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1.
Nature ; 442(7101): 461-5, 2006 Jul 27.
Artículo en Inglés | MEDLINE | ID: mdl-16688182

RESUMEN

Chronic inflammation has long been associated with increased incidence of malignancy and similarities in the regulatory mechanisms have been suggested for more than a century. Infiltration of innate immune cells, elevated activities of matrix metalloproteases and increased angiogenesis and vasculature density are a few examples of the similarities between chronic and tumour-associated inflammation. Conversely, the elimination of early malignant lesions by immune surveillance, which relies on the cytotoxic activity of tumour-infiltrating T cells or intra-epithelial lymphocytes, is thought to be rate-limiting for the risk to develop cancer. Here we show a molecular connection between the rise in tumour-associated inflammation and a lack of tumour immune surveillance. Expression of the heterodimeric cytokine interleukin (IL)-23, but not of its close relative IL-12, is increased in human tumours. Expression of these cytokines antagonistically regulates local inflammatory responses in the tumour microenvironment and infiltration of intra-epithelial lymphocytes. Whereas IL-12 promotes infiltration of cytotoxic T cells, IL-23 promotes inflammatory responses such as upregulation of the matrix metalloprotease MMP9, and increases angiogenesis but reduces CD8 T-cell infiltration. Genetic deletion or antibody-mediated elimination of IL-23 leads to increased infiltration of cytotoxic T cells into the transformed tissue, rendering a protective effect against chemically induced carcinogenesis. Finally, transplanted tumours are growth-restricted in hosts depleted for IL-23 or in IL-23-receptor-deficient mice. Although many strategies for immune therapy of cancer attempt to stimulate an immune response against solid tumours, infiltration of effector cells into the tumour tissue often appears to be a critical hurdle. We show that IL-23 is an important molecular link between tumour-promoting pro-inflammatory processes and the failure of the adaptive immune surveillance to infiltrate tumours.


Asunto(s)
Interleucinas/metabolismo , Neoplasias/metabolismo , Neoplasias/patología , Animales , Linfocitos T CD8-positivos/inmunología , División Celular , Predisposición Genética a la Enfermedad , Humanos , Inflamación/genética , Inflamación/patología , Interleucina-12/biosíntesis , Interleucina-12/inmunología , Interleucina-23 , Subunidad p19 de la Interleucina-23 , Interleucinas/biosíntesis , Interleucinas/deficiencia , Interleucinas/genética , Ratones , Ratones Endogámicos C57BL , Neoplasias/genética , Neoplasias/inmunología , Transducción de Señal
2.
J Exp Med ; 201(2): 233-40, 2005 Jan 17.
Artículo en Inglés | MEDLINE | ID: mdl-15657292

RESUMEN

Interleukin (IL)-23 is a heterodimeric cytokine composed of a unique p19 subunit, and a common p40 subunit shared with IL-12. IL-12 is important for the development of T helper (Th)1 cells that are essential for host defense and tumor suppression. In contrast, IL-23 does not promote the development of interferon-gamma-producing Th1 cells, but is one of the essential factors required for the expansion of a pathogenic CD4(+) T cell population, which is characterized by the production of IL-17, IL-17F, IL-6, and tumor necrosis factor. Gene expression analysis of IL-23-driven autoreactive T cells identified a unique expression pattern of proinflammatory cytokines and other novel factors, distinguishing them from IL-12-driven T cells. Using passive transfer studies, we confirm that these IL-23-dependent CD4(+) T cells are highly pathogenic and essential for the establishment of organ-specific inflammation associated with central nervous system autoimmunity.


Asunto(s)
Autoinmunidad/inmunología , Linfocitos T CD4-Positivos/metabolismo , Inflamación/inmunología , Interleucinas/metabolismo , Animales , Autoinmunidad/fisiología , Linfocitos T CD4-Positivos/patología , Sistema Nervioso Central/citología , Sistema Nervioso Central/metabolismo , Citocinas/metabolismo , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/metabolismo , Expresión Génica/fisiología , Perfilación de la Expresión Génica , Inflamación/metabolismo , Interleucina-12/metabolismo , Interleucina-17/metabolismo , Interleucina-23 , Subunidad p19 de la Interleucina-23 , Ratones , Factores de Tiempo
3.
Exp Lung Res ; 37(4): 227-38, 2011 May.
Artículo en Inglés | MEDLINE | ID: mdl-21309737

RESUMEN

Idiopathic interstitial pneumonias are a group of idiopathic interstitial lung diseases of which idiopathic pulmonary fibrosis (IPF) is the lesion of usual interstitial pneumonia. Although the pathogenic mechanisms remain incompletely understood, disease-specific changes in blood, a readily accessible biospecimen, have not been fully characterized. To identify biomarkers from blood and sera, the immune status of IPF patients and control subjects without structural lung disease was quantified by measuring cell surface markers, mRNA levels, and serum proteins. Statistically significant differences in cellular and molecular markers were observed between the 2 groups. The cytokine receptor IL-17RB was significantly higher in CD14+ peripheral blood mononuclear cells (PBMCs) from IPF patients, whereas expression of the chemokine receptor CXCR4 was lower. Gene expression analyses identified 18 differentially expressed genes out of 195 selected. Of these, EMR1, CCR3, UPAR, FCGR2A, OPN, CEACAM3, CD16a, CD18, CD11b, LTF, and LCN2 were up-regulated, whereas IL-17RB, IL-10, PDGFA, CD301/Clec10a, CD25/IL-2RA, IL-23p19, and IL-15 were down-regulated in IPF. Differentially regulated genes were in the functional areas of inflammation and cell signaling. Serum levels of UPAR and OPN were higher in IPF. These observations reveal significant differences in cell and molecular markers involved in monocyte/macrophage activation and migration, and suggest a role for IL-17RB in IPF.


Asunto(s)
Fibrosis Pulmonar Idiopática/patología , Macrófagos/patología , Monocitos/patología , Anciano , Anciano de 80 o más Años , Biomarcadores/análisis , Movimiento Celular , Humanos , Activación de Macrófagos , Macrófagos/metabolismo , Masculino , Persona de Mediana Edad , Monocitos/metabolismo , Receptores de Interleucina/fisiología , Receptores de Interleucina-17
4.
J Clin Invest ; 116(5): 1310-6, 2006 May.
Artículo en Inglés | MEDLINE | ID: mdl-16670770

RESUMEN

Uncontrolled mucosal immunity in the gastrointestinal tract of humans results in chronic inflammatory bowel disease (IBD), such as Crohn disease and ulcerative colitis. In early clinical trials as well as in animal models, IL-12 has been implicated as a major mediator of these diseases based on the ability of anti-p40 mAb treatment to reverse intestinal inflammation. The cytokine IL-23 shares the same p40 subunit with IL-12, and the anti-p40 mAbs used in human and mouse IBD studies neutralized the activities of both IL-12 and IL-23. IL-10-deficient mice spontaneously develop enterocolitis. To determine how IL-23 contributes to intestinal inflammation, we studied the disease susceptibility in the absence of either IL-23 or IL-12 in this model, as well as the ability of recombinant IL-23 to exacerbate IBD induced by T cell transfer. Our study shows that in these models, IL-23 is essential for manifestation of chronic intestinal inflammation, whereas IL-12 is not. A critical target of IL-23 is a unique subset of tissue-homing memory T cells, which are specifically activated by IL-23 to produce the proinflammatory mediators IL-17 and IL-6. This pathway may be responsible for chronic intestinal inflammation as well as other chronic autoimmune inflammatory diseases.


Asunto(s)
Colitis/patología , Inflamación/patología , Interleucina-17/fisiología , Interleucina-6/fisiología , Interleucinas/fisiología , Linfocitos T/patología , Animales , Enfermedades Autoinmunes/patología , Humanos , Interleucina-23 , Subunidad p19 de la Interleucina-23 , Mucosa Intestinal/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Linfocitos T/metabolismo
6.
Exp Lung Res ; 34(10): 631-62, 2008 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19085563

RESUMEN

Chronic obstructive pulmonary diseases (COPD) may increase air pollution-related mortality. The relationship of immune mechanisms to mortality caused by fine particulates in healthy and COPD populations is incompletely understood. The objective of this study was to determine whether fine particulates from a single biomass fuel alter stress and inflammation biomarkers in people with COPD. Healthy and COPD subjects were exposed to smoke in a controlled indoor setting. Immune responses were quantified by measuring cell surface marker expression with flow-cytometric analysis and mRNA levels with quantitative reverse transcriptase-polymerase chain reactions in whole blood before and after exposure. Preexposure COPD subjects had more leukocytes, mainly CD14(+) monocytes and neutrophils, but fewer CD3(+) T cells. Fifty-seven of 186 genes were differentially expressed between healthy and COPD subjects' peripheral blood mononuclear cells (PBMCs). Of these, only nuclear factor (NF)-kappa B1, TIMP-1, TIMP-2, and Duffy genes were up-regulated in COPD subjects. At 4 hours post smoke exposure, monocyte levels decreased only in healthy subjects. Fifteen genes, particular to inflammation, immune response, and cell-to-cell signaling, were differentially expressed in COPD subjects, versus 4 genes in healthy subjects. The authors observed significant differences in subjects' PBMCs, which may elucidate the adverse effects of air pollution particulates on people with COPD.


Asunto(s)
Biomasa , Material Particulado/efectos adversos , Enfermedad Pulmonar Obstructiva Crónica/inmunología , Humo/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores , Enfermedades Cardiovasculares/etiología , Citometría de Flujo , Perfilación de la Expresión Génica , Antígenos HLA-DR/análisis , Humanos , Inmunofenotipificación , Receptores de Lipopolisacáridos/análisis , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
7.
Cell Rep ; 3(5): 1378-88, 2013 May 30.
Artículo en Inglés | MEDLINE | ID: mdl-23623497

RESUMEN

Interleukin-23 (IL-23) is essential for the differentiation of pathogenic effector T helper 17 (Th17) cells, but its role in memory Th17 cell responses is unclear. Using the experimental autoimmune encephalomyelitis (EAE) model, we report that memory Th17 cells rapidly expanded in response to rechallenge and migrated to the CNS in high numbers, resulting in earlier onset and increased severity of clinical disease. Memory Th17 cells were generated from IL-17+ and RORγt+ precursors, and the stability of the Th17 cell phenotype depended on the amount of time allowed for the primary response. IL-23 was required for this enhanced recall response. IL-23 receptor blockade did not directly impact IL-17 production, but did impair the subsequent proliferation and generation of effectors coexpressing the Th1 cell-specific transcription factor T-bet. In addition, many genes required for cell-cycle progression were downregulated in Th17 cells that lacked IL-23 signaling, showing that a major mechanism for IL-23 in primary and memory Th17 cell responses operates via regulation of proliferation-associated pathways.


Asunto(s)
Interleucina-23/metabolismo , Células Th17/metabolismo , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/trasplante , Citocinas/metabolismo , Regulación de la Expresión Génica , Interleucina-17/metabolismo , Ratones , Ratones Endogámicos C57BL , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Transducción de Señal , Proteínas de Dominio T Box/metabolismo , Células Th17/citología , Células Th17/inmunología , Trasplante Homólogo
8.
Biomark Insights ; 7: 87-104, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22837640

RESUMEN

BACKGROUND: Biomarkers facilitate early detection of disease and measurement of therapeutic efficacy, both at clinical and experimental levels. Recent advances in analytics and disease models allow comprehensive screening for biomarkers in complex diseases, such as asthma, that was previously not feasible. OBJECTIVE: Using murine and nonhuman primate (NHP) models of asthma, identify biomarkers associated with early and chronic stages of asthma and responses to steroid treatment. METHODS: The total protein content from thymic stromal lymphopoietin transgenic (TSLP Tg) mouse BAL fluid was ascertained by shotgun proteomics analysis. A subset of these potential markers was further analyzed in BAL fluid, BAL cell mRNA, and lung tissue mRNA during the stages of asthma and following corticosteroid treatment. Validation was conducted in murine and NHP models of allergic asthma. RESULTS: Over 40 proteins were increased in the BAL fluid of TSLP Tg mice that were also detected by qRT-PCR in lung tissue and BAL cells, as well as in OVA-sensitive mice and house dust mite-sensitive NHP. Previously undescribed as asthma biomarkers, KLK1, Reg3γ, ITLN2, and LTF were modulated in asthmatic mice, and Clca3, Chi3l4 (YM2), and Ear11 were the first lung biomarkers to increase during disease and the last biomarkers to decline in response to therapy. In contrast, GP-39, LCN2, sICAM-1, YM1, Epx, Mmp12, and Klk1 were good indicators of early therapeutic intervention. In NHP, AMCase, sICAM-1, CLCA1, and GP-39 were reduced upon treatment with corticosteroids. CONCLUSIONS AND CLINICAL RELEVANCE: These results significantly advance our understanding of the biomarkers present in various tissue compartments in animal models of asthma, including those induced early during asthma and modulated with therapeutic intervention, and show that BAL cells (or their surrogate, induced sputum cells) are a viable choice for biomarker examination.

9.
Nat Immunol ; 8(9): 950-7, 2007 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-17676044

RESUMEN

T(H)-17 cells are a distinct lineage of proinflammatory T helper cells that are essential for autoimmune disease. In mice, commitment to the T(H)-17 lineage is dependent on transforming growth factor-beta and interleukin 6 (IL-6). Here we demonstrate that IL-23 and IL-1beta induced the development of human T(H)-17 cells expressing IL-17A, IL-17F, IL-22, IL-26, interferon-gamma, the chemokine CCL20 and transcription factor RORgammat. In situ, T(H)-17 cells were identified by expression of the IL-23 receptor and the memory T cell marker CD45RO. Psoriatic skin lesions contained IL-23-producing dendritic cells and were enriched in the cytokines produced by human T(H)-17 cells that promote the production of antimicrobial peptides in human keratinocytes. Our data collectively indicate that human and mouse T(H)-17 cells require distinct factors during differentiation and that human T(H)-17 cells may regulate innate immunity in epithelial cells.


Asunto(s)
Diferenciación Celular/inmunología , Citocinas/inmunología , Interleucina-17/biosíntesis , Subgrupos de Linfocitos T/citología , Linfocitos T Colaboradores-Inductores/citología , Péptidos Catiónicos Antimicrobianos/biosíntesis , Células Cultivadas , Ensayo de Inmunoadsorción Enzimática , Células Epiteliales/inmunología , Citometría de Flujo , Humanos , Inmunohistoquímica , Interleucina-23/metabolismo , Reacción en Cadena de la Polimerasa , Psoriasis/inmunología , Subgrupos de Linfocitos T/inmunología , Linfocitos T Colaboradores-Inductores/inmunología
10.
Infect Immun ; 74(11): 6092-9, 2006 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-16923792

RESUMEN

Interleukin-23 (IL-23), a member of the IL-12 family, is a heterodimeric cytokine that is composed of the p40 subunit of IL-12 plus a unique p19 subunit. IL-23 is critical for autoimmune inflammation, in part due to its stimulation of the proinflammatory cytokine IL-17A. It is less clear, however, if IL-23 is required during the immune response to pathogens. We examined the role of IL-23 during Mycobacterium bovis BCG infection. We found that IL-23 reduces the bacterial burden and promotes granuloma formation when IL-12 is absent. However, IL-23 does not contribute substantially to host resistance when IL-12 is present, as the ability to control bacterial growth and form granulomata is not affected in IL-23p19-deficient mice and mice treated with a specific anti-IL-23p19 antibody. IL-23p19-deficient mice are also able to mount an effective memory response to secondary infection with BCG. While IL-23p19-deficient mice do not produce IL-17A, this cytokine is not necessary for effective control of infection, and antibody blocking of IL-17A in both wild-type and IL-12-deficient mice also has little effect on the bacterial burden. These data suggest that IL-23 by itself does not play an essential role in the protective immune response to BCG infection; however, the presence of IL-23 can partially compensate for the absence of IL-12. Furthermore, neutralization of IL-23 or IL-17A does not increase susceptibility to mycobacterial BCG infection.


Asunto(s)
Interleucina-23/antagonistas & inhibidores , Interleucina-23/genética , Transducción de Señal/genética , Transducción de Señal/inmunología , Tuberculosis/inmunología , Animales , Femenino , Granuloma/genética , Granuloma/inmunología , Interleucina-12/biosíntesis , Interleucina-12/deficiencia , Interleucina-12/genética , Interleucina-23/deficiencia , Interleucina-23/fisiología , Subunidad p19 de la Interleucina-23/deficiencia , Subunidad p19 de la Interleucina-23/genética , Subunidad p19 de la Interleucina-23/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mycobacterium bovis/inmunología , Receptores de Interleucina/biosíntesis , Receptores de Interleucina/genética , Tuberculosis/genética
11.
Immunology ; 117(2): 177-87, 2006 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-16423053

RESUMEN

Immunoglobulin E (IgE)-mediated late-phase reactions can be induced in atopic humans by intradermal injection of relevant allergens or anti-IgE antibodies. The histology of these reactions resembles that of naturally occurring atopic dermatitis. Strikingly similar responses can be induced in dogs, suggesting that a canine model could prove valuable for preclinical investigation of drugs targeting late-phase reactions. This study was designed to characterize the cellular, cytokine and chemokine responses after intradermal anti-IgE injection in untreated and prednisolone-treated dogs. Normal beagles were untreated or treated with prednisolone before intradermal injection of polyclonal rabbit anti-canine IgE or normal rabbit IgG. Biopsies were taken before injection and 6, 24 and 48 hr after injection. Samples were evaluated by histological and immunohistochemical staining, as well as by real-time quantitative polymerase chain reaction analysis. Dermal eosinophil and neutrophil numbers increased dramatically within 6 hr after injection of rabbit anti-canine IgE, and remained moderately elevated at 48 hr. The numbers of CD1c(+) and CD3(+) mononuclear cells were also increased at 6 hr. The real-time quantitative polymerase chain reaction demonstrated marked increases in mRNA expression for interleukin-13 (IL-13), CCL2, CCL5 and CCL17. Levels of mRNA for IL-2, IL-4, IL-6 and IFN-gamma did not change within the limits of detection. Prednisolone administration suppressed the influx of neutrophils, eosinophils, CD1c(+) and CD3(+) cells, as well as expression of IL-13, CCL2, CCL5 and CCL17. These data document the cytokine and chemokine responses to anti-IgE injection in canine skin, and they demonstrate the ability of the model to characterize the anti-inflammatory effects of a known therapeutic agent.


Asunto(s)
Antiinflamatorios/uso terapéutico , Dermatitis Atópica/inmunología , Dermatitis Atópica/prevención & control , Modelos Animales de Enfermedad , Prednisolona/uso terapéutico , Animales , Anticuerpos Antiidiotipos/inmunología , Quimiotaxis de Leucocito/efectos de los fármacos , Dermatitis Atópica/patología , Perros , Eosinófilos/inmunología , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Inmunoglobulina E/inmunología , Inmunofenotipificación , Inyecciones Intradérmicas , Masculino , Mastocitos/patología , Neutrófilos/inmunología , Reacción en Cadena de la Polimerasa/métodos , Piel/inmunología
12.
J Immunol ; 172(4): 2225-31, 2004 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-14764690

RESUMEN

The recently discovered cytokine IL-27 belongs to the IL-6/IL-12 family of cytokines and induced proliferation of naive CD4(+) T cells and the generation of a Th1-type adaptive immune response. Although binding of IL-27 to the cytokine receptor WSX-1 was demonstrated, this interaction proved insufficient to mediate cellular effects. Hence, IL-27 was believed to form a heteromeric signaling receptor complex with WSX-1 and another, yet to be identified, cytokine receptor subunit. In this study, we describe that WSX-1 together with gp130 constitutes a functional signal-transducing receptor for IL-27. We show that neither of the two subunits itself is sufficient to mediate IL-27-induced signal transduction, but that the combination of both is required for this event. Expression analysis of WSX-1 and gp130 by quantitative PCR suggests that IL-27 might have a variety of cellular targets besides naive CD4(+) T cells: we demonstrate gene induction of a subset of inflammatory cytokines in primary human mast cells and monocytes in response to IL-27 stimulation. Thus, IL-27 not only contributes to the development of an adaptive immune response through its action on CD4(+) T cells, it also directly acts on cells of the innate immune system.


Asunto(s)
Antígenos CD/fisiología , Interleucinas/fisiología , Glicoproteínas de Membrana/fisiología , Receptores de Citocinas/fisiología , Transducción de Señal/inmunología , Animales , Anticuerpos Bloqueadores/farmacología , Anticuerpos Monoclonales/farmacología , Antígenos CD/biosíntesis , Antígenos CD/inmunología , Antígenos CD/metabolismo , Comunicación Autocrina/inmunología , Línea Celular Tumoral , Células Cultivadas , Receptor gp130 de Citocinas , Citocinas/biosíntesis , Citocinas/genética , Proteínas de Unión al ADN/antagonistas & inhibidores , Proteínas de Unión al ADN/metabolismo , Regulación de la Expresión Génica/inmunología , Humanos , Mediadores de Inflamación/metabolismo , Interleucinas/antagonistas & inhibidores , Mastocitos/inmunología , Mastocitos/metabolismo , Glicoproteínas de Membrana/biosíntesis , Glicoproteínas de Membrana/inmunología , Glicoproteínas de Membrana/metabolismo , Ratones , Monocitos/inmunología , Monocitos/metabolismo , Células 3T3 NIH , Fosforilación , ARN Mensajero/biosíntesis , Receptores de Citocinas/biosíntesis , Receptores de Interleucina , Factor de Transcripción STAT1 , Factor de Transcripción STAT3 , Transactivadores/antagonistas & inhibidores , Transactivadores/metabolismo , Transcripción Genética/inmunología , Activación Transcripcional , Tirosina/metabolismo
13.
Immunity ; 16(6): 779-90, 2002 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-12121660

RESUMEN

An efficient Th1-driven adaptive immune response requires activation of the T cell receptor and secretion of the T cell stimulatory cytokine IL-12 by activated antigen-presenting cells. IL-12 triggers Th1 polarization of naive CD4(+) T cells and secretion of IFN-gamma. We describe a new heterodimeric cytokine termed IL-27 that consists of EBI3, an IL-12p40-related protein, and p28, a newly discovered IL-12p35-related polypeptide. IL-27 is an early product of activated antigen-presenting cells and drives rapid clonal expansion of naive but not memory CD4(+) T cells. It also strongly synergizes with IL-12 to trigger IFN-gamma production of naive CD4(+) T cells. IL-27 mediates its biologic effects through the orphan cytokine receptor WSX-1/TCCR.


Asunto(s)
Linfocitos T CD4-Positivos/fisiología , Proteínas Portadoras/análisis , Glutatión Transferasa , Glicoproteínas/análisis , Interleucinas/fisiología , Células TH1/inmunología , Secuencia de Aminoácidos , Células Presentadoras de Antígenos/metabolismo , División Celular , Dimerización , Interferón gamma/biosíntesis , Interleucina-12/fisiología , Interleucinas/química , Antígenos de Histocompatibilidad Menor , Datos de Secuencia Molecular , Conformación Proteica , Receptores de Citocinas/metabolismo , Receptores de Interleucina , Alineación de Secuencia
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