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1.
Sci Rep ; 10(1): 18008, 2020 10 22.
Artículo en Inglés | MEDLINE | ID: mdl-33093460

RESUMEN

H5N1 highly pathogenic avian influenza virus (HPAIV) poses a huge threat to public health and the global economy. These viruses cause systemic infection in poultry and accidental human infection leads to severe pneumonia, associated with high mortality rates. The hemagglutinin (HA) of H5N1 HPAIV possesses multiple basic amino acids, as in the sequence RERRRKKR at the cleavage site; however, the role of this motif is not fully understood. Here, we showed that a 33-amino acid long peptide derived from HA of H5N1 HPAIV (HA314-46) has the potential to penetrate various cells and lung tissue through a sialic acid-independent endocytotic pathway. Mutant peptide analyses revealed that the cysteine residue at position 318 and multiple basic amino acids were essential for the cell-penetrating activity. Moreover, reassortant viruses possessing H5 HA could enter sialic acid-deficient cells, and virus internalisation was facilitated by cleavage with recombinant furin. Thus, our findings demonstrate that the HA314-46 motif exhibits cell-penetrating activity through a sialic acid-independent cell entry mechanism.


Asunto(s)
Péptidos de Penetración Celular/administración & dosificación , Glicoproteínas Hemaglutininas del Virus de la Influenza/metabolismo , Subtipo H5N1 del Virus de la Influenza A/patogenicidad , Infecciones por Orthomyxoviridae/virología , Internalización del Virus/efectos de los fármacos , Animales , Células CHO , Cricetulus , Ratones , Infecciones por Orthomyxoviridae/tratamiento farmacológico
2.
FEBS Open Bio ; 8(8): 1188-1201, 2018 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-30087825

RESUMEN

Mammalian eukaryotic translation initiation factor 3 (eIF3) is the largest complex of the translation initiation factors. The eIF3 complex is comprised of thirteen subunits, which are named eIF3a to eIF3 m in most multicellular organisms. The eIF3e gene locus is one of the most frequent integration sites of mouse mammary tumor virus (MMTV), which induces mammary tumors in mice. MMTV-integration events result in the expression of C-terminal-truncated eIF3e proteins, leading to mammary tumor formation. We have shown that tumor formation can be partly caused by activation of hypoxia-inducible factor 2α. To investigate the function of eIF3e in mammals, we generated eIF3e-deficient mice. These eIF3e-/- mice are embryonically lethal, while eIF3e+/- mice are much smaller than wild-type mice. In addition, eIF3e+/- mouse embryonic fibroblasts (MEFs) contained reduced levels of eIF3a and eIF3c subunits and exhibited reduced cellular proliferation. These results suggest that eIF3e is essential for embryonic development in mice and plays a role in maintaining eIF3 integrity.

3.
Immunity ; 43(1): 175-86, 2015 Jul 21.
Artículo en Inglés | MEDLINE | ID: mdl-26200013

RESUMEN

House dust mite-derived proteases contribute to allergic disorders in part by disrupting epithelial barrier function. Interleukin-33 (IL-33), produced by lung cells after exposure to protease allergens, can induce innate-type airway eosinophilia by activating natural helper (NH) cells, a member of group 2 innate lymphoid cells (ILC2), to secrete Th2 type-cytokines. Because IL-33 also can induce mast cells (MCs) to secrete Th2 type-cytokines, MCs are thought to cooperate with NH cells in enhancing protease or IL-33-mediated innate-type airway eosinophilia. However, we found that MC-deficient Kit(W-sh/W-sh) mice exhibited exacerbated protease-induced lung inflammation associated with reduced numbers of regulatory T (Treg) cells. Moreover, IL-2 produced by IL-33-stimulated MCs promoted expansion of numbers of Treg cells, thereby suppressing development of papain- or IL-33-induced airway eosinophilia. We have thus identified a unique anti-inflammatory pathway that can limit induction of innate-type allergic airway inflammation mediated by NH cells.


Asunto(s)
Inflamación/inmunología , Interleucina-2/inmunología , Interleucinas/inmunología , Mastocitos/inmunología , Linfocitos T Reguladores/inmunología , Animales , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Células Cultivadas , Eosinofilia/inducido químicamente , Humanos , Interleucina-10/inmunología , Interleucina-2/genética , Interleucina-33 , Interleucinas/genética , Interleucinas/farmacología , Pulmón/citología , Pulmón/inmunología , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Papaína/farmacología , Proteínas Proto-Oncogénicas c-kit/genética , Pyroglyphidae/inmunología , Células Th2/inmunología
4.
PLoS One ; 10(2): e0116715, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25650570

RESUMEN

Lateral flow tests also known as Immunochromatography (IC) is an antigen-detection method conducted on a nitrocellulose membrane that can be completed in less than 20 min. IC has been used as an important rapid test for clinical diagnosis and surveillance of influenza viruses, but the IC sensitivity is relatively low (approximately 60%) and the limit of detection (LOD) is as low as 10³ pfu per reaction. Recently, we reported an improved IC assay using antibodies conjugated with fluorescent beads (fluorescent immunochromatography; FLIC) for subtyping H5 influenza viruses (FLIC-H5). Although the FLIC strip must be scanned using a fluorescent reader, the sensitivity (LOD) is significantly improved over that of conventional IC methods. In addition, the antibodies which are specific against the subtypes of influenza viruses cannot be available for the detection of other subtypes when the major antigenicity will be changed. In this study, we established the use of FLIC to type seasonal influenza A and B viruses (FLIC-AB). This method has improved sensitivity to 100-fold higher than that of conventional IC methods when we used several strains of influenza viruses. In addition, FLIC-AB demonstrated the ability to detect influenza type A and influenza type B viruses from clinical samples with high sensitivity and specificity (Type A: sensitivity 98.7% (74/75), specificity 100% (54/54), Type B: sensitivity 100% (90/90), specificity 98.2% (54/55) in nasal swab samples) in comparison to the results of qRT-PCR. And furthermore, FLIC-AB performs better in the detection of early stage infection (under 13 h) than other conventional IC methods. Our results provide new strategies to prevent the early-stage transmission of influenza viruses in humans during both seasonal outbreaks and pandemics.


Asunto(s)
Cromatografía de Afinidad/métodos , Virus de la Influenza A/clasificación , Virus de la Influenza B/clasificación , Gripe Humana/diagnóstico , Tipificación Molecular/métodos , Adolescente , Adulto , Anciano , Animales , Aves , Niño , Preescolar , Fluorescencia , Humanos , Lactante , Recién Nacido , Virus de la Influenza A/aislamiento & purificación , Virus de la Influenza B/aislamiento & purificación , Gripe Aviar/virología , Masculino , Mamíferos/virología , Persona de Mediana Edad , Infecciones por Orthomyxoviridae/diagnóstico , Sensibilidad y Especificidad , Adulto Joven
6.
J Dermatol ; 40(3): 193-200, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23294459

RESUMEN

Drinking water is an important nutrient for human health. The mineral ingredients included in drinking water may affect the physical condition of people. Various kinds of natural water are in circulation as bottled water in developed countries; however, its influence on clinical conditions of patients with certain diseases has not been fully evaluated. In this study, effects of the natural groundwater from Jeju Island on clinical symptoms and skin barrier function in atopic dermatitis (AD) were evaluated. NC/Tnd mice, a model for human AD, with moderate to severe dermatitis were used. Mice were given different natural groundwater or tap water for 8 weeks from 4 weeks of age. Clinical skin severity scores were recorded every week. Scratching analysis and measurement of transepidermal water loss were performed every other week. The pathological condition of the dorsal skin was evaluated histologically. Real-time polymerase chain reaction analysis was performed for cytokine expression in the affected skin. The epidermal hyperplasia and allergic inflammation were reduced in atopic mice supplied with Jeju groundwater when compared to those supplied with tap water or other kinds of natural groundwater. The increase in scratching behavior with the aggravation of clinical severity of dermatitis was favorably controlled. Moreover, transepidermal water loss that reflects skin barrier function was recovered. The early inflammation and hypersensitivity in the atopic skin was alleviated in mice supplied with Jeju groundwater, suggesting its profitable potential on the daily care of patients with skin troubles including AD.


Asunto(s)
Balneología , Dermatitis Atópica/terapia , Agua Potable , Agua Subterránea , Animales , Citocinas/metabolismo , Dermatitis Atópica/inmunología , Dermatitis Atópica/patología , Modelos Animales de Enfermedad , Agua Potable/análisis , Factores de Transcripción Forkhead/metabolismo , Agua Subterránea/análisis , Humanos , Inmunoglobulina E/sangre , Ratones , Índice de Severidad de la Enfermedad , Piel/patología , Pérdida Insensible de Agua
7.
Vet J ; 196(3): 402-7, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23141960

RESUMEN

Circadian rhythms have a periodicity of approximately 24h and, in mammals, are regulated by clock genes. In this study, expression profiles of clock genes (per1, per2, clock, bmal1 and cry1) were investigated over a single 24h period by real-time PCR in peripheral blood mononuclear cells (PBMCs) of healthy dogs and canine PBMCs treated in vitro and in vivo with glucocorticoids. Only per1 mRNA exhibited daily rhythms in canine PBMCs. Canine PBMCs cultured with dexamethasone in vitro had dose- and time-dependent increases in per1 mRNA expression. Intravenous injection of dexamethasone increased expression of per1 in canine PBMCs in vivo. Rhythmic expression of per1 in PBMCs could be used as a molecular marker for monitoring circadian rhythms and the effects of drugs on clock genes in dogs.


Asunto(s)
Ritmo Circadiano , Dexametasona/farmacología , Perros/fisiología , Regulación de la Expresión Génica/fisiología , Proteínas Circadianas Period/metabolismo , Animales , Temperatura Corporal , Femenino , Glucocorticoides/farmacología , Masculino , Proteínas Circadianas Period/genética
8.
J Immunol ; 189(7): 3641-52, 2012 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-22942422

RESUMEN

IL-17A, IL-17F, and IL-25 are ligands for IL-17RA. In the current study, we demonstrated that IL-25-deficient mice-but not IL-17A-, IL-17F-, IL-17A/F-, IL-23p19-, or retinoic acid-related orphan receptor (ROR)-γt-deficient mice-showed significant suppression of 1) the number of eosinophils and the levels of proinflammatory mediators in bronchoalveolar lavage fluids, 2) airway hyperresponsiveness to methacholine, and 3) OVA-specific IgG1 and IgE levels in the serum during OVA-induced Th2-type/eosinophilic airway inflammation. The IL-25 deficiency did not affect lung dendritic cell migration or Ag-specific memory-Th2 cell expansion during Ag sensitization. Adoptive transfer of T cells, mast cells, or bone marrow cells from IL-25-deficient mice revealed that induction of Th2-type/eosinophilic airway inflammation was dependent on activation of lung epithelial cells and eosinophils by IL-25 produced by airway structural cells such as epithelial cells but not by such hematopoietic stem-cell-origin immune cells as T cells and mast cells. Therefore, airway structural cell-derived IL-25-rather than Th17 cell-derived IL-17A and IL-17F-is responsible for induction of local inflammation by promoting activation of lung epithelial cells and eosinophils in the elicitation phase of Th2-type/eosinophilic airway inflammation. It is not required for Ag-specific Th2 cell differentiation in the sensitization phase.


Asunto(s)
Asma/inmunología , Células Epiteliales/inmunología , Mediadores de Inflamación/fisiología , Interleucina-17/fisiología , Interleucinas/fisiología , Células Th17/inmunología , Animales , Asma/metabolismo , Asma/patología , Diferenciación Celular/inmunología , Células Cultivadas , Modelos Animales de Enfermedad , Eosinofilia/inmunología , Eosinofilia/metabolismo , Eosinofilia/patología , Células Epiteliales/metabolismo , Células Epiteliales/patología , Femenino , Interleucina-17/biosíntesis , Interleucina-17/deficiencia , Interleucinas/deficiencia , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Células Th17/metabolismo , Células Th2/inmunología , Células Th2/metabolismo , Células Th2/patología
9.
J Dermatol Sci ; 67(2): 130-9, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22748506

RESUMEN

BACKGROUND: Effects of probiotics on the prevention of atopic diseases have been proposed recently. Although we have already reported the suppressive effects of the probiotic, ImmuBalance™, on a mouse model for peanuts allergy, its influence on atopic diseases remains unclear. OBJECTIVE: Potential efficacy of ImmuBalance™, which is the fermented soy product, on treatment of atopic dermatitis (AD) was investigated using a mouse model for human AD, NC/Tnd mice. METHODS: For in vivo study, ImmuBalance containing chow or a control diet were fed to NC/Tnd mice with moderate dermatitis for 2 weeks. Topical application of FK506 ointment was used as a positive control. Clinical skin severity scores, scratching behaviors, trans-epidermal water loss (TEWL), and histological features were analyzed. For in vitro study, suppressive effect of ImmuBalance™ on nerve growth factor (NGF)-activated neurite outgrowth of PC12 cells was examined. RESULTS: Clinical skin severity scores of the mice fed with ImmuBalance containing chow were gradually reduced as well as the mice treated with FK506. Feeding with ImmuBalance completely inhibited the increase in scratching behavior of NC/Tnd mice. The value of TEWL of NC/Tnd mice fed with ImmuBalance was significantly decreased. In addition, histological examination revealed that application of ImmuBalance decreased the number of PGP9.5-positive neuronal fibers in the lesional skin. When ImmuBalance extract was added to the culture, NGF-activated neurite outgrowth of PC12 cells was diminished through the inhibition of the phosphatidylinositol 3-kinase phosphorylation. CONCLUSION: ImmuBalance could exhibit favorable alterations on AD symptoms, particularly through down regulation of the itch sensation.


Asunto(s)
Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/inmunología , Dermatitis/tratamiento farmacológico , Glycine max/metabolismo , Prurito/tratamiento farmacológico , Administración Oral , Administración Tópica , Animales , Regulación hacia Abajo , Fermentación , Hidrólisis , Masculino , Ratones , Factor de Crecimiento Nervioso/metabolismo , Células PC12 , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación , Ratas , Piel/patología , Tacrolimus/farmacología , Factores de Tiempo , Agua/química
10.
Allergol Int ; 61(2): 265-73, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22361513

RESUMEN

BACKGROUND: IL-33 is known to induce Th2-type cytokine production by various types of cells through its receptors, ST2 and IL-1RAcP. Polymorphism in the ST2 and/or IL-33 genes was found in patients with atopic dermatitis and asthma, implying that the IL-33/ST2 pathway is closely associated with susceptibility to these diseases. Exposure to allergens through damaged skin is suspected to be a trigger for allergen sensitization, resulting in development of such allergic disorders as asthma and atopic dermatitis. METHODS: To elucidate the role(s) of the IL-33/ST2 pathway in asthma in individuals who had been epicutaneously sensitized to an antigen, wild-type and ST2-/- mice were epicutaneously sensitized with ovalbumin (OVA) and then were intranasally challenged with OVA. The degree of airway inflammation, the number of leukocytes and the activities of myeloperoxidase (MPO) and eosinophil peroxidase (EPO) in bronchoalveolar lavage fluids (BALFs), The levels of cytokines and chemokines in lungs and OVA-specific IgE levels in sera were determined by histological analysis, a hemocytometer, colorimetric assay, quantitative PCR or ELISA, respectively. RESULTS: The number of eosinophils in BALFs, the levels of Th2 cytokines and chemoattractants in the lungs and OVA-specific IgE in sera from ST2-/- mice were significantly reduced compared with wild-type mice. Although the number of neutrophils in BALFs and the pulmonary levels of IL-17 were comparable in both mice, the levels of MPO activity in BALFs and neutrophil chemoattractants in the lung were reduced in ST2-/- mice. CONCLUSIONS: The IL-33/ST2 pathway is crucial for Th2-cytokine-mediated eosinophilic, rather than Th17-cytokine-mediated neutrophilic, airway inflammation in mice that had been epicutaneously sensitized with antigens and then challenged with antigen.


Asunto(s)
Asma/inmunología , Neumonía/inmunología , Receptores de Interleucina/metabolismo , Células Th17/inmunología , Células Th2/inmunología , Administración Cutánea , Animales , Modelos Animales de Enfermedad , Eosinófilos/patología , Humanos , Inmunización , Inmunoglobulina E/sangre , Proteína 1 Similar al Receptor de Interleucina-1 , Interleucina-33 , Interleucinas/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Ovalbúmina/administración & dosificación , Peroxidasa/metabolismo , Neumonía/inducido químicamente , Receptores de Interleucina/genética , Receptores de Interleucina/inmunología
11.
Circulation ; 124(11 Suppl): S187-96, 2011 Sep 13.
Artículo en Inglés | MEDLINE | ID: mdl-21911812

RESUMEN

BACKGROUND: Interleukin-17 (IL-17), which is predominantly produced by T helper 17 cells distinct from T helper 1 or T helper 2 cells, participates in the pathogenesis of infectious, autoimmune, and allergic disorders. However, the precise role in allograft rejection remains uncertain. In the present study, we investigated the role of IL-17 in acute allograft rejection using IL-17-deficient mice. METHODS AND RESULTS: Donor hearts from FVB mice were heterotopically transplanted into either C57BL/6J-IL-17-deficient (IL-17(-/-)) or -wild-type mice. Allograft survival was significantly prolonged in IL-17(-/-) recipient mice due to reduced local inflammation accompanied by decreased inflammatory cell recruitment and cytokine/chemokine expression. IL-17(-/-) recipient mice exhibited decreased IL-6 production and reciprocally enhanced regulatory T cell expansion, suggesting a contribution of regulatory T cells to prolonged allograft survival. Indeed, allografts transplanted into anti-CD25 mAb-treated IL-17(-/-) recipient mice (regulatory T cell-depleted) developed acute rejection similar to wild-type recipient mice. Surprisingly, we found that gamma delta T cells rather than CD4(+) and CD8(+) T cells were key IL-17 producers in the allografts. In support, equivalent allograft rejection was observed in Rag-2(-/-) recipient mice engrafted with either wild-type or IL-17(-/-) CD4(+) and CD8(+) T cells. Finally, hearts transplanted into gamma delta T cell-deficient mice resulted in decreased allograft rejection compared with wild-type controls. CONCLUSIONS: During heart transplantation, (1) IL-17 is crucial for acceleration of acute rejection; (2) IL-17-deficiency enhances regulatory T cell expansion; and (3) gamma delta T cells rather than CD4(+) and CD8(+) T cells are a potential source of IL-17. IL-17 neutralization may provide a potential target for novel therapeutic treatment for cardiac allograft rejection.


Asunto(s)
Proliferación Celular , Rechazo de Injerto/fisiopatología , Trasplante de Corazón/fisiología , Interleucina-17/fisiología , Linfocitos T Reguladores/patología , Animales , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/patología , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/patología , Células Cultivadas , Rechazo de Injerto/patología , Trasplante de Corazón/patología , Interleucina-17/deficiencia , Interleucina-17/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Animales , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Linfocitos T Reguladores/metabolismo , Células Th17/metabolismo , Células Th17/patología , Trasplante Homólogo
12.
PLoS One ; 6(4): e18404, 2011 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-21494550

RESUMEN

BACKGROUND: IL-33, a member of the IL-1 family of cytokines, provokes Th2-type inflammation accompanied by accumulation of eosinophils through IL-33R, which consists of ST2 and IL-1RAcP. We previously demonstrated that macrophages produce IL-33 in response to LPS. Some immune responses were shown to differ between ST2-deficient mice and soluble ST2-Fc fusion protein-treated mice. Even in anti-ST2 antibody (Ab)-treated mice, the phenotypes differed between distinct Ab clones, because the characterization of such Abs (i.e., depletion, agonistic or blocking Abs) was unclear in some cases. METHODOLOGY/PRINCIPAL FINDINGS: To elucidate the precise role of IL-33, we newly generated neutralizing monoclonal Abs for IL-33. Exogenous IL-33 potentiated LPS-mediated cytokine production by macrophages. That LPS-mediated cytokine production by macrophages was suppressed by inhibition of endogenous IL-33 by the anti-IL-33 neutralizing mAbs. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that LPS-mediated macrophage activation is accelerated by macrophage-derived paracrine IL-33 stimulation.


Asunto(s)
Interleucinas/metabolismo , Lipopolisacáridos/farmacología , Activación de Macrófagos/efectos de los fármacos , Comunicación Paracrina/efectos de los fármacos , Animales , Anticuerpos Monoclonales/inmunología , Células de la Médula Ósea/citología , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/metabolismo , Células Cultivadas , Humanos , Interleucina-33 , Mastocitos/citología , Mastocitos/efectos de los fármacos , Mastocitos/metabolismo , Ratones , Factor 6 Asociado a Receptor de TNF/metabolismo , Tioglicolatos/farmacología
13.
Immunology ; 132(4): 527-39, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-21214543

RESUMEN

Catestatin, a neuroendocrine peptide with effects on human autonomic function, has recently been found to be a cutaneous antimicrobial peptide. Human catestatin exhibits three single nucleotide polymorphisms: Gly364Ser, Pro370Leu and Arg374Gln. Given reports indicating that antimicrobial peptides and neuropeptides induce mast cell activation, we postulated that catestatin might stimulate numerous functions of human mast cells, thereby participating in the regulation of skin inflammatory responses. Catestatin and its naturally occurring variants caused the human mast cell line LAD2 and peripheral blood-derived mast cells to migrate, degranulate and release leukotriene C(4) and prostaglandins D(2) and E(2). Moreover, catestatins increased intracellular Ca(2+) mobilization in mast cells, and induced the production of pro-inflammatory cytokines/chemokines such as granulocyte-macrophage colony-stimulating factor, monocyte chemotactic protein-1/CCL2, macrophage inflammatory protein-1α/CCL3 and macrophage inflammatory protein-1ß/CCL4. Our evaluation of possible cellular mechanisms suggested that G-proteins, phospholipase C and the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) are involved in catestatin-induced mast cell activation as evidenced by the inhibitory effects of pertussis toxin (G-protein inhibitor), U-73122 (phospholipase C inhibitor) and U0126 (ERK inhibitor), respectively. We also found that human mast cells express the α7 subunit of the nicotinic acetylcholine receptor at both the mRNA and protein levels. Given that silencing the α7 receptor mRNA and an α7-specific inhibitor did not affect catestatin-mediated activation of mast cells, however, we concluded that this receptor is not likely to be functional in human mast cell stimulation by catestatins. Our finding that the neuroendocrine antimicrobial peptide catestatin activates human mast cells suggests that this peptide might have immunomodulatory functions, and provides a new link between neuroendocrine and cutaneous immune systems.


Asunto(s)
Degranulación de la Célula/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Cromogranina A/farmacología , Citocinas/metabolismo , Mastocitos/efectos de los fármacos , Fragmentos de Péptidos/farmacología , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Péptidos Catiónicos Antimicrobianos/farmacología , Western Blotting , Calcio/metabolismo , Quimiocinas/genética , Quimiocinas/metabolismo , Quimiotaxis/efectos de los fármacos , Cromogranina A/química , Cromogranina A/genética , Citocinas/genética , Dinoprostona/metabolismo , Estrenos/farmacología , Expresión Génica/efectos de los fármacos , Humanos , Leucotrieno C4/metabolismo , Mastocitos/metabolismo , Mastocitos/fisiología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Datos de Secuencia Molecular , Fragmentos de Péptidos/química , Fragmentos de Péptidos/genética , Toxina del Pertussis/farmacología , Fosforilación/efectos de los fármacos , Prostaglandina D2/metabolismo , Pirrolidinonas/farmacología , Interferencia de ARN , Receptores Nicotínicos/genética , Receptores Nicotínicos/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Receptor Nicotínico de Acetilcolina alfa 7
14.
Proc Natl Acad Sci U S A ; 107(43): 18581-6, 2010 Oct 26.
Artículo en Inglés | MEDLINE | ID: mdl-20937871

RESUMEN

IL-33, a member of the IL-1-related cytokines, is considered to be a proallergic cytokine that is especially involved in Th2-type immune responses. Moreover, like IL-1α, IL-33 has been suggested to act as an "alarmin" that amplifies immune responses during tissue injury. In contrast to IL-1, however, the precise roles of IL-33 in those settings are poorly understood. Using IL-1- and IL-33-deficient mice, we found that IL-1, but not IL-33, played a substantial role in induction of T cell-mediated type IV hypersensitivity such as contact and delayed-type hypersensitivity and autoimmune diseases such as experimental autoimmune encephalomyelitis. Most notably, however, IL-33 was important for innate-type mucosal immunity in the lungs and gut. That is, IL-33 was essential for manifestation of T cell-independent protease allergen-induced airway inflammation as well as OVA-induced allergic topical airway inflammation, without affecting acquisition of antigen-specific memory T cells. IL-33 was significantly involved in the development of dextran-induced colitis accompanied by T cell-independent epithelial cell damage, but not in streptozocin-induced diabetes or Con A-induced hepatitis characterized by T cell-mediated apoptotic tissue destruction. In addition, IL-33-deficient mice showed a substantially diminished LPS-induced systemic inflammatory response. These observations indicate that IL-33 is a crucial amplifier of mucosal and systemic innate, rather than acquired, immune responses.


Asunto(s)
Inmunidad Innata , Interleucinas/inmunología , Inmunidad Adaptativa , Animales , Autoinmunidad , Colitis/etiología , Colitis/inmunología , Inmunidad Mucosa , Interleucina-1/deficiencia , Interleucina-1/genética , Interleucina-1/inmunología , Interleucina-33 , Interleucinas/deficiencia , Interleucinas/genética , Lipopolisacáridos/toxicidad , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Ovalbúmina/inmunología , Hipersensibilidad Respiratoria/etiología , Hipersensibilidad Respiratoria/inmunología , Hipersensibilidad Respiratoria/patología , Choque Séptico/etiología , Choque Séptico/inmunología
15.
Allergol Int ; 59(4): 399-408, 2010 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-20864797

RESUMEN

BACKGROUND: IL-25, which is a member of the IL-17 family, induces Th2 cell differentiation and Th2 cytokine production, contributing to induction of Th2-type immune responses and diseases, as a result of which it suppresses Th1- and Th17-type immune responses. METHODS: To elucidate the role of IL-25 in the pathogenesis of IL-17-mediated delayed-type hypersensitivity (DTH), IL-25-deficient mice were sensitized with methylated BSA (mBSA), and then a DTH reaction was induced by mBSA challenge. mBSA-specific T-cell induction was assessed on the basis of cell proliferation and cytokine production. The DTH reaction was evaluated on the basis of tissue swelling, histology and inflammatory mediator expression. RESULTS: IL-25 expression was markedly reduced in local DTH lesions. However, mBSA-specific Th1, Th2 and Th17 cell induction, and the mBSA-induced DTH reaction were comparable in IL-25-deficient and wild-type mice. CONCLUSIONS: IL-25 is not essential for differentiation of Th1, Th2 and Th17 cells in the sensitization phase or induction of local inflammation in the elicitation phase of the mBSA-induced DTH reaction.


Asunto(s)
Hipersensibilidad Tardía/inmunología , Interleucina-17/metabolismo , Células Th17/metabolismo , Células Th2/metabolismo , Animales , Proliferación Celular , Células Cultivadas , Regulación hacia Abajo , Inmunización , Interleucina-17/genética , Interleucina-17/inmunología , Activación de Linfocitos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Células Th17/inmunología , Células Th17/patología , Células Th2/inmunología , Células Th2/patología
16.
Allergol Int ; 59(3): 277-284, 2010 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-20567134

RESUMEN

BACKGROUND: Amphiregulin (AR) is expressed in Th2 cells, rather than Th1 cells, and plays an important role in Th2 cell/cytokine-mediated host defense against nematodes. We also found earlier that AR mRNA expression was strongly upregulated in inflamed tissue during Th2 cell/cytokine-mediated fluorescein isothiocyanate (FITC)-induced contact hypersensitivity (CHS), suggesting a contribution of AR to the induction of those responses. METHODS: To elucidate the role of AR in the induction of FITC- or dinitrofluorobenzene (DNFB)-induced CHS, AR-deficient mice were sensitized and/or challenged with FITC or DNFB epicutaneously. The levels of FITC-mediated skin dendritic cell (DC) migration and FITC-specific lymph node cell proliferation and cytokine production were assessed by flow cytometry, [3H]-thymidine incorporation and ELISA, respectively, after FITC sensitization. The degree of ear swelling, the activities of myeloperoxidase (MPO) and eosinophil peroxidase (EPO) in inflammatory sites and the levels of FITC-specific immunoglobulin (Ig) in sera were determined by histological analysis, colorimetric assay and ELISA, respectively, after FITC challenge. RESULTS: DC migration and FITC-specific lymph node cell proliferation and cytokine production were normal in the AR-deficient mice. Ear swelling, tissue MPO and EPO activities and FITC-specific serum Ig levels were also similar in AR-deficient and -sufficient mice. CONCLUSIONS: Amphiregulin is not essential for the induction of FITC- or DNFB-induced CHS responses in mice.


Asunto(s)
Células Dendríticas/metabolismo , Dermatitis por Contacto/inmunología , Glicoproteínas/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Anfirregulina , Animales , Movimiento Celular/genética , Proliferación Celular , Citocinas/genética , Citocinas/metabolismo , Citocinas/farmacología , Células Dendríticas/inmunología , Células Dendríticas/patología , Dermatitis por Contacto/sangre , Dermatitis por Contacto/genética , Dinitrofluorobenceno/administración & dosificación , Familia de Proteínas EGF , Peroxidasa del Eosinófilo/sangre , Glicoproteínas/genética , Glicoproteínas/inmunología , Inmunoglobulinas/sangre , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Peroxidasa/sangre , Células Th2/inmunología
17.
J Allergy Clin Immunol ; 125(5): 1137-1145.e6, 2010 May.
Artículo en Inglés | MEDLINE | ID: mdl-20392487

RESUMEN

BACKGROUND: In human subjects platelet-activating factor (PAF) concentrations are markedly increased in the plasma after anaphylactic reactions, and these correlate strongly with the severity of the response. The mechanism for the systemic spread of mast cell (MC) activation in anaphylaxis is often assumed to relate to the hematogenous spread of allergen, but this is implausible, and amplification mechanisms need to be considered. OBJECTIVE: We have investigated the ability of PAF to induce human MC degranulation using skin, lung, and peripheral blood (PB)-derived cultured MCs and the signaling pathways activated in PB-derived MCs in response to PAF. METHODS: The expression of PAF receptor was investigated by means of RT-PCR and Western blot analysis. Cell-signaling pathways in PB-derived MCs in response to PAF were investigated by analyzing the effect of various inhibitors and the silencing of phospholipase C (PLC) mRNA on PAF-mediated histamine release. RESULTS: We show for the first time that PAF induces histamine release from human lung MCs and PB-derived MCs but not skin MCs. Activation of PAF receptor-coupled G(alphai) leads to degranulation through PLCgamma1 and PLCbeta2 activation in human MCs. PAF-induced degranulation was rapid, being maximal at 5 seconds, and was partially dependent on extracellular Ca(2+). CONCLUSION: Our findings provide a mechanism whereby PAF mediates an amplification loop for MC activation in the generation of anaphylaxis.


Asunto(s)
Mastocitos/inmunología , Factor de Activación Plaquetaria/metabolismo , Glicoproteínas de Membrana Plaquetaria/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Anafilaxia/inmunología , Anafilaxia/fisiopatología , Células Cultivadas , Liberación de Histamina , Humanos , Pulmón/citología , Mastocitos/citología , Mastocitos/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Piel/citología
18.
Allergol Int ; 59(2): 143-60, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20414050

RESUMEN

Interleukin-33 (IL-33) is a member of the IL-1 cytokine family, which includes IL-1 and IL-18. IL-33 is considered to be crucial for induction of Th2-type cytokine-associated immune responses such as host defense against nematodes and allergic diseases by inducing production of such Th2-type cytokines as IL-5 and IL-13 by Th2 cells, mast cells, basophils and eosinophils. In addition, IL-33 is involved in the induction of non-Th2-type acute and chronic inflammation as a proinflammatory cytokine, similar to IL-1 and IL-18. In this review, we summarize and discuss the current knowledge regarding the roles of IL-33 and IL-33 receptors in host defense and disease development.


Asunto(s)
Enfermedades Autoinmunes/inmunología , Hipersensibilidad/inmunología , Infecciones/inmunología , Interleucinas/inmunología , Células Th2/inmunología , Animales , Enfermedades Autoinmunes/genética , Interacciones Huésped-Patógeno , Humanos , Hipersensibilidad/genética , Inmunidad , Infecciones/genética , Inflamación , Proteína 1 Similar al Receptor de Interleucina-1 , Interleucina-33 , Ratones , Polimorfismo Genético , Receptores de Superficie Celular/inmunología , Receptores de Interleucina/inmunología , Receptores Toll-Like/inmunología
19.
Allergol Int ; 59(2): 207-11, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20414053

RESUMEN

BACKGROUND: The number of amphiregulin (AR)-positive mast cells in the bronchial mucosa and the levels of AR in sputum from asthmatic patients have been reported to be increased. In addition, AR can promote mucin gene expression in human epithelial cells, suggesting that AR contributes to the pathogenesis of allergic asthma. METHODS: To elucidate the role of AR in the pathogenesis of asthma, we immunized AR-deficient mice with ovalbumin (OVA) and then induced airway inflammation in them after OVA inhalation. The OVA-induced airway inflammation was assessed on the basis of the lung histology, number of leukocytes in the bronchoalveolar lavage (BAL) fluid, Th2 cytokine levels in the BAL fluid and OVA-specific IgG1 and IgE levels in the serum and compared between AR-sufficient and -deficient mice. RESULTS: The OVA-induced airway inflammation was comparable in the AR-sufficient and -deficient mice. CONCLUSIONS: Amphiregulin is not essential for induction of acute airway inflammation by OVA in mice.


Asunto(s)
Asma/inmunología , Hiperreactividad Bronquial/inmunología , Glicoproteínas/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Pulmón/patología , Ovalbúmina/administración & dosificación , Anfirregulina , Animales , Hiperreactividad Bronquial/sangre , Hiperreactividad Bronquial/inducido químicamente , Hiperreactividad Bronquial/genética , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/citología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Familia de Proteínas EGF , Glicoproteínas/genética , Glicoproteínas/inmunología , Humanos , Inmunización , Inmunoglobulina E/sangre , Inmunoglobulina G/sangre , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/inmunología , Ratones , Ratones Noqueados , Ovalbúmina/inmunología
20.
J Immunol ; 184(7): 3526-34, 2010 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-20190140

RESUMEN

In addition to their microbiocidal properties, human beta-defensins (hBDs) and cathelicidin LL-37 stimulate a number of mammalian cell activities, including migration, proliferation, and cytokine/chemokine production. Because hBDs and LL-37 cause mast cells to release pruritogens such as histamine and PGs, we hypothesized that these peptides would stimulate the secretion of a novel pruritogenic mediator IL-31, predominantly produced by T cells. hBDs and LL-37 enhanced IL-31 gene expression and IL-31 protein production and release in the human mast cell line LAD2, as well as in peripheral blood-derived cultured mast cells, suggesting that mast cells are another source of IL-31. Moreover, the expression of IL-31 was elevated in psoriatic skin mast cells, and hBD-2-4 and LL-37, but not hBD-1, enhanced its expression in vivo in rat skin mast cells. hBDs and LL-37 also induced the release of other pruritogenic mediators, including IL-2, IL-4, IL-6, GM-CSF, nerve growth factor, PGE(2), and leukotriene C(4), and increased mRNA expression of substance P. hBD- and LL-37-mediated IL-31 production/release was markedly reduced by pertussis toxin and wortmannin, inhibitors of G-protein and PI3K, respectively. As evidenced by the inhibitory effects of MAPK-specific inhibitors, hBD-2-4 and LL-37 activated the phosphorylation of MAPKs p38, ERK, and JNK that were required for IL-31 production and release. The ability of hBDs and LL-37 to stimulate the production and release of IL-31 by human mast cells provides a novel mechanism by which skin-derived antimicrobial peptides/proteins may contribute to inflammatory reactions and suggests a central role of these peptides in the pathogenesis of skin disorders.


Asunto(s)
Catelicidinas/inmunología , Inflamación/inmunología , Interleucinas/metabolismo , Mastocitos/metabolismo , Piel/inmunología , beta-Defensinas/inmunología , Animales , Western Blotting , Células Cultivadas , Ensayo de Inmunoadsorción Enzimática , Técnica del Anticuerpo Fluorescente , Expresión Génica , Regulación de la Expresión Génica/inmunología , Humanos , Mastocitos/inmunología , Ratas , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/inmunología
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