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1.
Blood ; 117(24): 6562-70, 2011 Jun 16.
Artículo en Inglés | MEDLINE | ID: mdl-21508410

RESUMEN

Whereas the final differentiation of conventional dendritic cells (CDCs) from committed precursors occurs locally in secondary lymphoid or peripheral tissues, plasmacytoid dendritic cells (PDCs) are thought to fully develop in the bone marrow from common DC progenitors before migrating to the periphery. In our study, we define, for the first time, a subpopulation of CCR9(-) major histocompatibility complex class II(low) PDCs in murine bone marrow, which express E2-2 and are immediate precursors of CCR9(+) fully differentiated PDCs. However, CCR9(-) PDCs have the plasticity to acquire the phenotype and function of CD11b(+) CD8α(-) major histocompatibility complex class II(high) CDC-like cells under the influence of soluble factors produced by intestinal epithelial cells or recombinant GM-CSF. This deviation from the PDC lineage commitment is regulated on the level of transcription factors reflected by down-regulation of E2-2 and up-regulation of ID2, PU.1, and BATF3. Thus, CCR9(-) PDCs are immediate PDC precursors that can be reprogrammed to differentiate into CDC-like cells with higher antigen-presenting and cytokine-producing capacity under the influence of the local tissue microenvironment.


Asunto(s)
Diferenciación Celular , Células Dendríticas/citología , Células Dendríticas/fisiología , Receptores CCR/metabolismo , Células Madre/fisiología , Animales , Presentación de Antígeno/fisiología , Antígeno CD11b/metabolismo , Diferenciación Celular/genética , Diferenciación Celular/fisiología , Separación Celular/métodos , Células Cultivadas , Células Dendríticas/metabolismo , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Fenotipo , Células Madre/citología , Células Madre/metabolismo
2.
Gastroenterology ; 141(3): 959-71, 2011 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-21699778

RESUMEN

BACKGROUND & AIMS: Matrix metalloproteases (MMPs) mediate pathogenesis of chronic intestinal inflammation. We characterized the role of the gelatinase (GelE), a metalloprotease from Enterococcus faecalis, in the development of colitis in mice. METHODS: Germ-free, interleukin-10-deficient (IL-10(-/-)) mice were monoassociated with the colitogenic E faecalis strain OG1RF and isogenic, GelE-mutant strains. Barrier function was determined by measuring E-cadherin expression, transepithelial electrical resistance (TER), and translocation of permeability markers in colonic epithelial cells and colon segments from IL-10(-/-) and TNF(ΔARE/Wt) mice. GelE specificity was shown with the MMP inhibitor marimastat. RESULTS: Histologic analysis (score 0-4) of E faecalis monoassociated IL-10(-/-) mice revealed a significant reduction in colonic tissue inflammation in the absence of bacteria-derived GelE. We identified cleavage sites for GelE in the sequence of recombinant mouse E-cadherin, indicating that it might be degraded by GelE. Experiments with Ussing chambers and purified GelE revealed the loss of barrier function and extracellular E-cadherin in mice susceptible to intestinal inflammation (IL-10(-/-) and TNF(ΔARE/Wt) mice) before inflammation developed. Colonic epithelial cells had reduced TER and increased translocation of permeability markers after stimulation with GelE from OG1RF or strains of E faecalis isolated from patients with Crohn's disease and ulcerative colitis. CONCLUSIONS: The metalloprotease GelE, produced by commensal strains of E faecalis, contributes to development of chronic intestinal inflammation in mice that are susceptible to intestinal inflammation (IL-10(-/-) and TNF(ΔARE/Wt) mice) by impairing epithelial barrier integrity.


Asunto(s)
Permeabilidad de la Membrana Celular/fisiología , Colitis/fisiopatología , Enterococcus faecalis/metabolismo , Gelatinasas/metabolismo , Infecciones por Bacterias Grampositivas/fisiopatología , Mucosa Intestinal/metabolismo , Metaloproteasas/metabolismo , Animales , Linfocitos T CD4-Positivos/fisiología , Cadherinas/metabolismo , Colitis/etiología , Colitis/metabolismo , Modelos Animales de Enfermedad , Infecciones por Bacterias Grampositivas/complicaciones , Infecciones por Bacterias Grampositivas/metabolismo , Interleucina-10/genética , Interleucina-10/metabolismo , Mucosa Intestinal/citología , Ratones , Ratones Noqueados , Ratones Mutantes , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo
3.
Cancer Res ; 67(18): 8519-26, 2007 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-17875691

RESUMEN

Caveolin-1 is a scaffold protein of caveolae that acts as a tumor modulator by interacting with cell adhesion molecules and signaling receptors. The role of caveolin-1 in the pathogenesis of gastric cancer (GC) is currently unknown. We show by confocal immunofluorescence microscopy and immunohistochemistry of biopsies from GC patients (n = 41) that the nonneoplastic mucosa expressed caveolin-1 in foveolar epithelial cells and adjacent connective tissue. GC cells of only 3 of 41 (7%) patients expressed caveolin-1 and were all of the intestinal type. Quantitative PCR and Western blotting confirmed that, compared with nonneoplastic tissue, the overall caveolin-1 mRNA was decreased in 14 of 19 (74%) GC patients and protein in 7 of 13 (54%), respectively. Strong caveolin-1 reactivity was found in the nonepithelial compartment (myocytes, fibroblasts, perineural, and endothelial cells) in both tumor-free and GC samples. In a series of human GC cell lines, caveolin-1 expression was low in cells derived from a primary tumor (AGS and SNU-1) but was increased in cell lines originating from distant metastases (MKN-7, MKN-45, NCI-N87, KATO-III, and SNU-5). Ectopic expression of caveolin-1 in AGS cells decreased proliferation but promoted anchorage-independent growth and survival. RNAi-mediated knockdown of endogenous caveolin-1 in MKN-45 cells accelerated cell growth. These data indicate that caveolin-1 exhibits a stage-dependent differential expression and function in GC and may thereby contribute to its pathogenesis.


Asunto(s)
Caveolina 1/biosíntesis , Neoplasias Gástricas/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Caveolina 1/genética , Caveolina 1/metabolismo , Adhesión Celular/fisiología , Procesos de Crecimiento Celular/fisiología , Línea Celular Tumoral , Progresión de la Enfermedad , Femenino , Mucosa Gástrica/metabolismo , Aparato de Golgi/metabolismo , Humanos , Inmunohistoquímica , Masculino , Microdominios de Membrana/metabolismo , Microscopía Confocal , Microscopía Fluorescente , Persona de Mediana Edad , Metástasis de la Neoplasia , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología
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