RESUMEN
Multiple sclerosis (MS) is a neurodegenerative and demyelinating autoimmune disease mediated by autoreactive T cells that affects the central nervous system (CNS). Electroacupuncture (EA) has emerged as an alternative or supplemental treatment for MS, but the mechanism by which EA may alleviate MS symptoms is unresolved. Here, we examined the effects of EA at the Zusanli (ST36) acupoint on mice with experimental autoimmune encephalomyelitis (EAE), the predominant animal model of MS. The effects of EA on EAE emergence, inflammatory cell levels, proinflammatory cytokines, and spinal cord pathology were examined. EA treatment attenuated the EAE clinical score and associated spinal cord demyelination, while reducing the presence of proinflammatory cytokines in mononuclear cells (MNCs), downregulating microRNA (miR)-155, and upregulating the opioid peptide precursor proopiomelanocortin (POMC) in the CNS. Experiments in which cultured neurons were transfected with a miR-155 mimic or a miR-155 inhibitor further showed that the direct modulation of miR-155 levels could regulate POMC levels in neurons. In conclusion, the alleviation of EAE by EA is characterized by reduced proportions of Th1/Th17 cells and increased proportions of Th2 cells, POMC upregulation, and miR-155 downregulation, while miR-155 itself can suppress POMC expression. These results, support the hypothesis that the effects of EA on EAE may involve the downregulation of miR-155.
Asunto(s)
Electroacupuntura , Encefalomielitis Autoinmune Experimental/terapia , MicroARNs/metabolismo , Esclerosis Múltiple/terapia , Animales , Regulación hacia Abajo/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Femenino , Humanos , Ratones , MicroARNs/agonistas , MicroARNs/antagonistas & inhibidores , Esclerosis Múltiple/inmunología , Proopiomelanocortina/genética , Células TH1/inmunología , Células Th17/inmunología , Células Th2/inmunología , Regulación hacia Arriba/inmunologíaRESUMEN
BACKGROUND: Psoriasis is a chronic inflammatory skin disease. Interleukin (IL)-17A plays a key role in the pathogenesis of psoriasis. Fingolimod, which is available for the treatment of multiple sclerosis, exerts anti-inflammatory effects by sequestrating inflammatory lymphocytes in secondary lymphoid tissues and the thymus. The effect of fingolimod on psoriasis has not been reported yet. OBJECTIVE: Our objectives were to investigate the effect of fingolimod on psoriasis utilizing mice with imiquimod (IMQ)-induced psoriasiform dermatitis, and explore the possibility of fingolimod as a therapeutic agent for psoriasis. METHODS: Psoriasiform dermatitis was induced by imiquimod application on murine shaved back skin for six days. Fingolimod prepared in phosphate-buffered saline (PBS), or PBS alone as a control, was administered intraperitoneally daily from days 0 to 5. RESULTS: Fingolimod ameliorated IMQ-induced psoriasis dermatitis clinically and histologically. On day 6, the mRNA expression level of IL-17A was lower in the skin of fingolimod-treated mice than in that of PBS-treated mice, whereas it was higher in the inguinal lymph nodes of fingolimod-treated mice than in those of PBS-treated mice. Flow cytometric analyses revealed that fingolimod reduced IL-17A-producing ?d T cells infiltrating into the skin, whereas it increased these cells in the inguinal lymph nodes. Fingolimod inhibited egress of Langerhans cells from the skin to lymph nodes. CONCLUSION: Our results demonstrated that fingolimod showed effectiveness for IMQ-induced psoriasiform dermatitis by hindering the emigration of IL-17A-producing ?d T cells from the lymph nodes to the skin, and suggest that fingolimod is a promising candidate for the treatment of psoriasis.
Asunto(s)
Clorhidrato de Fingolimod/farmacología , Linfocitos Intraepiteliales/efectos de los fármacos , Ganglios Linfáticos/efectos de los fármacos , Psoriasis/tratamiento farmacológico , Piel/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/inmunología , Evaluación Preclínica de Medicamentos , Femenino , Clorhidrato de Fingolimod/uso terapéutico , Humanos , Imiquimod/administración & dosificación , Imiquimod/inmunología , Interleucina-17/metabolismo , Linfocitos Intraepiteliales/inmunología , Linfocitos Intraepiteliales/metabolismo , Células de Langerhans/inmunología , Células de Langerhans/metabolismo , Ganglios Linfáticos/citología , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/metabolismo , Ratones , Psoriasis/inmunología , Psoriasis/patología , Piel/citología , Piel/inmunología , Piel/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/inmunologíaRESUMEN
Macroenvironmental factors, including a patient's physical and social environment, play a role in cancer risk and progression. Our previous preclinical studies have shown that the enriched environment (EE) confers anti-obesity and anti-cancer phenotypes that are associated with enhanced adaptive immunity and are mediated by brain-derived neurotrophic factor (BDNF). Natural killer (NK) cells have anti-cancer and anti-viral properties, and their absence or depletion is associated with inferior clinical outcomes. In this study, we investigated the effects of EE on NK cell maturation following their depletion. Mice living in EE displayed a higher proportion of NK cells in the spleen, bone marrow, and blood, compared to those living in the standard environment (SE). EE enhanced NK cell maturation in the spleen and was associated with upregulation of BDNF expression in the hypothalamus. Hypothalamic BDNF overexpression reproduced the EE effects on NK cell maturation in secondary lymphoid tissues. Conversely, hypothalamic BDNF knockdown blocked the EE modulation on NK cell maturation. Our results demonstrate that a bio-behavior intervention enhanced NK cell maturation and was mediated at least in part by hypothalamic BDNF.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/inmunología , Hipotálamo/inmunología , Células Asesinas Naturales/inmunología , Animales , Ambiente , Tejido Linfoide/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Neoplasias/inmunología , Bazo/inmunología , Regulación hacia Arriba/inmunologíaRESUMEN
Recently, we identified that the atypical protein kinase C isoform ι (PKCι) enhances the expression of Yes-associated protein 1 (YAP1) to promote the tumorigenesis of pancreatic adenocarcinoma harboring mutant KRAS (mu-KRAS). To advance our understanding about underlying mechanisms, we analyze the transcription of YAP1 in pancreatic cancer cells and reveal that transcription factor specificity protein 1 (Sp1) is upregulated by PKCι and subsequently binds to multiple sites in YAP1 promoter to drive the transactivation of YAP1 in pancreatic cancer cells carrying mu-KRAS. The bioinformatics analysis further substantiates that the expression of PKCι, Sp1 and YAP1 is correlated and associated with the stages and prognosis of pancreatic tumors. Moreover, our apoptotic detection data demonstrate that combination of PKCι and Sp1 inhibitors at subtoxic doses displays synergistic effects on inducing apoptosis and reversing the immunosuppression of pancreatic cancer cells, establishing the combination of PKCι and Sp1 inhibitors as a promising novel therapeutic approach, or an adjuvant strategy to potentiate the antitumor effects of other immunotherapeutic agents in pancreatic cancer treatment.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Isoenzimas/metabolismo , Neoplasias Pancreáticas/genética , Proteína Quinasa C/metabolismo , Factor de Transcripción Sp1/genética , Factores de Transcripción/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apoptosis/efectos de los fármacos , Apoptosis/genética , Apoptosis/inmunología , Carcinogénesis/efectos de los fármacos , Carcinogénesis/genética , Carcinogénesis/inmunología , Línea Celular Tumoral , Biología Computacional , Conjuntos de Datos como Asunto , Sinergismo Farmacológico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/inmunología , Humanos , Isoenzimas/antagonistas & inhibidores , Mutación , Páncreas/inmunología , Páncreas/patología , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Pronóstico , Regiones Promotoras Genéticas/genética , Proteína Quinasa C/antagonistas & inhibidores , Proteínas Proto-Oncogénicas p21(ras)/genética , RNA-Seq , Factor de Transcripción Sp1/antagonistas & inhibidores , Factor de Transcripción Sp1/metabolismo , Activación Transcripcional/efectos de los fármacos , Activación Transcripcional/inmunología , Escape del Tumor/efectos de los fármacos , Escape del Tumor/genética , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/inmunología , Proteínas Señalizadoras YAPRESUMEN
Glycyrrhizic acid ammonium salt (GAAS) is derived from glycyrrhizic acid, which is an active compound extracted from the Chinese traditional medicine licorice. GAAS is clinically applied to treat immune-mediated liver injury, but its mechanism remains elusive. Therefore, this study aimed to investigate the mechanism in which GAAS alleviates immune-mediated liver injury induced by Concanavalin A (ConA). After ten days of intragastric administration of GAAS, 20 mg/kg ConA was injected via tail vein to establish the immune-mediated liver injury model of BALB/C mice. Then, the concentrations of ALT, AST, and TBIL in the serum of mice were determined. H&E staining was performed to observe the pathological changes in the liver, and the expression of liver cytokines was detected by qPCR. Immunohistochemistry and Western blot analysis was employed to detect the expression of liver-related proteins. The apoptosis in liver tissue was detected by TUNEL. Our results suggest that GAAS demonstrated excellent protective effects in the liver. We found that GAAS down-regulated the mRNA expression of IL-1ß, IL-6, TNF-α, IFN-γ, and IL-17A, and it up-regulated the mRNA expression of IL-4 and TGF-ß. Additionally, GAAS may modulate the balance of four immune cells (Th1, Th2, Th17, and Treg) by regulating the expression of T-bet, GATA3, RORγt, and Foxp3 to alleviate liver injury in mice. Furthermore, GAAS decreased hepatocyte apoptosis by blocking the JAK1/STAT1/IRF1 pathway, suppressing oxidative stress, decreasing p-JNK expression, and regulating the expression of apoptosis-related proteins. In summary, the mechanism of GAAS in liver injury alleviation acts to regulate the balance of Th cells in the liver to inhibit hepatocyte apoptosis. This study may provide a new strategy for the treatment of immune-mediated liver injury.
Asunto(s)
Compuestos de Amonio/inmunología , Apoptosis/inmunología , Enfermedad Hepática Inducida por Sustancias y Drogas/inmunología , Concanavalina A/inmunología , Ácido Glicirrínico/inmunología , Hepatocitos/inmunología , Subgrupos de Linfocitos T/inmunología , Animales , Citocinas/inmunología , Regulación hacia Abajo/inmunología , Hígado/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Regulación hacia Arriba/inmunologíaRESUMEN
BACKGROUND: Despite the convergence of rapid technological advances in genomics and the maturing field of ecoimmunology, our understanding of the genes that regulate immunity in wild populations is still nascent. Previous work to assess immune function has relied upon relatively crude measures of immunocompetence. However, with next-generation RNA-sequencing, it is now possible to create a profile of gene expression in response to an immune challenge. In this study, captive zebra finch (Taeniopygia guttata; adult males) were challenged with bacterial lipopolysaccharide (LPS) or vehicle to stimulate the innate immune system. 2 hours after injection, birds were euthanized and hypothalami, spleen, and red blood cells (RBCs) were collected. Taking advantage of the fully sequenced genome of zebra finch, total RNA was isolated, sequenced, and partially annotated in these tissue/cells. RESULTS: In hypothalamus, there were 707 significantly upregulated transcripts, as well as 564 and 144 in the spleen and RBCs, respectively, relative to controls. Also, 155 transcripts in the hypothalamus, 606 in the spleen, and 61 in the RBCs were significantly downregulated. More specifically, a number of immunity-related transcripts (e.g., IL-1ß, RSAD2, SOCS3) were upregulated among tissues/cells. Additionally, transcripts involved in metabolic processes (APOD, LRAT, RBP4) were downregulated. CONCLUSIONS: These results suggest a potential trade-off in expression of genes that regulate immunity and metabolism in birds challenged with LPS. This finding is consistent with a hypothermic response to LPS treatment in small birds. Unlike mammals, birds have nucleated RBCs, and these results support a novel transcriptomic response of avian RBCs to immune challenge.
Asunto(s)
Pinzones/genética , Pinzones/inmunología , Perfilación de la Expresión Génica , Lipopolisacáridos/farmacología , Animales , Eritrocitos/efectos de los fármacos , Eritrocitos/inmunología , Eritrocitos/metabolismo , Ontología de Genes , Hipotálamo/efectos de los fármacos , Hipotálamo/inmunología , Hipotálamo/metabolismo , Bazo/efectos de los fármacos , Bazo/inmunología , Bazo/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/inmunologíaRESUMEN
OBJECTIVE: This study aims to explore whether the inhibitory role of metformin could inhibit LPS-induced inflammatory response in vascular smooth muscle cells (VSMCs) and its underlying mechanism. MATERIALS AND METHODS: VSMCs were extracted from aorta of Sprague Dawley rats. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay was performed to detect VSMCs viability after treatment with different concentrations of metformin. Levels of monocyte chemoattractant protein-1 (MCP-1), interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) in VSMCs were detected by ELISA (enzyme-linked immunosorbent assay) and qRT-PCR (quantitative Real time-polymerase chain reaction). Protein and mRNA levels of toll like receptor 4 (TLR4) and peroxisome proliferators activated receptor γ (PPAR-γ) in VSMCs were detected by Western blot and qRT-PCR, respectively. Finally, VSMCs were treated with the PPAR-γ antagonist GW9662 and inflammatory indicators in cells were detected. RESULTS: No significant difference in VSMCs viability was found after 0-2 mM metformin treatment or 500 µg/L LPS induction for 24 h. After 500 µg/L LPS induction in VSMCs for 24 h, levels of MCP-1, TNF-α and IL-6 were remarkably elevated. Both mRNA and protein levels of TLR4 in VSMCs were upregulated after 500 µg/L LPS induction for 24 h, which were remarkably reversed by the treatment of different concentrations of metformin. Knockdown of TLR4 remarkably inhibited LPS-induced inflammatory response in VSMCs, manifesting as decreased levels of MCP1, TNF-α and IL-6, which were further downregulated after combination treatment of TLR4 knockdown and 20 mM metformin. Furthermore, both mRNA and protein levels of PPAR-γ in VSMCs were downregulated after 500 µg/L LPS induction for 24 h, which were remarkably reversed by the treatment of different concentrations of metformin. GW9662 treatment resulted in elevated expressions of MCP-1, TNF-α and IL-6, which were reversed by metformin treatment. CONCLUSIONS: Metformin can effectively inhibit the mRNA and protein expressions of IL-6, MCP-1, and TNF-α in LPS-induced VSMCs. The anti-inflammatory effects of metformin inhibit the inflammatory response through downregulating rely on the downregulation of TLR4 expression and upregulation ofng PPAR-γ activity.
Asunto(s)
Metformina/farmacología , Músculo Liso Vascular/citología , Miocitos del Músculo Liso/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Animales , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/inmunología , Células Cultivadas , Quimiocina CCL2/inmunología , Quimiocina CCL2/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/inmunología , Evaluación Preclínica de Medicamentos , Endotelio Vascular/inmunología , Humanos , Interleucina-6/inmunología , Interleucina-6/metabolismo , Lipopolisacáridos/inmunología , Masculino , Metformina/uso terapéutico , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/inmunología , Miocitos del Músculo Liso/inmunología , PPAR gamma/metabolismo , Cultivo Primario de Células , Ratas , Transducción de Señal/inmunología , Receptor Toll-Like 4/metabolismo , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/inmunologíaRESUMEN
Octopamine (OA), a biogenic monoamine, is known to mediate several immune responses. This study analyzed the effects of OA on immunological regulation in the tiger shrimp Penaeus monodon. The immune parameters including total haemocyte count, differential haemocyte count, phenoloxidase activity, respiratory bursts, superoxide dismutase activity, and phagocytic activity and clearance efficiency in response to the pathogen, Photobacterium damselae, were determined when shrimp were individually injected with saline or OA at 100 or 1000â¯pmol shrimp-1. In addition, the intracellular second messengers in haemocyte such as Ca2+ and adenosine 3',5'-cyclic monophosphate (cAMP) were examined in shrimp receiving saline or OA at 1 or 10â¯nmol shrimp-1. Results showed that all of the immune parameters significantly increased at 2-4â¯h in OA-injected shrimp except hyaline cells in 100â¯pmol shrimp-1-injected shrimp at 4â¯h, but phenoloxidase activity per granulocyte significantly decreased at 2-4â¯h. However, these had returned to saline control levels after receiving OA for 8â¯h except differential haemocyte count and phenoloxidase activity per granulocyte for 16â¯h. An injection of OA also significantly increased the survival rate of shrimp challenged with Pho. damselae. Shrimp receiving OA at 1 and 10â¯nmol shrimp-1 significantly increased the intracellular Ca2+ concentration ([Ca2+]i) at 30-60â¯min and 30â¯min, and cAMP concentration [cAMP]i) at 5-15â¯min and 15â¯min, respectively. However, [Ca2+]i at 50-60â¯min, and [cAMP]i at 30-60â¯min returned to saline control when the shrimp received OA at 10â¯nmol shrimp-1, and at 1 and 10â¯nmol shrimp-1, respectively. These results suggest that OA administration by injection at ≤1000â¯pmol shrimp-1 mediates transient upregulation of immunity together with the increased resistance of P. monodon to Pho. damselae, which are modulated through intracellular Ca2+ and cAMP second messenger pathways.
Asunto(s)
Regulación de la Expresión Génica/inmunología , Inmunidad Innata/efectos de los fármacos , Octopamina/metabolismo , Penaeidae/genética , Penaeidae/inmunología , Transducción de Señal/inmunología , Adyuvantes Inmunológicos/farmacología , Agonistas alfa-Adrenérgicos/administración & dosificación , Agonistas alfa-Adrenérgicos/metabolismo , Animales , Calcio/metabolismo , AMP Cíclico/metabolismo , Perfilación de la Expresión Génica , Octopamina/administración & dosificación , Photobacterium/fisiología , Transducción de Señal/efectos de los fármacos , Regulación hacia Arriba/inmunologíaRESUMEN
The prostaglandin E2 receptor, EP2, plays an important role in physiology and in a variety of pathological conditions. Studies indicate that EP2 is pro-inflammatory in chronic peripheral and central nervous system disease and cancer models. Thus, targeting the EP2 receptor with small molecules could be a therapeutic strategy for treating inflammatory diseases and cancer. We recently reported a novel class of competitive antagonists of the EP2 receptor. However, earlier leads displayed low selectivity against the DP1 prostanoid receptor, moderate plasma half-life, and low aqueous solubility, which renders them suboptimal for testing in animal models of disease. We now report a novel compound TG8-69, which has suitable drug-like properties. We present synthesis, lead-optimization studies, pharmacological characterization, and anti-inflammatory properties of this compound that support its use in chronic peripheral inflammatory diseases, including rheumatoid arthritis, endometriosis, and cancer, in which EP2 appears to play a pathogenic role.
Asunto(s)
Antiinflamatorios/farmacología , Mediadores de Inflamación/metabolismo , Subtipo EP2 de Receptores de Prostaglandina E/antagonistas & inhibidores , Regulación hacia Arriba/efectos de los fármacos , Animales , Antiinflamatorios/química , Antiinflamatorios/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/inmunología , Línea Celular , Dinoprostona/inmunología , Dinoprostona/metabolismo , Evaluación Preclínica de Medicamentos , Endometriosis/tratamiento farmacológico , Endometriosis/inmunología , Femenino , Semivida , Mediadores de Inflamación/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Ratas , Receptores de Prostaglandina/metabolismo , Subtipo EP2 de Receptores de Prostaglandina E/inmunología , Subtipo EP2 de Receptores de Prostaglandina E/metabolismo , Subtipo EP4 de Receptores de Prostaglandina E/metabolismo , Solubilidad , Regulación hacia Arriba/inmunología , Agua/químicaRESUMEN
BACKGROUND: Mechanisms that govern priming and degranulation of human mast cells (MCs) remain elusive. Besides, most of our knowledge is based on experiments from which data only reflect an average of all stimulated cells. This study aims at investigating the effects of proinflammatory cytokines IL-6, IL-33, and TNF-α on IgE-dependent and IgE-independent activation of individual MCs. METHODS: MCs were derived from CD34+ progenitors isolated from 50 mL whole blood from 4 healthy controls and 5 birch pollen allergic patients. Passively sensitized MCs were preincubated with IL-6, IL-33, or TNF-α and stimulated with anti-IgE/birch pollen allergen or substance P, the latter being a ligand for the G-protein-coupled MRGPRX2-receptor. Activation-i.e., upregulation of CD203c-and anaphylactic degranulation-i.e., appearance of CD63-were measured using flow cytometry. RESULTS: Preincubation with IL-33 demonstrated upregulated CD203c density without degranulation. Subsequent IgE-dependent stimulation (anti-IgE/birch pollen allergen) resulted in higher appearance of CD63 as compared to cells without preincubation, indicating IL-33 to exert a priming effect (P = 0.04). IL-6 only increased allergen-specific responses but to a lesser extent than IL-33. Combination of IL-33/IL-6 had a synergistic effect, demonstrating more degranulation in response to allergen. TNF-α had no effect on IgE-mediated activation, nor synergistic effects with IL-33. Stimulation with substance P resulted in degranulation that could not be enhanced by preincubation. CONCLUSIONS: In conclusion, IL-33, and in a lesser extent IL-6, prime individual MCs for subsequent IgE-mediated activation. Moreover, this priming effect is synergistic. In contrast, none of the cytokines had a priming effect on MRGPRX2-mediated activation of MCs. © 2017 International Clinical Cytometry Society.
Asunto(s)
Interleucina-33/inmunología , Interleucina-6/inmunología , Mastocitos/inmunología , Factor de Necrosis Tumoral alfa/inmunología , Alérgenos/inmunología , Betula/inmunología , Estudios de Casos y Controles , Células Cultivadas , Regulación hacia Abajo , Citometría de Flujo/métodos , Humanos , Hipersensibilidad/inmunología , Inmunoglobulina E/inmunología , Proteínas del Tejido Nervioso/inmunología , Polen/inmunología , Análisis de la Célula Individual/métodos , Sustancia P/inmunología , Tetraspanina 30/inmunología , Regulación hacia Arriba/inmunologíaRESUMEN
Background Immunity and Longevity Methods A water extract of Curcuma longa (L.) [vern. Turmeric] roots (TurmericImmune™) standardized for a minimum 20â% of turmeric polysaccharides ukonan A, B, C and D was evaluated for its biological properties in in vitro tissue culture studies. Results The water extract of turmeric (TurP) exhibited induced-nitric oxide (NO) production in RAW264.7 macrophages. These results suggested the immunomodulatory effects of TurP. In addition, the polysaccharides up-regulated function of telomerase reverse transcriptase (TERT) equally to the phenolic compound from turmeric, curcumin. Conclusions The ukonan family of polysaccharides may assist in promoting cellular immune responses, tissue repair and lifespan by enhancing immune response and telomere function.
Asunto(s)
Curcuma , Hepatocitos/efectos de los fármacos , Macrófagos/efectos de los fármacos , Extractos Vegetales/farmacología , Raíces de Plantas , Telomerasa/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Animales , Biomarcadores/metabolismo , Hepatocitos/enzimología , Hepatocitos/inmunología , Macrófagos/metabolismo , Ratones , Óxido Nítrico/metabolismo , Células RAW 264.7 , Ratas , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Regulación hacia Arriba/inmunología , AguaRESUMEN
TLR signaling is critical to innate immune system regulation; however, aberrant TLR signaling is involved in several diseases, including insulin resistance, Alzheimer's disease, and tumor metastasis. Moreover, a recent study found that TLR-4 signaling pathway inhibition might be a target for the suppression of chronic inflammatory disorders. In this article, we show that the green tea polyphenol epigallocatechin-3-O-gallate (EGCG) increases the expression of Toll interacting protein, a strong inhibitor of TLR4 signaling, by suppressing the expression of E74-like ETS transcription factor 1 (Elf-1). A mechanistic study revealed that EGCG suppressed Elf-1 expression via protein phosphatase 2A/cyclic GMP (cGMP)-dependent mechanisms. We also confirmed that orally administered EGCG and a cGMP inducer upregulated Toll interacting protein expression, increased intracellular levels of cGMP in macrophages, and suppressed Elf-1 expression. These data support EGCG and a cGMP inducer as potential candidate suppressors of TLR4 signaling.
Asunto(s)
Catequina/análogos & derivados , Proteínas de Unión al ADN/inmunología , Péptidos y Proteínas de Señalización Intracelular/inmunología , Proteínas Nucleares/inmunología , Sistemas de Mensajero Secundario/inmunología , Té/química , Factores de Transcripción/inmunología , Regulación hacia Arriba/inmunología , Animales , Catequina/química , Catequina/farmacología , GMP Cíclico/genética , GMP Cíclico/inmunología , Proteínas de Unión al ADN/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Masculino , Ratones , Ratones Endogámicos BALB C , Proteínas Nucleares/genética , Proteína Fosfatasa 2/genética , Proteína Fosfatasa 2/inmunología , Sistemas de Mensajero Secundario/genética , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/inmunología , Factores de Transcripción/genéticaRESUMEN
In this study, we prepared and characterized the oats origin of nano scale ß-glucan (NBG) and investigated the immunomodulatory properties in zebrafish larvae. Newly prepared NBG (average particle size of 465 nm) was fully soluble in water. Zebrafish larvae survival rate was increased against pathogenic bacteria Edwardsiella tarda, when NBG was added to the water (500 µg/mL) compared to NBG non-exposed controls. Moreover, quantitative real time PCR (qRT-PCR) results showed up-regulation of immune functional genes including TNF-α, IL-1ß, ß-defensin, lysozyme, IL 10, IL 12 and C-Rel indicating higher survival rate could be due to stronger immunomodulatory function of NBG (500 µg/mL). Thus, non-toxic, water soluble and biodegradable NBG from oats could be considered as the potential immunostimulant for larval aquaculture.
Asunto(s)
Avena/química , Suplementos Dietéticos , Infecciones por Enterobacteriaceae/veterinaria , Enfermedades de los Peces/inmunología , Pez Cebra/inmunología , beta-Glucanos/inmunología , Adyuvantes Inmunológicos , Animales , Edwardsiella tarda/fisiología , Infecciones por Enterobacteriaceae/inmunología , Nanopartículas , Reacción en Cadena en Tiempo Real de la Polimerasa/veterinaria , Regulación hacia Arriba/inmunología , beta-Glucanos/administración & dosificaciónRESUMEN
Objective To identify the effect and mechanism of recombinant platanus pollen allergen 2 (rPla a2) on the transcription and expression of orosomucoid 1-like 3 (ORMDL3) gene in NIH3T3 cells. Methods Quantitative real-time PCR and Western blot analysis were used to detect the influence of rPla a2 on the mRNA and protein levels of ORMDL3 and GATA3. After transfection of GATA3 siRNA or pcDNA-GATA3, the role of GATA3 was evaluated in rPla a2 regulating ORMDL3 expression. Dual-luciferase reporter assay was performed to measure the influence of rPla a2 and GATA3 on ORMDL3 promoter activity. Results The rPla a2 induced mRNA and protein expressions of ORMDL3 and GATA3. Knockdown of GATA3 inhibited the induction of rPla a2 upon ORMDL3. In addition, the induction effect was enhanced by over-expression of GATA3. ORMDL3 promoter activity was significantly promoted by rPla a2 and inhibited by knockdown of GATA3. Conclusion The rPla a2 up-regulates the expression of ORMDL3 mRNA and protein, which is mediated by GATA3 through targeting promoter region of ORMDL3.
Asunto(s)
Alérgenos/inmunología , Factor de Transcripción GATA3/inmunología , Magnoliopsida/inmunología , Proteínas de la Membrana/inmunología , Polen/inmunología , Proteínas Recombinantes/inmunología , Regulación hacia Arriba/inmunología , Animales , Línea Celular , Ratones , Células 3T3 NIH , Rinitis Alérgica Estacional/inmunologíaRESUMEN
Although all-trans-retinoic acid (atRA) is a key regulator of intestinal immunity, its role in colorectal cancer (CRC) is unknown. We found that mice with colitis-associated CRC had a marked deficiency in colonic atRA due to alterations in atRA metabolism mediated by microbiota-induced intestinal inflammation. Human ulcerative colitis (UC), UC-associated CRC, and sporadic CRC specimens have similar alterations in atRA metabolic enzymes, consistent with reduced colonic atRA. Inhibition of atRA signaling promoted tumorigenesis, whereas atRA supplementation reduced tumor burden. The benefit of atRA treatment was mediated by cytotoxic CD8(+) T cells, which were activated due to MHCI upregulation on tumor cells. Consistent with these findings, increased colonic expression of the atRA-catabolizing enzyme, CYP26A1, correlated with reduced frequencies of tumoral cytotoxic CD8(+) T cells and with worse disease prognosis in human CRC. These results reveal a mechanism by which microbiota drive colon carcinogenesis and highlight atRA metabolism as a therapeutic target for CRC.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Neoplasias Colorrectales/inmunología , Microbiota/inmunología , Tretinoina/metabolismo , Animales , Linfocitos T CD8-positivos/metabolismo , Carcinogénesis/inmunología , Colon/inmunología , Colon/metabolismo , Neoplasias Colorrectales/metabolismo , Femenino , Humanos , Ratones , Ratones Endogámicos C57BL , Ácido Retinoico 4-Hidroxilasa/metabolismo , Transducción de Señal/inmunología , Regulación hacia Arriba/inmunologíaRESUMEN
In the present study, we examined the effects of antihistamine on the up-regulation of H1R mRNA in the nasal mucosa of patients with pollinosis induced by controlled exposure to pollen using an environmental exposure unit. Out of 20 patients, we designated 14 responders, whose levels of H1R mRNA in the nasal mucosa were increased after the first pollen exposure and excluded 6 non-responders. Accordingly, the first exposure to pollen without treatment significantly induced both nasal symptoms and the up-regulation of H1R mRNA in the nasal mucosa of the responders. Subsequently, prophylactic administration of antihistamine prior to the second pollen exposure significantly inhibited both of the above effects in the responders. Moreover, the nasal expression of H1R mRNA before the second pollen exposure in the responders pretreated with antihistamine was significantly decreased, as compared with that before the first pollen exposure without treatment. These findings suggest that antihistamines suppressed histamine-induced transcriptional activation of H1R gene in the nasal mucosa, in addition to their blocking effect against histamine on H1R, resulting in a decrease of nasal symptoms. These findings further suggest that by their inverse agonistic activity, antihistamines suppress the basal transcription of nasal H1R in the absence of histamine in responders.
Asunto(s)
Contaminantes Atmosféricos/inmunología , Cryptomeria/inmunología , Exposición a Riesgos Ambientales , Antagonistas de los Receptores Histamínicos/farmacología , Antagonistas de los Receptores Histamínicos/uso terapéutico , Mucosa Nasal/inmunología , Mucosa Nasal/metabolismo , Polen/inmunología , ARN Mensajero/metabolismo , Receptores Histamínicos H1/genética , Receptores Histamínicos H1/metabolismo , Rinitis Alérgica Estacional/tratamiento farmacológico , Rinitis Alérgica Estacional/inmunología , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/inmunología , Adulto , Femenino , Expresión Génica/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Rinitis Alérgica Estacional/metabolismoRESUMEN
In this study, the effects of oral administration of different levels of Dunaliella salina (a natural ß-carotene source) on growth parameters, immunological and hematological indices, as well as skin carotenoids, of Heros severus were investigated. One hundred and eighty H. severus weighing 27 ± 0.5 g were divided randomly into four groups in triplicate (15 fish in each replicate). Groups 1-4 received food supplemented with 0, 50, 100 and 200 mg kg⻹ D. salina powder, respectively. After 6 weeks, the growth parameters were compared among the groups. Blood samples were taken from each group, and hematological parameters including red blood cell count (RBC), white blood cell count (WBC), hematocrit (PCV), hemoglobin (Hb) and immunological indices (serum and mucus lysozyme and bactericidal activity, resistance against Aeromonas hydrophila infection) as well as carotenoid content of skin were evaluated. Results showed that some growth indices increased significantly in fish fed with 100 and 200 mg kg⻹ D. salina-supplemented food (P < 0.05). Although serum lysozyme activity was increased in fish fed with food supplemented with 100 and 200 mg kg⻹ D. salina (P < 0.05), no significant change was observed in serum and mucus bactericidal activity and mucus lysozyme activity among the groups (P > 0.05). Most of the hematological parameters such as WBC, RBC, PCV and Hb significantly increased in D. salina-treated fish compared with controls (P < 0.05). Mortality induced after challenge with A. hydrophila in 200 mg kg⻹ D. salina-treated fish was 36.67 %, which significantly decreased compared with control (P < 0.05). Skin carotenoid content in all D. salina treatments was statistically higher than that of control (P < 0.05). Conclusively, D. salina as a food additive can affect positively the growth, immunological and hematological parameters of H. severus.
Asunto(s)
Acuicultura , Chlorophyta , Cíclidos , Dieta , Aeromonas hydrophila/patogenicidad , Animales , Acuicultura/métodos , Carotenoides/metabolismo , Chlorophyta/inmunología , Cíclidos/inmunología , Infecciones por Bacterias Gramnegativas/inmunología , Infecciones por Bacterias Gramnegativas/prevención & control , Moco/enzimología , Moco/metabolismo , Muramidasa/inmunología , Distribución Aleatoria , Prueba Bactericida de Suero , Piel/enzimología , Piel/inmunología , Piel/metabolismo , Regulación hacia Arriba/inmunologíaRESUMEN
ALA (α-lipoic acid) is a natural, endogenous antioxidant that acts as a PPAR-γ (peroxisome-proliferator-activated receptor-γ) agonist to counteract oxidative stress. Thus far, the antioxidative and immunomodulatory effects of ALA on EAE (experimental autoimmune encephalomyelitis) are not well understood. In this study, we found that ALA restricts the infiltration of inflammatory cells into the CNS (central nervous system) in MOG (myelin oligodendrocyte glycoprotein)-EAE mice, thus reducing the disease severity. In addition, we revealed that ALA significantly suppresses the number and percentage of encephalitogenic Th1 and Th17 cells and increases splenic Treg-cells (regulatory T-cells). Strikingly, we further demonstrated that ALA induces endogenous PPAR-γ centrally and peripherally but has no effect on HO-1 (haem oxygenase 1). Together, these data suggest that ALA can up-regulate endogenous systemic and central PPAR-γ and enhance systemic Treg-cells to inhibit the inflammatory response and ameliorate MOG-EAE. In conclusion, our data provide the first evidence that ALA can augment the production of PPAR-γ in vivo and modulate adaptive immunity both centrally and peripherally in EAE and may reveal further antioxidative and immunomodulatory mechanisms for the application of ALA in human MS (multiple sclerosis).
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Antioxidantes/uso terapéutico , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , PPAR gamma/efectos de los fármacos , Ácido Tióctico/uso terapéutico , Animales , Antioxidantes/farmacología , Evaluación Preclínica de Medicamentos/métodos , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/metabolismo , Hemo-Oxigenasa 1/biosíntesis , Hemo-Oxigenasa 1/efectos de los fármacos , Inmunosupresores/farmacología , Inmunosupresores/uso terapéutico , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Proteínas de la Membrana/biosíntesis , Proteínas de la Membrana/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , PPAR gamma/biosíntesis , Bazo/inmunología , Bazo/trasplante , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células Th17/efectos de los fármacos , Células Th17/inmunología , Ácido Tióctico/farmacología , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/inmunologíaRESUMEN
Mycobacterium tuberculosis disease represents an enormous global health problem, with exceptionally high morbidity and mortality in HIV-seropositive (HIV(+)) persons. Alveolar macrophages from HIV(+) persons demonstrate specific and targeted impairment of critical host cell responses, including impaired M. tuberculosis-mediated tumor necrosis factor (TNF) release and macrophage apoptosis. Vitamin D may promote anti-M. tuberculosis responses through upregulation of macrophage NO, NADPH oxidase, cathelicidin, and autophagy mechanisms, but whether vitamin D promotes anti-M. tuberculosis mechanisms in HIV(+) macrophages is not known. In the current study, human macrophages exposed to M. tuberculosis demonstrated robust release of TNF, IκB degradation, and NF-κB nuclear translocation, and these responses were independent of vitamin D pretreatment. In marked contrast, HIV(+) U1 human macrophages exposed to M. tuberculosis demonstrated very low TNF release and no significant IκB degradation or NF-κB nuclear translocation, whereas vitamin D pretreatment restored these critical responses. The vitamin D-mediated restored responses were dependent in part on macrophage CD14 expression. Importantly, similar response patterns were observed with clinically relevant human alveolar macrophages from healthy individuals and asymptomatic HIV(+) persons at high clinical risk of M. tuberculosis infection. Taken together with the observation that local bronchoalveolar lavage fluid (BALF) levels of vitamin D are severely deficient in HIV(+) persons, the data from this study demonstrate that exogenous vitamin D can selectively rescue impaired critical innate immune responses in vitro in alveolar macrophages from HIV(+) persons at risk for M. tuberculosis disease, supporting a potential role for exogenous vitamin D as a therapeutic adjuvant in M. tuberculosis infection in HIV(+) persons.
Asunto(s)
Seropositividad para VIH/microbiología , Macrófagos Alveolares/inmunología , Mycobacterium tuberculosis/inmunología , Receptores Toll-Like/inmunología , Factor de Necrosis Tumoral alfa/inmunología , Vitamina D/farmacología , Líquido del Lavado Bronquioalveolar/inmunología , Línea Celular , Seropositividad para VIH/inmunología , Seropositividad para VIH/metabolismo , Humanos , Receptores de Lipopolisacáridos/genética , Receptores de Lipopolisacáridos/inmunología , Receptores de Lipopolisacáridos/metabolismo , Macrófagos Alveolares/efectos de los fármacos , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/virología , Mycobacterium tuberculosis/metabolismo , FN-kappa B/inmunología , FN-kappa B/metabolismo , ARN Mensajero/genética , ARN Mensajero/inmunología , ARN Mensajero/metabolismo , Transducción de Señal/inmunología , Receptores Toll-Like/metabolismo , Tuberculosis/metabolismo , Tuberculosis/virología , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Células U937 , Regulación hacia Arriba/inmunología , Vitamina D/inmunología , Vitamina D/metabolismoRESUMEN
BACKGROUND: Invariant natural killer T (iNKT) cells recognize lipids presented by CD1d and have been implicated in the pathogenesis of allergic asthma. Recognition of plant pollen lipids by iNKT cells and their role in allergic responses are poorly defined. OBJECTIVE: Our goal was to investigate whether iNKT cells can be activated by monocyte-derived dendritic cells (DCs) exposed to lipid antigens from Olea europaea. METHODS: DCs generated in vitro were exposed to O europaea pollen grains or lipids isolated from them. Expression of lipid-presenting molecules (CD1), as well as maturation markers (HLA-DR, HLA-I, CD86, and CD80 molecules), on DCs was analyzed. iNKT cell activation after coculture with DCs was evaluated based on expansion, cytokine production, and cytotoxicity tests. RESULTS: DCs upregulated CD1d and CD86 expression and downregulated CD1a expression after exposure to a whole extract of olive pollen lipids. CD1d and CD1a were regulated at the transcriptional level in a peroxisome proliferator-activated receptor γ activation-dependent manner. Polar lipids, diacylglycerols, free fatty acids, and triacylglycerols isolated from pollen grains upregulate CD1d. The increase in CD1d expression on the DC cell surface induced by polar lipids was not regulated at the RNA level. iNKT cells efficiently recognize DCs treated with the different lipids isolated from olive pollen grains. CONCLUSIONS: Lipids from O europaea pollen upregulate CD1d and CD86 molecules on DCs, which are then able to activate iNKT cells through a CD1d-dependent pathway.