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1.
Br J Cancer ; 127(7): 1175-1176, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-36064587

RESUMEN

Aryl hydrocarbon receptor-interacting protein (AIP) is a co-chaperone to heat shock proteins and nuclear receptors. Loss-of-function heterozygote germline mutations lead to predisposition to growth hormone- or prolactin-secreting pituitary typically presenting in childhood. Based on these data AIP behaves as a tumour suppressor. However, previously in diffuse large B cell lymphoma and now in this new manuscript in the British Journal of Cancer on colorectal cancer, it seems that high expression of AIP is associated with tumour development and more aggressive disease. AIP, therefore, joins a distinguished group of proteins that can behave both as a tumour suppressor and as an oncogene.


Asunto(s)
Mutación de Línea Germinal , Prolactina , Hormona del Crecimiento , Proteínas de Choque Térmico , Humanos , Oncogenes/genética
2.
Nat Immunol ; 9(8): 873-9, 2008 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-18568027

RESUMEN

Interleukin 23 (IL-23) is integral to the pathogenesis of chronic inflammation. The resolution of acute inflammation is an active process mediated by specific signals and mediators such as resolvin E1 (RvE1). Here we provide evidence that RvE1, in nanogram quantities, promoted the resolution of inflammatory airway responses in part by directly suppressing the production of IL-23 and IL-6 in the lung. Also contributing to the pro-resolution effects of RvE1 treatment were higher concentrations of interferon-gamma in the lungs of RvE1-treated mice. Our findings indicate a pivotal function for IL-23 and IL-6, which promote the survival and differentiation of IL-17-producing T helper cells, in maintaining inflammation and also identify an RvE1-initiated resolution program for allergic airway responses.


Asunto(s)
Asma/tratamiento farmacológico , Asma/inmunología , Ácido Eicosapentaenoico/análogos & derivados , Mediadores de Inflamación/metabolismo , Lipoxinas/metabolismo , Pulmón/efectos de los fármacos , Animales , Asma/patología , Modelos Animales de Enfermedad , Ácido Eicosapentaenoico/metabolismo , Ácido Eicosapentaenoico/farmacología , Inflamación , Mediadores de Inflamación/fisiología , Interferón gamma/metabolismo , Interleucina-23/metabolismo , Pulmón/inmunología , Pulmón/patología , Ratones
3.
Semin Immunol ; 27(3): 194-9, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25944272

RESUMEN

A common feature of seasonal colds and other infections is painful joints. This is due to an acute reactive inflammatory arthritis which almost always resolves. Unfortunately, for some people the inflammation never completely resolves but rather precedes progression to chronic inflammatory arthritis. The existing dogma that accounts for why chronic inflammatory joint disease persists is that it is due to an excess of pro-inflammatory signals and that resolution occurs by pro-inflammatory mediator catabolism. Recent discoveries have supported a new paradigm which proposes that the resolution of inflammation is an active process with genetic, molecular and cellular programs that promote catabasis. By seeking to understand the mechanisms behind the spontaneous resolution of inflammation, we can gain insight into why inflammation sometimes fails to resolve. This review seeks to highlight the mechanisms behind the resolution of joint inflammation and how endogenous pro-resolving mediators could be used to treat chronic persistent inflammatory joint disease.


Asunto(s)
Artritis/patología , Aspirina/uso terapéutico , Inflamación/tratamiento farmacológico , Inflamación/patología , Articulaciones/patología , Antiinflamatorios no Esteroideos/uso terapéutico , Artritis/tratamiento farmacológico , Artritis/inmunología , Ácidos Docosahexaenoicos/inmunología , Humanos , Inflamación/inmunología , Mediadores de Inflamación/inmunología , Articulaciones/inmunología , Metabolismo de los Lípidos/inmunología , Transducción de Señal/inmunología
4.
J Immunol ; 189(4): 1983-91, 2012 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-22802419

RESUMEN

Asthma is a disease of airway inflammation that in most cases fails to resolve. The resolution of inflammation is an active process governed by specific chemical mediators, including D-series resolvins. In this study, we determined the impact of resolvin D1 (RvD1) and aspirin-triggered RvD1 (AT-RvD1) on the development of allergic airway responses and their resolution. Mice were allergen sensitized, and RvD1, AT-RvD1 (1, 10, or 100 ng), or vehicle was administered at select intervals before or after aerosol allergen challenge. RvD1 markedly decreased airway eosinophilia and mucus metaplasia, in part by decreasing IL-5 and IκBα degradation. For the resolution of established allergic airway responses, AT-RvD1 was even more efficacious than RvD1, leading to a marked decrease in the resolution interval for lung eosinophilia, decrements in select inflammatory peptide and lipid mediators, and more rapid resolution of airway hyperreactivity to methacholine. Relative to RvD1, AT-RvD1 resisted metabolic inactivation by macrophages, and AT-RvD1 significantly enhanced macrophage phagocytosis of IgG-OVA-coated beads in vitro and in vivo, a new proresolving mechanism for the clearance of allergen from the airways. In conclusion, RvD1 and AT-RvD1 can serve as important modulators of allergic airway responses by decreasing eosinophils and proinflammatory mediators and promoting macrophage clearance of allergen. Together, these findings identify D-series resolvins as potential proresolving therapeutic agents for allergic responses.


Asunto(s)
Asma/inmunología , Ácidos Docosahexaenoicos/inmunología , Hipersensibilidad/inmunología , Animales , Aspirina/farmacología , Asma/metabolismo , Western Blotting , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/inmunología , Quimiotaxis de Leucocito/inmunología , Citocinas/biosíntesis , Modelos Animales de Enfermedad , Ácidos Docosahexaenoicos/metabolismo , Perfilación de la Expresión Génica , Hipersensibilidad/metabolismo , Inmunohistoquímica , Macrófagos/inmunología , Masculino , Ratones , Isoformas de Proteínas/inmunología , Isoformas de Proteínas/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
5.
J Immunol ; 186(11): 6129-35, 2011 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-21515793

RESUMEN

Immune responses are pathologically sustained in several common diseases, including asthma. To determine endogenous proresolving mechanisms for adaptive immune responses, we used a murine model of self-limited allergic airway inflammation. After cessation of allergen exposure, eosinophils and T cells were cleared concomitant with the appearance of increased numbers of NK cells in the lung and mediastinal lymph nodes. The mediastinal lymph node NK cells were activated, expressing CD27, CD11b, CD69, CD107a, and IFN-γ. NK cell depletion disrupted the endogenous resolution program, leading to delayed clearance of airway eosinophils and Ag-specific CD4(+) T cells. NK cell trafficking to inflamed tissues for resolution was dependent upon CXCR3 and CD62L. During resolution, eosinophils and Ag-specific CD4(+) T cells expressed NKG2D ligands, and a blocking Ab for the NKG2D receptor delayed clearance of these leukocytes. Of interest, NK cells expressed CMKLR1, a receptor for the proresolving mediator resolvin E1, and depletion of NK cells decreased resolvin E1-mediated resolution of allergic inflammation. Resolvin E1 regulated NK cell migration in vivo and NK cell cytotoxicity in vitro. Together, these findings indicate new functions in catabasis for NK cells that can also serve as targets for proresolving mediators in the resolution of adaptive immunity.


Asunto(s)
Ácido Eicosapentaenoico/análogos & derivados , Inflamación/inmunología , Células Asesinas Naturales/inmunología , Hipersensibilidad Respiratoria/inmunología , Inmunidad Adaptativa/inmunología , Traslado Adoptivo , Animales , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Antígeno CD11b/inmunología , Antígeno CD11b/metabolismo , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Ácido Eicosapentaenoico/metabolismo , Ácido Eicosapentaenoico/farmacología , Eosinófilos/inmunología , Eosinófilos/metabolismo , Citometría de Flujo , Inflamación/metabolismo , Células Asesinas Naturales/metabolismo , Células Asesinas Naturales/trasplante , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/patología , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/metabolismo , Ganglios Linfáticos/patología , Ratones , Ratones Endogámicos BALB C , Hipersensibilidad Respiratoria/metabolismo , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/metabolismo , Mucosa Respiratoria/patología , Factores de Tiempo , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/inmunología , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismo
6.
Biochim Biophys Acta ; 1812(9): 1164-9, 2011 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-21616147

RESUMEN

Omega-3 polyunsaturated fatty acids (n-3 PUFA) have been implicated in the alleviation of asthma. Recent studies have demonstrated that the n-3 PUFA derived lipid mediators, protectin D1 and resolvin E1, may act as potent resolution agonists in airway inflammation. The effects of the n-3 PUFA tissue status itself on asthma pathogenesis remains to be further investigated. In this study allergic airway inflammation induced by allergen sensitization and aerosol challenge in Fat-1 and wild-type mice was investigated. Fat-1 transgenic mice displayed increased endogenous lung n-3 PUFA. When allergen-sensitized and aerosol-challenged, these animals had decreased airway inflammation with decreased leukocyte accumulation in bronchoalveolar lavage fluid and lung parenchyma. The Fat-1 mice had a shift to the right in the dose-response relationship for methacholine induced bronchoconstriction with a significant increase in the log ED200. The Fat-1 mice had lower BALF concentrations of the pro-inflammatory cytokines IL-1α, IL-2, IL-5, IL-9, IL-13, G-CSF, KC and RANTES. Furthermore, increased lung tissue amounts of the counter-regulatory mediators protectin D1 and resolvin E1 were found in Fat-1 mice after bronchoprovocative challenge. These results therefore demonstrate a direct protective role for lung n-3 PUFA in allergic airway responses and an increased generation of protectin D1 and resolvin E1 in this context.


Asunto(s)
Asma/prevención & control , Proteínas de Caenorhabditis elegans/genética , Ácido Graso Desaturasas/genética , Ácidos Grasos Omega-3/metabolismo , Animales , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/inmunología , Proteínas de Caenorhabditis elegans/biosíntesis , Quimiocinas/metabolismo , Citocinas/metabolismo , Ácidos Docosahexaenoicos/metabolismo , Ácido Eicosapentaenoico/análogos & derivados , Ácido Eicosapentaenoico/metabolismo , Ácido Graso Desaturasas/biosíntesis , Femenino , Pulmón/metabolismo , Masculino , Ratones , Ratones Transgénicos , Hipersensibilidad Respiratoria/prevención & control
7.
Immunology ; 133(3): 288-95, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21466550

RESUMEN

CD248 (endosialin) is a transmembrane glycoprotein that is dynamically expressed on pericytes and fibroblasts during tissue development, tumour neovascularization and inflammation. Its role in tissue remodelling is associated with increased stromal cell proliferation and migration. We show that CD248 is also uniquely expressed by human, but not mouse (C57BL/6), CD8(+) naive T cells. CD248 is found only on CD8(+) CCR7(+) CD11a(low) naive T cells and on CD8 single-positive T cells in the thymus. Transfection of the CD248 negative T-cell line MOLT-4 with CD248 cDNA surprisingly reduced cell proliferation. Knock-down of CD248 on naive CD8 T cells increased cell proliferation. These data demonstrate opposing functions for CD248 on haematopoietic (CD8(+)) versus stromal cells and suggests that CD248 helps to maintain naive CD8(+) human T cells in a quiescent state.


Asunto(s)
Antígenos CD/metabolismo , Antígenos de Neoplasias/metabolismo , Linfocitos T CD8-positivos/inmunología , Células del Estroma/inmunología , Animales , Western Blotting , Proliferación Celular , Citometría de Flujo , Humanos , Ratones
8.
Am J Respir Crit Care Med ; 178(6): 574-82, 2008 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-18583575

RESUMEN

RATIONALE: Airway inflammation is common in severe asthma despite antiinflammatory therapy with corticosteroids. Lipoxin A(4) (LXA(4)) is an arachidonic acid-derived mediator that serves as an agonist for resolution of inflammation. OBJECTIVES: Airway levels of LXA(4), as well as the expression of lipoxin biosynthetic genes and receptors, in severe asthma. METHODS: Samples of bronchoalveolar lavage fluid were obtained from subjects with asthma and levels of LXA(4) and related eicosanoids were measured. Expression of lipoxin biosynthetic genes was determined in whole blood, bronchoalveolar lavage cells, and endobronchial biopsies by quantitative polymerase chain reaction, and leukocyte LXA(4) receptors were monitored by flow cytometry. MEASUREMENTS AND MAIN RESULTS: Individuals with severe asthma had significantly less LXA(4) in bronchoalveolar lavage fluids (11.2 +/- 2.1 pg/ml) than did subjects with nonsevere asthma (150.1 +/- 38.5 pg/ml; P < 0.05). In contrast, levels of cysteinyl leukotrienes were increased in both asthma cohorts compared with healthy individuals. In severe asthma, 15-lipoxygenase-1 mean expression was decreased fivefold in bronchoalveolar lavage cells. In contrast, 15-lipoxgenase-1 was increased threefold in endobronchial biopsies, but expression of both 5-lipoxygenase and 15-lipoxygenase-2 in these samples was decreased. Cyclooxygenase-2 expression was decreased in all anatomic compartments sampled in severe asthma. Moreover, LXA(4) receptor gene and protein expression were significantly decreased in severe asthma peripheral blood granulocytes. CONCLUSIONS: Mechanisms underlying pathological airway responses in severe asthma include lipoxin underproduction with decreased expression of lipoxin biosynthetic enzymes and receptors. Together, these results indicate that severe asthma is characterized, in part, by defective lipoxin counterregulatory signaling circuits.


Asunto(s)
Asma/metabolismo , Bronquios/metabolismo , Lipoxinas/biosíntesis , Receptores de Formil Péptido/metabolismo , Receptores de Lipoxina/metabolismo , Adulto , Asma/sangre , Líquido del Lavado Bronquioalveolar/química , Femenino , Citometría de Flujo , Humanos , Ácidos Hidroxieicosatetraenoicos/sangre , Lipoxinas/sangre , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa
9.
Front Immunol ; 10: 1699, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31396220

RESUMEN

Formerly considered as a passive process, the resolution of acute inflammation is now recognized as an active host response, with a cascade of coordinated cellular and molecular events that promotes termination of the inflammatory response and initiates tissue repair and healing. In a state of immune fitness, the resolution of inflammation is contained in time and space enabling the restoration of tissue homeostasis. There is increasing evidence that poor and/or inappropriate resolution of inflammation participates in the pathogenesis of chronic inflammatory diseases, extending in time the actions of pro-inflammatory mechanisms, and responsible in the long run for excessive tissue damage and pathology. In this review, we will focus on how resolution can be the target for therapy in "Th1/Th17 cell-driven" immune diseases and "Th2 cell-driven" immune diseases, with inflammatory bowel diseases (IBD) and asthma, as relevant examples. We describe the main cells and mediators stimulating the resolution of inflammation and discuss how pharmacological and dietary interventions but also life style factors, physical and psychological conditions, might influence the resolution phase. A better understanding of the impact of endogenous and exogenous factors on the resolution of inflammation might open a whole area in the development of personalized therapies in non-resolving chronic inflammatory diseases.


Asunto(s)
Asma/inmunología , Homeostasis/inmunología , Inflamación/inmunología , Enfermedades Inflamatorias del Intestino/inmunología , Animales , Enfermedad Crónica , Humanos , Mediadores de Inflamación/inmunología
10.
Oncogene ; 38(27): 5381-5395, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-30867568

RESUMEN

The molecular mechanisms leading to aryl hydrocarbon receptor interacting protein (AIP) mutation-induced aggressive, young-onset growth hormone-secreting pituitary tumors are not fully understood. In this study, we have identified that AIP-mutation-positive tumors are infiltrated by a large number of macrophages compared to sporadic tumors. Tissue from pituitary-specific Aip-knockout (AipFlox/Flox;Hesx1Cre/+) mice recapitulated this phenotype. Our human pituitary tumor transcriptome data revealed the "epithelial-to-mesenchymal transition (EMT) pathway" as one of the most significantly altered pathways in AIPpos tumors. Our in vitro data suggest that bone marrow-derived macrophage-conditioned media induces more prominent EMT-like phenotype and enhanced migratory and invasive properties in Aip-knockdown somatomammotroph cells compared to non-targeting controls. We identified that tumor-derived cytokine CCL5 is upregulated in AIP-mutation-positive human adenomas. Aip-knockdown GH3 cell-conditioned media increases macrophage migration, which is inhibited by the CCL5/CCR5 antagonist maraviroc. Our results suggest that a crosstalk between the tumor and its microenvironment plays a key role in the invasive nature of AIP-mutation-positive tumors and the CCL5/CCR5 pathway is a novel potential therapeutic target.


Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/genética , Mutación , Invasividad Neoplásica , Neoplasias Hipofisarias/genética , Microambiente Tumoral , Animales , Biomarcadores de Tumor/metabolismo , Quimiocina CCL5/metabolismo , Transición Epitelial-Mesenquimal , Humanos , Ratones , Ratones Noqueados , Receptores CCR5/metabolismo
11.
Cell Rep ; 27(5): 1461-1471.e4, 2019 04 30.
Artículo en Inglés | MEDLINE | ID: mdl-31042473

RESUMEN

B cell lymphoma-6 (BCL6) is highly expressed in germinal center B cells, but how its expression is maintained is still not completely clear. Aryl hydrocarbon receptor interacting protein (AIP) is a co-chaperone of heat shock protein 90. Deletion of Aip in B cells decreased BCL6 expression, reducing germinal center B cells and diminishing adaptive immune responses. AIP was required for optimal AKT signaling in response to B cell receptor stimulation, and AIP protected BCL6 from ubiquitin-mediated proteasomal degradation by the E3-ubiquitin ligase FBXO11 by binding to the deubiquitinase UCHL1, thus helping to maintain the expression of BCL6. AIP was highly expressed in primary diffuse large B cell lymphomas compared to healthy tissue and other tumors. Our findings describe AIP as a positive regulator of BCL6 expression with implications for the pathobiology of diffuse large B cell lymphoma.


Asunto(s)
Linfocitos B/inmunología , Centro Germinal/inmunología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Linfoma de Células B Grandes Difuso/inmunología , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Animales , Proteínas F-Box/metabolismo , Femenino , Centro Germinal/citología , Células HEK293 , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Masculino , Ratones , Persona de Mediana Edad , Complejo de la Endopetidasa Proteasomal/metabolismo , Unión Proteica , Proteína-Arginina N-Metiltransferasas/metabolismo , Proteolisis , Ubiquitina Tiolesterasa/metabolismo , Ubiquitinación
13.
J Leukoc Biol ; 79(2): 303-11, 2006 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-16330528

RESUMEN

Recent studies have demonstrated that neutrophils are not a homogenous population of cells. Here, we have identified a subset of human neutrophils with a distinct profile of cell-surface receptors [CD54(high), CXC chemokine receptor 1(low) (CXCR1(low))], which represent cells that have migrated through an endothelial monolayer and then re-emerged by reverse transmigration (RT). RT neutrophils, when in contact with endothelium, were rescued from apoptosis, demonstrate functional priming, and were rheologically distinct from neutrophils that had not undergone transendothelial migration. In vivo, 1-2% of peripheral blood neutrophils in patients with systemic inflammation exhibit a RT phenotype. A smaller population existed in healthy donors ( approximately 0.25%). RT neutrophils were distinct from naïve circulatory neutrophils (CD54(low), CXCR1(high)) and naïve cells after activation with formyl-Met-Leu-Phe (CD54(low), CXCR1(low)). It is important that the RT phenotype (CD54(high), CXCR1(low)) is also distinct from tissue-resident neutrophils (CD54(low), CXCR1(low)). Our results demonstrate that neutrophils can migrate in a retrograde direction across endothelial cells and suggest that a population of tissue-experienced neutrophils with a distinct phenotype and function are present in the peripheral circulation in humans in vivo.


Asunto(s)
Células Endoteliales/citología , Neutrófilos/clasificación , Neutrófilos/inmunología , Apoptosis/inmunología , Movimiento Celular/efectos de los fármacos , Movimiento Celular/inmunología , Células Cultivadas , Células Endoteliales/efectos de los fármacos , Humanos , Técnicas In Vitro , Fenotipo , Receptores de Superficie Celular/inmunología , Factores de Tiempo , Factor de Necrosis Tumoral alfa/farmacología , Venas Umbilicales/citología , Venas Umbilicales/efectos de los fármacos
14.
JCI Insight ; 1(5): e85922, 2016 Apr 21.
Artículo en Inglés | MEDLINE | ID: mdl-27158677

RESUMEN

Rheumatoid arthritis (RA) is a debilitating disease characterized by persistent accumulation of leukocytes within the articular cavity and synovial tissue. Metabololipidomic profiling of arthritic joints from omega-3 supplemented mice identified elevated levels of specialized proresolving lipid mediators (SPM) including resolvin D1 (RvD1). Profiling of human RA synovial fluid revealed physiological levels of RvD1, which - once applied to human neutrophils - attenuated chemotaxis. These results prompted analyses of the antiarthritic properties of RvD1 in a model of murine inflammatory arthritis. The stable epimer 17R-RvD1 (100 ng/day) significantly attenuated arthritis severity, cachexia, hind-paw edema, and paw leukocyte infiltration and shortened the remission interval. Metabololipidomic profiling in arthritic joints revealed 17R-RvD1 significantly reduced PGE2 biosynthesis, while increasing levels of protective SPM. Molecular analyses indicated that 17R-RvD1 enhanced expression of genes associated with cartilage matrix synthesis, and direct intraarticular treatment induced chondroprotection. Joint protective actions of 17R-RvD1 were abolished in RvD1 receptor-deficient mice termed ALX/fpr2/3-/- . These investigations open new therapeutic avenues for inflammatory joint diseases, providing mechanistic substance for the benefits of omega-3 supplementation in RA.

15.
FEBS Lett ; 579(12): 2569-75, 2005 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-15862292

RESUMEN

Fibroblasts are a diverse cell type and display clear topographic differentiation and positional memory. In a screen for fibroblast specific markers we have characterized four monoclonal antibodies to endosialin (TEM1/CD248). Previous studies have reported that endosialin is a tumour endothelium marker and is localized intracellularly. We demonstrate conclusively that endosialin is a cell surface glycoprotein and is predominantly expressed by fibroblasts and a subset of pericytes associated with tumour vessels but not by tumour endothelium. These novel antibodies will facilitate the isolation and classification of fibroblast and pericyte lineages as well as the further functional analysis of endosialin.


Asunto(s)
Biomarcadores/metabolismo , Endotelio Vascular/metabolismo , Fibroblastos/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Células del Estroma/metabolismo , Animales , Anticuerpos Monoclonales/metabolismo , Antígenos CD , Antígenos de Neoplasias , Células COS , Línea Celular Tumoral , Células Cultivadas , Chlorocebus aethiops , Citometría de Flujo , Técnica del Anticuerpo Fluorescente Indirecta , Colorantes Fluorescentes , Células HL-60 , Células HeLa , Humanos , Radioisótopos de Yodo/metabolismo , Pericitos/metabolismo , Pruebas de Precipitina , Succinimidas , Venas Umbilicales/citología
16.
Joint Bone Spine ; 72(1): 10-6, 2005 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-15681242

RESUMEN

Rheumatoid arthritis (RA) is a debilitating, chronic, persistent inflammatory disease that is characterised by painful and swollen joints. The aetiology of RA is unknown, however whereas past research has concentrated on the role of immune or inflammatory infiltrating cells in inflammation, it is becoming clear that stromal cells play a critical part in regulating the quality and duration of an inflammatory response. In this review we assess the role of fibroblasts within the inflamed synovium in modulating immune responses; in particular we examine the role of stromal cells in the switch from resolving to persistent inflammation as is found in the rheumatoid synovium.


Asunto(s)
Artritis Reumatoide/inmunología , Artritis Reumatoide/patología , Comunicación Celular/inmunología , Leucocitos/citología , Células del Estroma/citología , Animales , Enfermedad Crónica , Humanos , Leucocitos/inmunología , Sinovitis/inmunología , Sinovitis/patología
18.
Neuron ; 87(2): 341-54, 2015 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-26119026

RESUMEN

Lung nociceptors initiate cough and bronchoconstriction. To elucidate if these fibers also contribute to allergic airway inflammation, we stimulated lung nociceptors with capsaicin and observed increased neuropeptide release and immune cell infiltration. In contrast, ablating Nav1.8(+) sensory neurons or silencing them with QX-314, a charged sodium channel inhibitor that enters via large-pore ion channels to specifically block nociceptors, substantially reduced ovalbumin- or house-dust-mite-induced airway inflammation and bronchial hyperresponsiveness. We also discovered that IL-5, a cytokine produced by activated immune cells, acts directly on nociceptors to induce the release of vasoactive intestinal peptide (VIP). VIP then stimulates CD4(+) and resident innate lymphoid type 2 cells, creating an inflammatory signaling loop that promotes allergic inflammation. Our results indicate that nociceptors amplify pathological adaptive immune responses and that silencing these neurons with QX-314 interrupts this neuro-immune interplay, revealing a potential new therapeutic strategy for asthma.


Asunto(s)
Remodelación de las Vías Aéreas (Respiratorias)/inmunología , Nociceptores/fisiología , Hipersensibilidad Respiratoria/inmunología , Anestésicos Locales/farmacología , Animales , Animales Recién Nacidos , Capsaicina/farmacología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Adyuvante de Freund/toxicidad , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Interleucina-5/metabolismo , Lidocaína/análogos & derivados , Lidocaína/farmacología , Ratones , Nociceptores/efectos de los fármacos , Nociceptores/metabolismo , Ovalbúmina/toxicidad , Hipersensibilidad Respiratoria/inducido químicamente , Factores de Tiempo , Péptido Intestinal Vasoactivo/metabolismo
19.
Arthritis Res Ther ; 15(5): R108, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24016860

RESUMEN

INTRODUCTION: Monocytic cells play a central role in the aetiology of rheumatoid arthritis, and manipulation of the activation of these cells is an approach currently under investigation to discover new therapies for this and associated diseases. CD148 is a transmembrane tyrosine phosphatase that is highly expressed in monocytes and macrophages and, since this family of molecules plays an important role in the regulation of cell activity, CD148 is a potential target for the manipulation of macrophage activation. For any molecule to be considered a therapeutic target, it is important for it to be increased in activity or expression during disease. METHODS: We have investigated the expression of CD148 in two murine models of arthritis and in joints from rheumatoid arthritis (RA) patients using real-time PCR, immunohistochemistry, and studied the effects of proinflammatory stimuli on CD148 activity using biochemical assays. RESULTS: We report that CD148 mRNA is upregulated in diseased joints of mice with collagen-induced arthritis. Furthermore, we report that in mice CD148 protein is highly expressed in infiltrating monocytes of diseased joints, with a small fraction of T cells also expressing CD148. In human arthritic joints both T cells and monocytes expressed high levels of CD148, however, we show differential expression of CD148 in T cells and monocytes from normal human peripheral blood compared to peripheral blood from RA and both normal and RA synovial fluid. Finally, we show that synovial fluid from rheumatoid arthritis patients suppresses CD148 phosphatase activity. CONCLUSIONS: CD148 is upregulated in macrophages and T cells in human RA samples, and its activity is enhanced by treatment with tumour necrosis factor alpha (TNFα), and reduced by synovial fluid or oxidising conditions. A greater understanding of the role of CD148 in chronic inflammation may lead to alternative therapeutic approaches to these diseases.


Asunto(s)
Artritis Experimental/genética , Artritis Reumatoide/genética , Perfilación de la Expresión Génica , Leucocitos Mononucleares/metabolismo , Animales , Artritis Experimental/metabolismo , Artritis Experimental/patología , Artritis Reumatoide/metabolismo , Artritis Reumatoide/patología , Humanos , Peróxido de Hidrógeno/farmacología , Inmunohistoquímica , Articulaciones/metabolismo , Articulaciones/patología , Leucocitos Mononucleares/patología , Macrófagos/metabolismo , Macrófagos/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Microscopía Confocal , Monocitos/metabolismo , Monocitos/patología , Oxidantes/farmacología , Proteínas Tirosina Fosfatasas Clase 3 Similares a Receptores/genética , Proteínas Tirosina Fosfatasas Clase 3 Similares a Receptores/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Líquido Sinovial/metabolismo , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo , Linfocitos T/patología , Factor de Necrosis Tumoral alfa/farmacología , Regulación hacia Arriba
20.
Arthritis Res Ther ; 12(4): R161, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-20738854

RESUMEN

INTRODUCTION: Monocytes/macrophages accumulate in the rheumatoid (RA) synovium where they play a central role in inflammation and joint destruction. Identification of molecules involved in their accumulation and differentiation is important to inform therapeutic strategies. This study investigated the expression and function of chemokine receptor CCR9 in the peripheral blood (PB) and synovium of RA, non-RA patients and healthy volunteers. METHODS: CCR9 expression on PB monocytes/macrophages was analysed by flow cytometry and in synovium by immunofluorescence. Chemokine receptor CCR9 mRNA expression was examined in RA and non-RA synovium, monocytes/macrophages from PB and synovial fluid (SF) of RA patients and PB of healthy donors using the reverse transcription polymerase chain reaction (RT-PCR). Monocyte differentiation and chemotaxis to chemokine ligand 25 (CCL25)/TECK were used to study CCR9 function. RESULTS: CCR9 was expressed by PB monocytes/macrophages in RA and healthy donors, and increased in RA. In RA and non-RA synovia, CCR9 co-localised with cluster of differentiation 14+ (CD14+) and cluster of differentiation 68+ (CD68+) macrophages, and was more abundant in RA synovium. CCR9 mRNA was detected in the synovia of all RA patients and in some non-RA controls, and monocytes/macrophages from PB and SF of RA and healthy controls. CCL25 was detected in RA and non-RA synovia where it co-localised with CD14+ and CD68+ cells. Tumour necrosis factor alpha (TNFα) increased CCR9 expression on human acute monocytic leukemia cell line THP-1 monocytic cells. CCL25 induced a stronger monocyte differentiation in RA compared to healthy donors. CCL25 induced significant chemotaxis of PB monocytes but not consistently among individuals. CONCLUSIONS: CCR9 expression by monocytes is increased in RA. CCL25 may be involved in the differentiation of monocytes to macrophages particularly in RA.


Asunto(s)
Artritis Reumatoide/patología , Quimiocinas CC/genética , Macrófagos/patología , Monocitos/patología , Receptores CCR/genética , Adulto , Anciano , Anciano de 80 o más Años , Artritis Reumatoide/inmunología , Artritis Reumatoide/metabolismo , Diferenciación Celular/inmunología , Línea Celular , Quimiocinas CC/metabolismo , Femenino , Citometría de Flujo , Humanos , Macrófagos/inmunología , Macrófagos/metabolismo , Masculino , Persona de Mediana Edad , Monocitos/inmunología , Monocitos/metabolismo , Receptores CCR/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Membrana Sinovial/inmunología , Membrana Sinovial/metabolismo , Membrana Sinovial/patología , Factor de Necrosis Tumoral alfa/farmacología , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/inmunología
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