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1.
Mediators Inflamm ; 2019: 8146257, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31772507

RESUMEN

Acute appendicitis is the most frequent surgical abdominal emergency, but its etiology remains poorly understood. Histological examination of the appendix, following its removal due to acute appendicitis, consistently shows features in common with bronchial asthma, suggesting an allergic reaction as a candidate etiologic factor. Here, we propose the concept of appendicular lavage and use it to study the levels of the Th2 cytokines IL-4, IL-5, and IL-9 in patients with a clinical diagnosis of acute appendicitis. The study group included 20 patients with a histological diagnosis of phlegmonous appendicitis, 13 patients with gangrenous appendicitis, and a control group of 8 patients with a clinical diagnosis of appendicitis but with normal histology. Cytokine levels were higher in acute appendicitis. The difference was more pronounced when comparing phlegmonous appendicitis with nonpathological appendicitis (p = 0.01) for IL-4 (48.3 vs. 21.3 pg/mL), IL-5 (29.2 vs. 8.0 pg/mL), and IL-9 (34.1 vs. 16.6 pg/mL). This Th2 cytokine profile is compatible with the hypothesis of allergy as an etiologic factor for acute appendicitis and may have important implications for the diagnosis, prevention, and treatment of this condition.


Asunto(s)
Apendicitis/etiología , Apendicitis/metabolismo , Citocinas/metabolismo , Hipersensibilidad/complicaciones , Hipersensibilidad/metabolismo , Células Th2/metabolismo , Enfermedad Aguda , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven
2.
Eur J Immunol ; 42(7): 1843-9, 2012 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-22585713

RESUMEN

Effective CD8(+) T-cell responses against tumor or microbial antigens that are not directly expressed in antigen-presenting cells (APCs) depend on the cross-presentation of these antigens on MHC class I in APCs. To identify signaling molecules that regulate cross-presentation, we used lentiviral-based RNA interference to test the roles of hundreds of kinases and phosphatases in this process. Our study uncovered eight previously unknown genes, consisting of one positive and seven negative regulators of antigen cross-presentation. Depletion of Acvr1c, a type I receptor for TGF-ß family of signaling molecules, led to an increase in CD80 and CD86 co-stimulator surface expression and secreted IL-12 in mouse bone marrow-derived DCs, as well as antigen-specific T-cell proliferation.


Asunto(s)
Presentación de Antígeno/inmunología , Células Dendríticas/enzimología , Células Dendríticas/inmunología , Monoéster Fosfórico Hidrolasas/inmunología , Fosfotransferasas/inmunología , Receptores de Activinas Tipo I/genética , Receptores de Activinas Tipo I/inmunología , Animales , Presentación de Antígeno/genética , Western Blotting , Reactividad Cruzada/genética , Reactividad Cruzada/inmunología , Citometría de Flujo , Silenciador del Gen/inmunología , Inmunidad Innata/genética , Inmunidad Innata/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Monoéster Fosfórico Hidrolasas/genética , Fosfotransferasas/genética , ARN/química , ARN/genética , Interferencia de ARN/inmunología
3.
Blood ; 115(12): 2407-11, 2010 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-20101024

RESUMEN

On the path to successful immunotherapy of hematopoietic tumors, gammadelta T cells offer great promise because of their human leukocyte antigen (HLA)-unrestricted targeting of a wide variety of leukemias/lymphomas. However, the molecular mechanisms underlying lymphoma recognition by gammadelta T cells remain unclear. Here we show that the expression levels of UL16-binding protein 1 (ULBP1) determine lymphoma susceptibility to gammadelta T cell-mediated cytolysis. Consistent with this, blockade of NKG2D, the receptor for ULBP1 expressed on all Vgamma9(+) T cells, significantly inhibits lymphoma cell killing. Specific loss-of-function studies demonstrate that the role of ULBP1 is nonredundant, highlighting a thus far unique physiologic relevance for tumor recognition by gammadelta T cells. Importantly, we observed a very wide spectrum of ULBP1 expression levels in primary biopsies obtained from lymphoma and leukemia patients. We suggest this will impact on the responsiveness to gammadelta T cell-based immunotherapy, and therefore propose ULBP1 to be used as a leukemia/lymphoma biomarker in upcoming clinical trials.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas de la Membrana/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Linfocitos T Citotóxicos/metabolismo , Biomarcadores de Tumor/inmunología , Biopsia , Línea Celular Tumoral , Ensayos Clínicos como Asunto/métodos , Proteínas Ligadas a GPI , Humanos , Inmunoterapia/métodos , Péptidos y Proteínas de Señalización Intracelular/genética , Leucemia de Células B/metabolismo , Leucemia de Células B/patología , Leucemia de Células B/terapia , Leucemia de Células T/metabolismo , Leucemia de Células T/patología , Leucemia de Células T/terapia , Linfoma/metabolismo , Linfoma/patología , Linfoma/terapia , Proteínas de la Membrana/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , ARN Interferente Pequeño , Linfocitos T Citotóxicos/inmunología
4.
Elife ; 112022 12 07.
Artículo en Inglés | MEDLINE | ID: mdl-36476511

RESUMEN

Anthracyclines are among the most used and effective anticancer drugs. Their activity has been attributed to DNA double-strand breaks resulting from topoisomerase II poisoning and to eviction of histones from select sites in the genome. Here, we show that the extensively used anthracyclines Doxorubicin, Daunorubicin, and Epirubicin decrease the transcription of nuclear factor kappa B (NF-κB)-dependent gene targets, but not interferon-responsive genes in primary mouse (Mus musculus) macrophages. Using an NMR-based structural approach, we demonstrate that anthracyclines disturb the complexes formed between the NF-κB subunit RelA and its DNA-binding sites. The anthracycline variants Aclarubicin, Doxorubicinone, and the newly developed Dimethyl-doxorubicin, which share anticancer properties with the other anthracyclines but do not induce DNA damage, also suppressed inflammation, thus uncoupling DNA damage from the effects on inflammation. These findings have implications for anticancer therapy and for the development of novel anti-inflammatory drugs with limited side effects for life-threatening conditions such as sepsis.


Asunto(s)
Antraciclinas , FN-kappa B , Animales , Ratones , Antraciclinas/farmacología , Antibióticos Antineoplásicos/farmacología , Doxorrubicina/farmacología , Daño del ADN , ADN
5.
Nat Cell Biol ; 12(1): 19-30; sup pp 1-13, 2010 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-19966785

RESUMEN

Exosomes are secreted membrane vesicles that share structural and biochemical characteristics with intraluminal vesicles of multivesicular endosomes (MVEs). Exosomes could be involved in intercellular communication and in the pathogenesis of infectious and degenerative diseases. The molecular mechanisms of exosome biogenesis and secretion are, however, poorly understood. Using an RNA interference (RNAi) screen, we identified five Rab GTPases that promote exosome secretion in HeLa cells. Among these, Rab27a and Rab27b were found to function in MVE docking at the plasma membrane. The size of MVEs was strongly increased by Rab27a silencing, whereas MVEs were redistributed towards the perinuclear region upon Rab27b silencing. Thus, the two Rab27 isoforms have different roles in the exosomal pathway. In addition, silencing two known Rab27 effectors, Slp4 (also known as SYTL4, synaptotagmin-like 4) and Slac2b (also known as EXPH5, exophilin 5), inhibited exosome secretion and phenocopied silencing of Rab27a and Rab27b, respectively. Our results therefore strengthen the link between MVEs and exosomes, and introduce ways of manipulating exosome secretion in vivo.


Asunto(s)
Comunicación Celular , Endosomas/fisiología , Exosomas/metabolismo , Proteínas de Unión al GTP rab/metabolismo , Membrana Celular/metabolismo , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Silenciador del Gen , Células HeLa , Humanos , Immunoblotting , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Interferente Pequeño/farmacología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Fracciones Subcelulares , Proteínas de Transporte Vesicular/antagonistas & inhibidores , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismo , Proteínas de Unión al GTP rab/antagonistas & inhibidores , Proteínas de Unión al GTP rab/genética , Proteínas rab27 de Unión a GTP
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