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1.
J Immunol ; 198(1): 128-137, 2017 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-27872212

RESUMEN

Type 2 innate lymphoid cells (ILC2) mediate inflammatory immune responses in the context of diseases triggered by the alarmin IL-33. In recent years, IL-33 has been implicated in the pathogenesis of immune-mediated liver diseases. However, the immunoregulatory function of ILC2s in the inflamed liver remains elusive. Using the murine model of Con A-induced immune-mediated hepatitis, we showed that selective expansion of ILC2s in the liver was associated with highly elevated hepatic IL-33 expression, severe liver inflammation, and infiltration of eosinophils. CD4+ T cell-mediated tissue damage and subsequent IL-33 release were responsible for the activation of hepatic ILC2s that produced the type 2 cytokines IL-5 and IL-13 during liver inflammation. Interestingly, ILC2 depletion correlated with less severe hepatitis and reduced accumulation of eosinophils in the liver, whereas adoptive transfer of hepatic ILC2s aggravated liver inflammation and tissue damage. We further showed that, despite expansion of hepatic ILC2s, 3-d IL-33 treatment before Con A challenge potently suppressed development of immune-mediated hepatitis. We found that IL-33 not only activated hepatic ILC2s but also expanded CD4+ Foxp3+ regulatory T cells (Treg) expressing the IL-33 receptor ST2 in the liver. This Treg subset also accumulated in the liver during resolution of immune-mediated hepatitis. In summary, hepatic ILC2s are poised to respond to the release of IL-33 upon liver tissue damage through expression of type 2 cytokines thereby participating in the pathogenesis of immune-mediated hepatitis. Inflammatory activity of ILC2s might be regulated by IL-33-elicited ST2+ Tregs that also arise in immune-mediated hepatitis.


Asunto(s)
Hepatitis Autoinmune/inmunología , Activación de Linfocitos/inmunología , Linfocitos/inmunología , Traslado Adoptivo , Animales , Citocinas/biosíntesis , Citocinas/inmunología , Modelos Animales de Enfermedad , Citometría de Flujo , Humanos , Inmunohistoquímica , Interleucina-33/biosíntesis , Interleucina-33/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Reacción en Cadena en Tiempo Real de la Polimerasa , Linfocitos T Reguladores/inmunología
2.
J Med Genet ; 48(8): 557-62, 2011 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21709168

RESUMEN

BACKGROUND AND AIMS: Autoimmune pancreatitis (AIP) represents a rare but clinically relevant cause of pancreatic inflammation. Using MRL/Mp mice as a model of spontaneous AIP, the genetic basis of the disease was studied. METHODS: To identify quantitative trait loci (QTL) of AIP, an advanced intercross line was studied, originating from MRL/MpJ parental mice and the following three mouse strains: Cast (healthy controls), BXD2 (susceptible to collagen induced arthritis), and NZM (a model of lupus erythematosus). This concept was chosen to identify both general autoimmune disease associated loci and AIP specific QTL. Therefore, generation G4 of outbred intercross mice was characterised phenotypically by scoring histopathological changes of the pancreas and genotyped with single nucleotide polymorphism (SNP) arrays. Data were analysed with the R implementation of HAPPY. RESULTS: Five QTLs, correlating with the severity of AIP, were identified. Two of them mapped to chromosome 4 and one to chromosomes 2, 5, and 6, respectively. The QTL on chromosome 6 displays the highest LOD score (5.4) and contains the C-type lectin domain family 4 member a2 in its peak region, which encodes a receptor protein of dendritic cells that has previously been implicated in autoimmune diseases such as Sjogren's syndrome. AIP candidate genes of other QTL's include heterogeneous nuclear ribonucleoprotein A3; nuclear factor, erythroid derived 2, like 2; Sjogren syndrome antigen B; and ubiquitin protein ligase E3 component n-recognin 3. CONCLUSIONS: This study has identified QTLs and putative candidate genes of murine AIP. Their functional role and relevance to human AIP will be studied further.


Asunto(s)
Enfermedades Autoinmunes/genética , Pancreatitis/genética , Sitios de Carácter Cuantitativo/genética , Animales , Enfermedades Autoinmunes/patología , Cruzamientos Genéticos , Femenino , Estudios de Asociación Genética , Inmunohistoquímica , Masculino , Ratones , Fenotipo
3.
Lab Hematol ; 18(4): 30-41, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-23253865

RESUMEN

Multiple myeloma (MM) is a plasma cell disorder that occurs in about 10% of all hematologic cancers. The majority of patients (99%) are over 50 years of age when diagnosed. In the bone marrow (BM), stromal and hematopoietic stem cells (HSCs) are responsible for the production of blood cells. Therefore any destruction or/and changes within the BM undesirably impacts a wide range of hematopoiesis, causing diseases and influencing patient survival. In order to establish an effective therapeutic strategy, recognition of the biology and evaluation of bioinformatics models for myeloma cells are necessary to assist in determining suitable methods to cure or prevent disease complications in patients. This review presents the evaluation of molecular and cellular aspects of MM such as genetic translocation, genetic analysis, cell surface marker, transcription factors, and chemokine signaling pathways. It also briefly reviews some of the mechanisms involved in MM in order to develop a better understanding for use in future studies.


Asunto(s)
Médula Ósea/patología , Regulación Neoplásica de la Expresión Génica , Células Madre Hematopoyéticas/patología , Mieloma Múltiple/genética , Mieloma Múltiple/patología , Células del Estroma/patología , Antígenos CD/biosíntesis , Antígenos CD/genética , Biomarcadores/metabolismo , Médula Ósea/metabolismo , Biología Computacional , Citocinas/biosíntesis , Citocinas/genética , Células Madre Hematopoyéticas/metabolismo , Humanos , Modelos Moleculares , Mieloma Múltiple/metabolismo , Estadificación de Neoplasias , Transducción de Señal , Células del Estroma/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Translocación Genética
4.
Cell J ; 17(3): 395-411, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26464811

RESUMEN

Signal transducers and activators of transcription (STATs) are cytoplasmic transcription factors that have a key role in cell fate. STATs, a protein family comprised of seven members, are proteins which are latent cytoplasmic transcription factors that convey signals from the cell surface to the nucleus through activation by cytokines and growth factors. The signaling pathways have diverse biological functions that include roles in cell differentiation, proliferation, development, apoptosis, and inflammation which place them at the center of a very active area of research. In this review we explain Janus kinase (JAK)/STAT signaling and focus on STAT3, which is transient from cytoplasm to nucleus after phosphorylation. This procedure controls fundamental biological processes by regulating nuclear genes controlling cell proliferation, survival, and development. In some hematopoietic disorders and cancers, overexpression and activation of STAT3 result in high proliferation, suppression of cell differentiation and inhibition of cell maturation. This article focuses on STAT3 and its role in malignancy, in addition to the role of microRNAs (miRNAs) on STAT3 activation in certain cancers.

5.
PLoS One ; 10(9): e0136298, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26325540

RESUMEN

The mouse strain MRL/MpJ is prone to spontaneously develop autoimmune pancreatitis (AIP). To elucidate the genetic control towards the development of the phenotype and to characterize contributions of immunocompetent cell types, MRL/MpJ mice were interbred with three additional strains (BXD2/TYJ, NZM2410/J, CAST/EIJ) for four generations in an advanced intercross line. Cellular phenotypes were determined by flow cytometric quantification of splenic leukocytes and complemented by the histopathological evaluation of pancreatic lesions. An Illumina SNP array was used for genotyping. QTL analyses were performed with the R implementation of HAPPY. Out of 41 leukocyte subpopulations (B cells, T cells and dendritic cells), only three were significantly associated with AIP: While CD4+/CD44high memory T cells and CD4+/CD69+ T helper (Th) cells correlated positively with the disease, the cytotoxic T cell phenotype CD8+/CD44low showed a negative correlation. A QTL for AIP on chromosome 2 overlapped with QTLs for CD4+/CD44high and CD8+/CD44high memory T cells, FoxP3+/CD4+ and FoxP3+/CD8+ regulatory T cells (Tregs), and CD8+/CD69+ cytotoxic T cells. On chromosome 6, overlapping QTLs for AIP and CD4+/IL17+ Th17 cells and again FoxP3+/CD8+ Tregs were observed. In conclusion, CD4+/CD44high memory T cells are the only leukocyte subtype that could be linked to AIP both by correlation studies and from observed overlapping QTL. The potential role of this cell type in the pathogenesis of AIP warrants further investigations.


Asunto(s)
Enfermedades Autoinmunes/genética , Linfocitos T CD4-Positivos/inmunología , Receptores de Hialuranos/genética , Pancreatitis Crónica/genética , Sitios de Carácter Cuantitativo/genética , Animales , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Femenino , Citometría de Flujo , Receptores de Hialuranos/inmunología , Masculino , Ratones , Ratones Endogámicos , Páncreas/inmunología , Páncreas/patología , Pancreatitis Crónica/inmunología , Pancreatitis Crónica/patología , Subgrupos de Linfocitos T/inmunología
6.
Arch Iran Med ; 13(1): 26-33, 2010 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-20039766

RESUMEN

BACKGROUND: Arsenic trioxide and 1,25-(OH)2D3 (vitamin D3) are used for the treatment of lymphocytic leukemia. However, the effects of combined treatment of these drugs are controversial. In this study, the combined effects of these drugs on the induction of apoptosis in NB4 cells were investigated using the neutral comet assay. METHODS: NB4 cells were treated with various doses of arsenic trioxide (0.1 - 3 microM) and vitamin D3 (100 - 600 nM (alone or in combination. Twenty-four hours after treatment, neutral comet assay was performed and apoptotic cells were scored under a fluorescent microscope following staining with ethidium bromide. RESULTS: Results show that all doses of arsenic trioxide used in this study induced apoptosis in NB4 cells. The frequency of induced apoptosis was dose dependent and significantly higher than the controls (P<0.05 - 0.01). In contrast, vitamin D3 at concentrations of 100 - 600 nM produced no significant effect on apoptosis induction compared to the controls. Treatment of NB4 cells with a combination of arsenic trioxide and vitamin D3 resulted in reduction of apoptosis induced by arsenic trioxide which was not dependent on the dose of vitamin D3 (P<0.05). CONCLUSION: Results indicate that arsenic trioxide is a potent inducer of apoptosis in NB4 cells and vitamin D3 significantly decreased the sensitivity of cells to the induction of apoptosis by arsenic trioxide. These findings suggest that 1,25-(OH)2D3 might be involved in anti-apoptotic processes via reactive oxygen species scavenging or other mechanisms not yet known.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Arsenicales/farmacología , Colecalciferol/farmacología , Óxidos/farmacología , Antineoplásicos/antagonistas & inhibidores , Trióxido de Arsénico , Arsenicales/antagonistas & inhibidores , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Leucemia Promielocítica Aguda/tratamiento farmacológico , Óxidos/antagonistas & inhibidores
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