlER24 significantly enhanced the salt tolerance of tomato, and the functional deficiency of SlER24 decreased the tolerance of tomato to salt stress. SlER24 enhanced antioxidant enzyme activity to reduce the accumulation of reactive oxygen species (ROS) and alleviated plasma membrane damage under salt stress. SlER24 upregulated the expression levels of salt stress-related genes to enhance salt tolerance in tomato. In conclusion, this study provides basic information for the study of the MBF1 family of Solanaceae under abiotic stress, as well as a reference for the study of other plants.
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Proteínas de Plantas , Estrés Salino , Solanaceae , Regulación de la Expresión Génica de las Plantas , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Plantas Modificadas Genéticamente/genética , Estrés Salino/genética , Cloruro de Sodio/farmacología , Estrés Fisiológico/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Solanaceae/genética , Solanaceae/fisiologíaRESUMEN
The B-box proteins (BBXs) are a family of zinc-finger transcription factors with one/two B-Box domain(s) and play important roles in plant growth and development as well as stress responses. Wolfberry (Lycium barbarum L.) is an important traditional medicinal and food supplement in China, and its genome has recently been released. However, comprehensive studies of BBX genes in Lycium species are lacking. In this study, 28 LbaBBX genes were identified and classified into five clades by a phylogeny analysis with BBX proteins from Arabidopsis thaliana and the LbaBBXs have similar protein motifs and gene structures. Promoter cis-regulatory element prediction revealed that LbaBBXs might be highly responsive to light, phytohormone, and stress conditions. A synteny analysis indicated that 23, 20, 8, and 5 LbaBBX genes were orthologous to Solanum lycopersicum, Solanum melongena, Capsicum annuum, and Arabidopsis thaliana, respectively. The gene pairs encoding LbaBBX proteins evolved under strong purifying selection. In addition, the carotenoid content and expression patterns of selected LbaBBX genes were analyzed. LbaBBX2 and LbaBBX4 might play key roles in the regulation of zeaxanthin and antheraxanthin biosynthesis. Overall, this study improves our understanding of LbaBBX gene family characteristics and identifies genes involved in the regulation of carotenoid biosynthesis in wolfberry.
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Arabidopsis , Lycium , Arabidopsis/genética , Arabidopsis/metabolismo , Carotenoides , Regulación de la Expresión Génica de las Plantas , Lycium/genética , Lycium/metabolismo , Filogenia , Proteínas de Plantas/metabolismoRESUMEN
BACKGROUND/AIMS: Tropomyosin-2 (TPM2) plays important roles in functions of the cytoskeleton, such as cytokinesis, vesicle transport, cell proliferation, migration and apoptosis,and these functions imply that TPM2 also plays a role in cancer development. Indeed, it has been shown that TPM2 plays a critical role in some cancers. However, the role of TPM2 in breast cancer is still poorly characterized. Thus, we explored the role of TPM2 in breast cancer. METHODS: We analysed TPM2 expression and its correlation with the clinicopathological features in breast cancer. Then, we examined the influence of hypoxia on TPM2 expression and methylation status using bisulfite sequencing PCR. Furthermore, we performed TPM2-mediated migration and invasion assays in the context of hypoxia and examined changes in matrix metalloproteinase-2 (MMP2) expression. Finally, we detected the influence of TPM2 on survival and chemotherapy drug sensitivity. RESULTS: We found that TPM2 expression is down-regulated in breast cancer cells compared to that in normal breast cells. The data from TCGA supported these results. Promoter methylation of TPM2, which could be induced by hypoxia, was responsible for its low expression. Hypoxia might regulate cell invasiveness partly by TPM2 down-regulation-mediated changes of MMP2 expression. Importantly, low TPM2 expression was correlated with lymph node metastasis (P=0.031), tumour node metastasis stage (P=0.01), histological grade (P=0.037), and shorter overall survival (P=0.028). Univariate and multivariate analyses indicated that TPM2 was an independent predictor in breast cancer patients. Paclitaxel chemotherapy did not benefit patients with low TPM2 expression (P<0.0001). TPM2 knockdown significantly reduced cell sensitivity to paclitaxel. CONCLUSION: TPM2 is a potential novel tumour suppressor gene in breast cancer. TPM2 is associated with poor survival and chemoresistance to paclitaxel in breast cancer, and TPM2 may represent a promising therapeutic gene target for breast cancer patients with chemoresistance.
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Neoplasias de la Mama/patología , Hipoxia de la Célula , Tropomiosina/metabolismo , Antineoplásicos Fitogénicos/uso terapéutico , Antineoplásicos Fitogénicos/toxicidad , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/mortalidad , Línea Celular Tumoral , ADN/aislamiento & purificación , ADN/metabolismo , Metilación de ADN , Regulación hacia Abajo/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/antagonistas & inhibidores , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Metástasis Linfática , Células MCF-7 , Metaloproteinasa 2 de la Matriz/metabolismo , Persona de Mediana Edad , Paclitaxel/uso terapéutico , Paclitaxel/toxicidad , Pronóstico , Regiones Promotoras Genéticas , Interferencia de ARN , Tropomiosina/antagonistas & inhibidores , Tropomiosina/genéticaRESUMEN
Phagocytosis is a critical cellular process for innate immune defense against microbial infection. The regulation of phagocytosis process is complex and has not been well defined. An intracellular molecule might regulate cell surface-initiated phagocytosis, but the underlying molecular mechanism is poorly understood (1). In this study, we found that microtubule-associated protein 1S (MAP1S), a protein identified recently that is involved in autophagy (2), is expressed primarily in macrophages. MAP1S-deficient macrophages are impaired in the phagocytosis of bacteria. Furthermore, we demonstrate that MAP1S interacts directly with MyD88, a key adaptor of Toll-like receptors (TLRs), upon TLR activation and affects the TLR signaling pathway. Intriguingly, we also observe that, upon TLR activation, MyD88 participates in autophagy processing in a MAP1S-dependent manner by co-localizing with MAP1 light chain 3 (MAP1-LC3 or LC3). Therefore, we reveal that an intracellular autophagy-related molecule of MAP1S controls bacterial phagocytosis through TLR signaling.
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Macrófagos/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Factor 88 de Diferenciación Mieloide/agonistas , Fagocitosis , Salmonella typhimurium/inmunología , Transducción de Señal , Staphylococcus aureus/inmunología , Animales , Células de la Médula Ósea/citología , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/microbiología , Células Cultivadas , Células HEK293 , Humanos , Macrófagos/citología , Macrófagos/inmunología , Macrófagos/microbiología , Macrófagos Peritoneales/citología , Macrófagos Peritoneales/inmunología , Macrófagos Peritoneales/metabolismo , Macrófagos Peritoneales/microbiología , Ratones , Ratones Noqueados , Proteínas Asociadas a Microtúbulos/genética , Factor 88 de Diferenciación Mieloide/metabolismo , Transporte de Proteínas , Células RAW 264.7 , Organismos Libres de Patógenos Específicos , Receptores Toll-Like/agonistas , Receptores Toll-Like/metabolismoRESUMEN
The activation of pro-inflammatory gene programs by nuclear factor-kappaB (NF-kappaB) is primarily regulated through cytoplasmic sequestration of NF-kappaB by the inhibitor of kappaB (IkappaB) family of proteins. IkappaBbeta, a major isoform of IkappaB, can sequester NF-kappaB in the cytoplasm, although its biological role remains unclear. Although cells lacking IkappaBbeta have been reported, in vivo studies have been limited and suggested redundancy between IkappaBalpha and IkappaBbeta. Like IkappaBalpha, IkappaBbeta is also inducibly degraded; however, upon stimulation by lipopolysaccharide (LPS), it is degraded slowly and re-synthesized as a hypophosphorylated form that can be detected in the nucleus. The crystal structure of IkappaBbeta bound to p65 suggested this complex might bind DNA. In vitro, hypophosphorylated IkappaBbeta can bind DNA with p65 and c-Rel, and the DNA-bound NF-kappaB:IkappaBbeta complexes are resistant to IkappaBalpha, suggesting hypophosphorylated, nuclear IkappaBbeta may prolong the expression of certain genes. Here we report that in vivo IkappaBbeta serves both to inhibit and facilitate the inflammatory response. IkappaBbeta degradation releases NF-kappaB dimers which upregulate pro-inflammatory target genes such as tumour necrosis factor-alpha (TNF-alpha). Surprisingly, absence of IkappaBbeta results in a dramatic reduction of TNF-alpha in response to LPS even though activation of NF-kappaB is normal. The inhibition of TNF-alpha messenger RNA (mRNA) expression correlates with the absence of nuclear, hypophosphorylated-IkappaBbeta bound to p65:c-Rel heterodimers at a specific kappaB site on the TNF-alpha promoter. Therefore IkappaBbeta acts through p65:c-Rel dimers to maintain prolonged expression of TNF-alpha. As a result, IkappaBbeta(-/-) mice are resistant to LPS-induced septic shock and collagen-induced arthritis. Blocking IkappaBbeta might be a promising new strategy for selectively inhibiting the chronic phase of TNF-alpha production during the inflammatory response.
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Artritis Experimental/metabolismo , Regulación de la Expresión Génica , Proteínas I-kappa B/genética , Proteínas I-kappa B/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Adyuvantes Inmunológicos/farmacología , Animales , Línea Celular , Citocinas/sangre , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Lipopolisacáridos/farmacología , Masculino , Ratones , Ratones Endogámicos DBA , Ratones Noqueados , Factor de Necrosis Tumoral alfa/sangreRESUMEN
The recognition of pathogen-associated molecular patterns by Toll-like receptors (TLRs) is pivotal in both innate and adaptive immune responses. Here we demonstrate that deletion of Lgr4/Gpr48 (G-protein-coupled receptor 48), a seven-transmembrane glycoprotein hormone receptor, potentiates TLR2/4-associated cytokine production and attenuates mouse resistance to septic shock. The expression of CD14, a co-receptor for TLR2/4-associated pathogen-associated molecular patterns, is increased significantly in Lgr4-deficient macrophages, which is consistent with the increased immune response, whereas the binding activity of cAMP-response element-binding protein is decreased significantly in Lgr4-deficient macrophages, which up-regulate the expression of CD14 at the transcriptional level. Together, our data demonstrate that Lgr4/Gpr48 plays a critical role in modulating the TLR2/4 signaling pathway and represents a useful therapeutic approach of targeting Lgr4/Gpr48 in TLR2/4-associated septic shock and autoimmune diseases.
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Inmunidad Innata/fisiología , Receptores de Lipopolisacáridos/biosíntesis , Receptores Acoplados a Proteínas G/metabolismo , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 4/metabolismo , Regulación hacia Arriba/fisiología , Animales , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/metabolismo , Enfermedades Autoinmunes/terapia , Línea Celular , Humanos , Receptores de Lipopolisacáridos/genética , Receptores de Lipopolisacáridos/inmunología , Macrófagos/citología , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones , Ratones Noqueados , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/inmunología , Choque Séptico/genética , Choque Séptico/inmunología , Choque Séptico/metabolismo , Choque Séptico/terapia , Transducción de Señal/fisiología , Receptor Toll-Like 2/genética , Receptor Toll-Like 2/inmunología , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/inmunologíaRESUMEN
Activated silica matrix fluorescent materials doped with Al3+ and Eu2+ are prepared by sol-gel method. The effects of different atmospheres and annealing temperatures on luminescent properties are characterized by analysis techniques including X-ray diffraction, infrared spectroscopy and fluorescence spectra. When being excited at 281 nm wavelength, the fluorescent materials show a strong broad blue emission band, with the emission center at 430 nm and the FWHM of 56 nm. The results indicate that the blue emission is derived from 4f6 5d to 4f7 transition of the Eu2+ ions. Al3+ ion plays a key role in the process of deoxidization from Eu3+ to Eu2+. Al3+ and B3+ can enhance the blue-emission intensity. Also it is found that the highest luminescent intensity of the samples occurs in the sample Eu-03 annealed at 1150 degrees C in N2 atmosphere.
RESUMEN
In this paper, with spherical SiO2 particles fabricated via Stöber method, monodispersed and uniform SiO2 @Y2O3:Eu3+ core-shell submicrospheres were prepared through a simply homogeneous precipitation method. SEM, TEM and XRD analysis indicated that the as-prepared samples were uniform and well monodispersed spheres. The SiO2 core was perfectly coated by the shell composed of cubic crystalline Y2O3:Eu3+ and the thickness of the shell was about 26 nm. Photoluminescence spectra showed that the luminescence efficiency was improved remarkably after being coated on the SiO2 core. The 3D PL spectra showed that almost all UV photons in the range from 200 nm to 400 nm can be converted to visible photons by the as-prepared samples. Results showed that when the SiO2 core was synthesized in the TEOS single feeding model with the amount of core being 0.4 g, doping concentration being 4% and annealing at 800 degrees C, the sample has the best performance on luminescence. By dispersing the as-prepared sample in the anti-reflection sol to prepared the wavelength conversion and anti-reflection film and apply it to the silicon solar cell, the photoelectric conversion efficiency can be increased by 7.41% in maximum.
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Microtubule (MT) dynamics is tightly regulated by microtubule-associated proteins (MAPs) and various post-translational modifications (PTMs) of tubulin. Here, we introduce OligoMT and OligoTIP as genetically encoded oligomeric MT binders designed for real-time visualization and manipulation of MT behaviors within living cells. OligoMT acts as a reliable marker to label the MT cytoskeleton, while OligoTIP allows for live monitoring of the growing MT plus-ends. These engineered MT binders have been successfully utilized to label the MT network, monitor cell division, track MT plus-ends, and assess the effect of tubulin acetylation on the MT stability at the single-cell level. Moreover, OligoMT and OligoTIP can be repurposed as biosensors for quantitative assessment of drug actions and for reporting enzymatic activity. Overall, these engineered MT binders hold promise for advancing the mechanistic dissection of MT biology and have translational applications in cell-based high-throughput drug discovery efforts.
RESUMEN
Toll-like receptors (TLRs) are a key family of pattern recognition receptors (PRRs) in the innate immune system. The activation of TLRs will not only prevent pathogen infection but also respond to damage-induced danger signaling. Increasing evidence suggests that TLRs play a critical role in breast cancer development and treatment. However, the activation of TLRs is a double-edged sword that can induce either pro-tumor activity or anti-tumor effect. The underlying mechanisms of these opposite effects of TLR signaling in cancer are not fully understood. Targeting TLRs is a promising strategy for improving breast cancer treatment, either as monotherapies or by improving other current therapies. Here we provide an update on the role of TLRs in breast cancer immunity and immunotherapy.
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Neoplasias de la Mama , Inmunoterapia , Transducción de Señal , Receptores Toll-Like , Humanos , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/terapia , Receptores Toll-Like/metabolismo , Receptores Toll-Like/inmunología , Femenino , Inmunoterapia/métodos , Animales , Inmunidad InnataRESUMEN
Toll-like receptors (TLRs) are key molecular sensors used by the mammalian innate immune system to detect microorganisms. Although TLR functions in colonic immune homeostasis and tolerance to commensal bacteria have been intensively researched, the precise roles of different TLRs in response to pathogen infection in the gut remain elusive. Peyer patches are the major entrance of Salmonella infection and antigen transportation in intestine. Here, we report that, in contrast to TLR5 as a "carrier of Salmonella," TLR11 works as a "blocker of Salmonella" to prevent highly invasive Salmonella from penetrating into the murine Peyer patches and spreading systemically. TLR11 plays an important role in mediating TNF-α induction and systemic inflammation in response to Salmonella infection. Remarkably, in mice lacking TLR11, apparent hemorrhages at Peyer patches are induced by highly invasive Salmonella, a phenotype resembling human Salmonella infection. Therefore, our results indicate a potentially important role for TLR11 in preventing murine intestinal infection and modulating antigen transportation in the gut and imply an important role for various TLRs in cooperation with tight control of pathogens penetrating into Peyer patches. The TLR11 knock-out mouse can serve as a good animal model to study Salmonella infection.
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Traslocación Bacteriana/inmunología , Mucosa Intestinal/inmunología , Ganglios Linfáticos Agregados/inmunología , Infecciones por Salmonella/inmunología , Salmonella typhimurium/fisiología , Receptores Toll-Like/inmunología , Animales , Antígenos Bacterianos/genética , Antígenos Bacterianos/inmunología , Traslocación Bacteriana/genética , Transporte Biológico Activo/genética , Transporte Biológico Activo/inmunología , Células CHO , Cricetinae , Cricetulus , Modelos Animales de Enfermedad , Humanos , Inmunidad Innata/genética , Mucosa Intestinal/microbiología , Ratones , Ratones Noqueados , Ganglios Linfáticos Agregados/microbiología , Ganglios Linfáticos Agregados/patología , Infecciones por Salmonella/genética , Infecciones por Salmonella/patología , Receptor Toll-Like 5/genética , Receptor Toll-Like 5/metabolismo , Receptores Toll-Like/genéticaRESUMEN
Toll-like receptors (TLRs) recognize altered gut microbiota triggering an immune response. These responses play a critical role in the pathogenesis and treatment of inflammatory bowel disease (IBD). IBD is characterized by inflammation of the intestinal tracts as in Crohn's disease and ulcerative colitis. However, one challenge in determining the role of a specific TLR in IBD and its underlying mechanism is disparity. Variance in age, gender, race, and ethnicity shows a dramatic difference in the disease incidence, severity, and response to treatment. Delineating the role of TLRs in IBD relies on both a knockout mouse and a disease model. Here, we describe a detailed protocol on how to use nearly identical genetic backgrounds of TLR wild-type and knockout littermate mice in a dextran sodium sulfate (DSS)-induced colitis model.
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Colitis Ulcerosa , Colitis , Enfermedad de Crohn , Enfermedades Inflamatorias del Intestino , Animales , Ratones , Enfermedades Inflamatorias del Intestino/genética , Receptores Toll-Like/genética , Ratones NoqueadosRESUMEN
C-type lectin receptors (CLRs) such as Dectin-2 function as pattern recognition receptors to sense fungal infection. However, the signaling pathways induced by these receptors remain largely unknown. Previous studies suggest that the CLR-induced signaling pathway may utilize similar signaling components as the B cell receptor-induced signaling pathway. Phospholipase Cγ2 (PLCγ2) is a key component in B cell receptor signaling, but its role in other signaling pathways has not been fully characterized. Here, we show that PLCγ2 functions downstream of Dectin-2 in response to the stimulation by the hyphal form of Candida albicans, an opportunistic pathogenic fungus. Using PLCγ2- and PLCγ1-deficient macrophages, we found that the lack of PLCγ2, but not PLCγ1, impairs cytokine production in response to infection with C. albicans. PLCγ2 deficiency results in the defective activation of NF-κB and MAPK and a significantly reduced production of reactive oxygen species following fungal challenge. In addition, PLCγ2-deficient mice are defective in clearing C. albicans infection in vivo. Together, these findings demonstrate that PLCγ2 plays a critical role in CLR-induced signaling pathways, governing antifungal innate immune responses.
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Lectinas Tipo C/metabolismo , Fosfolipasa C gamma/inmunología , Animales , Antifúngicos/farmacología , Médula Ósea/metabolismo , Candida albicans/metabolismo , Sistema Inmunológico , Inmunidad Innata , Lectinas/química , Sistema de Señalización de MAP Quinasas , Macrófagos/metabolismo , Masculino , Ratones , Ratones Transgénicos , FN-kappa B/metabolismo , Especies Reactivas de Oxígeno , Transducción de SeñalRESUMEN
Toll-like receptors (TLRs) are the key molecular sensors used by the mammalian innate immune system to detect various types of pathogens. Tlr13 is a novel and uncharacterized member of the mammalian TLR family. Here we report the cloning and characterization of tlr13. Tlr13 is predominantly expressed in the spleen, particularly in dendritic cells and macrophages. Tlr13 appears to activate a MyD88- and TAK1-dependent TLR signaling pathway, inducing the activation of NF-κB. This receptor can also activate type 1 interferon through IRF7. Furthermore, Tlr13 seems to be another intracellular TLR. Remarkably, cells expressing tlr13 fail to respond to known TLR ligands but instead respond specifically to vesicular stomatitis virus. Cells with the knockdown of tlr13 are highly susceptible to vesicular stomatitis virus infection. Thus, these results provide an important insight into the potential role of the novel Toll-like receptor tlr13 in the recognition of viral infection.
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Infecciones por Rhabdoviridae/metabolismo , Receptores Toll-Like/metabolismo , Vesiculovirus/metabolismo , Animales , Clonación Molecular , Técnicas de Silenciamiento del Gen , Factor 7 Regulador del Interferón/genética , Factor 7 Regulador del Interferón/inmunología , Factor 7 Regulador del Interferón/metabolismo , Interferón Tipo I/genética , Interferón Tipo I/inmunología , Interferón Tipo I/metabolismo , Quinasas Quinasa Quinasa PAM/genética , Quinasas Quinasa Quinasa PAM/inmunología , Quinasas Quinasa Quinasa PAM/metabolismo , Ratones , Ratones Noqueados , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/inmunología , Factor 88 de Diferenciación Mieloide/metabolismo , FN-kappa B/genética , FN-kappa B/inmunología , FN-kappa B/metabolismo , Células 3T3 NIH , Infecciones por Rhabdoviridae/genética , Infecciones por Rhabdoviridae/inmunología , Transducción de Señal/inmunología , Receptores Toll-Like/genética , Receptores Toll-Like/inmunología , Vesiculovirus/inmunologíaRESUMEN
Gram-negative bacteria belonging to the Brucella species cause chronic infections that can result in undulant fever, arthritis, and osteomyelitis in humans. Remarkably, Brucella sp. genomes encode a protein, named TcpB, that bears significant homology with mammalian Toll/IL-1 receptor domains and whose expression causes degradation of the phosphorylated, signal competent form of the adapter MyD88-adapter-like (MAL). This effect of TcpB is mediated through its box 1 region and has no effect on other TLR adapter proteins such as MyD88 or TIR-domain containing adapter protein-inducing IFNbeta. TcpB also does not affect a mutant, signal-incompetent form of MAL that cannot be phosphorylated. Interestingly, the presence of TcpB leads to enhanced polyubiquitination of MAL, which is likely responsible for its accelerated degradation. A Brucella abortus mutant lacking TcpB fails to reduce levels of MAL in infected macrophages. Therefore, TcpB represents a unique pathogen-derived molecule that suppresses host innate-immune responses by specifically targeting an individual adapter molecule in the TLR signaling pathway for degradation.
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Brucella/patogenicidad , Inmunidad Innata , Glicoproteínas de Membrana/metabolismo , Receptores de Interleucina-1/metabolismo , Línea Celular , Humanos , Fosforilación , Homología de Secuencia de Aminoácido , Receptor Toll-Like 4/metabolismo , Ubiquitina , Proteínas Virales/fisiologíaRESUMEN
The 3D network Na2Ti2O4(OH)2 nanotube film was prepared by combining interface chemical reaction with hydrothermal reaction. It can be readily indexed based on an orthorhombic system Na2Ti2O4(OH)2 (JCPDS, 47-0124), corresponding with (200), (110), (600), and (020). The nanotubes are commonly multiwalled with a diameter about 40 nm, and a length more than 2000 nm. The interlamellar space of the nanotubes is about 0.9 nm, and these nanotubes loaded with silver exhibit a strong UV-Vis-NIR absorption from 200 nm to 1000 nm, with a resonance-absorption peak at 490 nm. In addition, the formation mechanism of 3D network Na2Ti2O4(OH)2 nanotube film was investigated, the formation mechanism can be expressed as follows: Ti --> TiCl3 --> TiO2(anatase) --> Na2Ti2O4(OH)2(nanotube).
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Lung cancer is currently the leading cause of cancer-related deaths worldwide. Significant improvements in lung cancer therapeutics have relied on a better understanding of lung cancer immunity and the development of novel immunotherapies, as best exemplified by the introduction of PD-1/PD-L1-based therapies. However, this improvement is limited to lung cancer patients who respond to anti-PD-1 immunotherapy. Further improvements in immunotherapy may benefit from a better understanding of innate immune response mechanisms in the lung. Toll-like receptors (TLRs) are a key component of the innate immune response and mediate the early recognition of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). TLR signaling modulates the tumor microenvironment from "cold" to "hot" leading to immune sensitization of tumor cells to treatments and improved patient prognosis. In addition, TLR signaling activates the adaptive immune response to improve the response to cancer immunotherapy through the regulation of anti-tumor T cell activity. This review will highlight recent progress in our understanding of the role of TLRs in lung cancer immunity and immunotherapy.
Asunto(s)
Neoplasias Pulmonares , Receptores Toll-Like , Humanos , Neoplasias Pulmonares/terapia , Inmunidad Innata , Inmunidad Adaptativa , Factores Inmunológicos , Moléculas de Patrón Molecular Asociado a Patógenos , Inmunoterapia , Microambiente TumoralRESUMEN
BACKGROUND: There are few studies on trends in injury death rates in China during the recent decades of tremendous change in this society. This paper examined trends in injury mortality rates among women aged 15 years or older in Macheng City from 1984-2008. METHODS: Data on injury deaths in women from 1984 to 2008 were obtained from the Death Registry System in Macheng City. Injuries were classified using the International Classification of Diseases (ICD), 9th and 10th editions. RESULTS: The average overall injury death rate of women aged 15 or older was 87.6/100,000 in Macheng City from 1984-2008. Injuries were the leading cause of death for women aged 15-44 and the fourth cause of death for all women during this period. The all-cause injury mortality rate decreased from 149.01 per 100,000 population in 1984 to 32.90 per 100,000 population in 2008 for women. Road traffic injury (RTI) was the only injury for which the mortality rate increased dramatically from 1984 (1.35 per 100,000) to 2008 (4.63 per 100,000). For all age groups, suicide was the leading cause of injury death. For women aged 15 to 64, RTI and drowning were the second and third leading causes of injury deaths, respectively. CONCLUSIONS: The injury mortality rate for women aged 15 years or older decreased by 77.92% from 1984-2008. In contrast, RTI deaths increased sharply in the 2000s compared with the 1980s. Although the suicide rate decreased dramatically, it was still the leading cause of injury death for women. Research is needed to identify risk factors contributing to the increase in RTI and decrease in suicides.