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1.
Eur J Oral Sci ; 126(6): 485-492, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30341786

RESUMEN

Genetic factors, especially those related to immune system functioning, have been intensively studied to determine their role in the development of recurrent aphthous stomatitis (RAS). The aim of the present study was to analyze gene variability in interleukin (IL)2, IL4 (and its receptor α, IL4Rα), IL10, and IL13, which were selected based on literature review and/or their functional relevance, in Czech patients with RAS and in healthy controls. In total, 252 subjects (178 controls and 74 patients with RAS) were enrolled in this case-control study, and their detailed anamnestic, clinical, and laboratory data were obtained. Nine polymorphisms in the genes encoding interleukins were determined using PCR techniques. There were no significant differences in allele or genotype frequencies of the IL2, IL4, IL4Rα, IL10, and IL13 polymorphisms rs2069762/rs2069763, rs2243250/rs79071878, rs1801275, rs1800896, and rs1800925, respectively, between controls and patients with RAS. The minority alleles rs1800871 and rs1800872, which encode variants of IL10, were associated with a statistically significantly higher risk of RAS, as confirmed by the results of genotype and haplotype analyses. We suggest that variability in the IL10 gene may play an important role in the development of RAS in the Czech population.


Asunto(s)
Variación Genética , Interleucinas/genética , Interleucinas/metabolismo , Epidemiología Molecular , Estomatitis Aftosa/epidemiología , Estomatitis Aftosa/inmunología , Adulto , Alelos , Estudios de Casos y Controles , República Checa/epidemiología , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Haplotipos , Humanos , Interleucina-10/genética , Interleucina-10/metabolismo , Interleucina-13/genética , Interleucina-13/metabolismo , Interleucina-2/genética , Interleucina-4/genética , Interleucina-4/metabolismo , Subunidad alfa del Receptor de Interleucina-4/genética , Subunidad alfa del Receptor de Interleucina-4/metabolismo , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Polimorfismo Genético
2.
Front Immunol ; 9: 888, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29930549

RESUMEN

Interleukin (IL)-4 and IL-13 are related cytokines that regulate many aspects of allergic inflammation. They play important roles in regulating the responses of lymphocytes, myeloid cells, and non-hematopoietic cells. In T-cells, IL-4 induces the differentiation of naïve CD4 T cells into Th2 cells, in B cells, IL-4 drives the immunoglobulin (Ig) class switch to IgG1 and IgE, and in macrophages, IL-4 and IL-13 induce alternative macrophage activation. This review gives a short insight into the functional formation of these cytokine receptors. I will discuss both the binding kinetics of ligand/receptor interactions and the expression of the receptor chains for these cytokines in various cell types; both of which are crucial factors in explaining the efficiency by which these cytokines induce intracellular signaling and gene expression. Work initiated in part by William (Bill) E. Paul on IL-4 some 30 years ago has now grown into a major building block of our current understanding of basic immunology and the immune response. This knowledge on IL-4 has growing clinical importance, as therapeutic approaches targeting the cytokine and its signal transduction are becoming a part of the clinical practice in treating allergic diseases. Just by reading the reference list of this short review, one can appreciate the enormous input Bill has had on shaping our understanding of the pathophysiology of allergic inflammation and in particular the role of IL-4 in this process.


Asunto(s)
Hipersensibilidad/inmunología , Interleucina-13/inmunología , Subunidad alfa del Receptor de Interleucina-4/inmunología , Interleucina-4/inmunología , Receptores de Interleucina-13/inmunología , Humanos , Inmunidad Celular , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Subunidad alfa del Receptor de Interleucina-4/metabolismo , Linfocitos/inmunología , Linfocitos/metabolismo , Células Mieloides/inmunología , Células Mieloides/metabolismo , Receptores de Interleucina-13/metabolismo , Transducción de Señal/inmunología
3.
Glia ; 66(8): 1775-1787, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29693281

RESUMEN

Glial cells play important roles in the development and maintenance of neuropathic pain. In particular, activated microglia in the spinal cord facilitate the hyper-excitability of dorsal horn neurons after peripheral nerve injury via pro-inflammatory molecules. In this study, we investigated the possible involvement of the anti-inflammatory cytokine, interleukin-4 (IL-4), in neuropathic pain. We did not detect the expression of IL-4 mRNA in the rat dorsal root ganglion or spinal cord; however, peripheral nerve injury induced the expression of IL-4 receptor (IL-4R) alpha mRNA in the spinal cord. A histological analysis revealed that nerve injury induced IL-4R alpha mRNA in activated spinal microglia ipsilateral to the injury site. Additionally, the increases in IL-4R alpha were coincident with the increased expression of phosphorylated signal transducer and activator of transcription 6 (pSTAT6) in spinal microglia. Intrathecal administration of recombinant IL-4 suppressed mechanical hypersensitivity in neuropathic rats, and the analgesic effect of IL-4 was accompanied by further enhancement of pSTAT6 expression in spinal microglia. Taken together, these results suggest that the adaptive responses of microglia to nerve injury involve both inflammatory and anti-inflammatory signaling, including IL-4R alpha and pSTAT6. These findings support that utilizing the endogenous anti-nociceptive activity of IL-4R alpha may modify the cell lineage of pro-nociceptive microglia, thus providing a novel therapeutic strategy for neuropathic pain.


Asunto(s)
Subunidad alfa del Receptor de Interleucina-4/metabolismo , Interleucina-4/metabolismo , Microglía/metabolismo , Neuralgia/metabolismo , Neuroglía/metabolismo , Animales , Ganglios Espinales/metabolismo , Neuralgia/patología , Ratas Sprague-Dawley , Transducción de Señal/fisiología , Médula Espinal/metabolismo , Médula Espinal/patología
4.
EBioMedicine ; 29: 92-103, 2018 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-29463471

RESUMEN

Chronic hepatitis leads to liver fibrosis and cirrhosis. Cirrhosis is a major cause of worldwide morbidity and mortality. Macrophages play a key role in fibrosis progression and reversal. However, the signals that determine fibrogenic vs fibrolytic macrophage function remain ill defined. We studied the role of interleukin-4 receptor α (IL-4Rα), a potential central switch of macrophage polarization, in liver fibrosis progression and reversal. We demonstrate that inflammatory monocyte infiltration and liver fibrogenesis were suppressed in general IL-4Rα-/- as well as in macrophage-specific IL-4Rα-/- (IL-4RαΔLysM) mice. However, with deletion of IL-4RαΔLysM spontaneous fibrosis reversal was retarded. Results were replicated by pharmacological intervention using IL-4Rα-specific antisense oligonucleotides. Retarded resolution was linked to the loss of M2-type resident macrophages, which secreted MMP-12 through IL-4 and IL-13-mediated phospho-STAT6 activation. We conclude that IL-4Rα signaling regulates macrophage functional polarization in a context-dependent manner. Pharmacological targeting of macrophage polarization therefore requires disease stage-specific treatment strategies. RESEARCH IN CONTEXT: Alternative (M2-type) macrophage activation through IL-4Rα promotes liver inflammation and fibrosis progression but speeds up fibrosis reversal. This demonstrates context dependent, opposing roles of M2-type macrophages. During reversal IL-4Rα induces fibrolytic MMPs, especially MMP-12, through STAT6. Liver-specific antisense oligonucleotides efficiently block IL-4Rα expression and attenuate fibrosis progression.


Asunto(s)
Subunidad alfa del Receptor de Interleucina-4/metabolismo , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Macrófagos/metabolismo , Transducción de Señal , Animales , Citocinas/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Expresión Génica , Subunidad alfa del Receptor de Interleucina-4/genética , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/etiología , Activación de Macrófagos/inmunología , Macrófagos/inmunología , Metaloproteinasas de la Matriz/genética , Metaloproteinasas de la Matriz/metabolismo , Ratones , Ratones Noqueados , Células Mieloides/inmunología , Células Mieloides/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Células RAW 264.7 , Factor de Transcripción STAT6/metabolismo , Bazo/inmunología , Bazo/metabolismo , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo
5.
Sci Rep ; 8(1): 3221, 2018 02 19.
Artículo en Inglés | MEDLINE | ID: mdl-29459738

RESUMEN

Immune-specific genes as well as genes responsible for the formation and integrity of the epidermal barrier have been implicated in the pathogeneses of allergic sensitization. This study sought to determine whether an epistatic effect (gene-gene interaction) between genetic variants within interleukin 4 receptor (IL4R) and filaggrin (FLG) genes predispose to the development of allergic sensitization. Data from two birth cohort studies were analyzed, namely the Isle of Wight (IOW; n = 1,456) and the Manchester Asthma and Allergy Study (MAAS; n = 1,058). In the IOW study, one interaction term (IL4R rs3024676 × FLG variants) showed statistical significance (interaction term: P = 0.003). To illustrate the observed epistasis, stratified analyses were performed, which showed that FLG variants were associated with allergic sensitization only among IL4R rs3024676 homozygotes (OR, 1.97; 95% CI, 1.27-3.05; P = 0.003). In contrast, FLG variants effect was masked among IL4R rs3024676 heterozygotes (OR, 0.53; 95% CI, 0.22-1.32; P = 0.175). Similar results were demonstrated in the MAAS study. Epistasis between immune (IL4R) and skin (FLG) regulatory genes exist in the pathogenesis of allergic sensitization. Hence, genetic susceptibility towards defective epidermal barrier and deviated immune responses could work together in the development of allergic sensitization.


Asunto(s)
Epistasis Genética , Predisposición Genética a la Enfermedad , Hipersensibilidad/genética , Inmunización , Subunidad alfa del Receptor de Interleucina-4/metabolismo , Proteínas de Filamentos Intermediarios/metabolismo , Adolescente , Niño , Preescolar , Frecuencia de los Genes , Técnicas de Genotipaje , Humanos , Lactante , Subunidad alfa del Receptor de Interleucina-4/genética , Proteínas de Filamentos Intermediarios/genética , Estudios Longitudinales
6.
Blood ; 131(18): 2036-2046, 2018 05 03.
Artículo en Inglés | MEDLINE | ID: mdl-29467182

RESUMEN

Primary mediastinal large B-cell lymphoma (PMBCL) is a distinct subtype of diffuse large B-cell lymphoma thought to arise from thymic medullary B cells. Gene mutations underlying the molecular pathogenesis of the disease are incompletely characterized. Here, we describe novel somatic IL4R mutations in 15 of 62 primary cases of PMBCL (24.2%) and in all PMBCL-derived cell lines tested. The majority of mutations (11/21; 52%) were hotspot single nucleotide variants in exon 8, leading to an I242N amino acid change in the transmembrane domain. Functional analyses establish this mutation as gain of function leading to constitutive activation of the JAK-STAT pathway and upregulation of downstream cytokine expression profiles and B cell-specific antigens. Moreover, expression of I242N mutant IL4R in a mouse xenotransplantation model conferred growth advantage in vivo. The pattern of concurrent mutations within the JAK-STAT signaling pathway suggests additive/synergistic effects of these gene mutations contributing to lymphomagenesis. Our data establish IL4R mutations as novel driver alterations and provide a strong preclinical rationale for therapeutic targeting of JAK-STAT signaling in PMBCL.


Asunto(s)
Subunidad alfa del Receptor de Interleucina-4/genética , Quinasas Janus/metabolismo , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/metabolismo , Neoplasias del Mediastino/genética , Neoplasias del Mediastino/metabolismo , Mutación , Factores de Transcripción STAT/metabolismo , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Femenino , Humanos , Subunidad alfa del Receptor de Interleucina-4/metabolismo , Ratones , Fosforilación , Transducción de Señal
7.
Arch Toxicol ; 92(4): 1495-1505, 2018 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-29380012

RESUMEN

Allergic contact dermatitis is a widespread health disorder and occupational skin disease. Hence, screening for contact-sensitizing chemicals is highly relevant to toxicology, dermatology, and occupational medicine. The use of animal tests for this purpose is constrained by ethical considerations, need for high-throughput screening, and legislation (e.g., for cosmetics in the European Union). T cell activation is the final and most specific key event of the "adverse outcome pathway" for skin sensitization and therefore a promising target for the development of in vitro sensitization assays. We present a novel in vitro sensitization assay with a lymphocyte endpoint as an add-on to the loose-fit coculture-based sensitization assay (LCSA): the LCSA-ly. While the LCSA measures dendritic cell activation, the LCSA-ly offers the option for an additional lymphocyte endpoint which can be measured concurrently. We incorporated lymphocytes in our previously established coculture of primary human keratinocytes and monocyte-derived dendritic cells and tested nine substances: five sensitizers [2,4-dinitrochlorobenzene (DNCB) 1.25-15 µmol/l, p-phenylenediamine (PPD) 15.6-125 µmol/l, 2-mercaptobenzothiazole (MBT) 50-1000 µmol/l, coumarin, and resorcinol (both: 250-1500 µmol/l)] and four non-sensitizers (monochlorobenzene, caprylic acid, glycerol, and salicylic acid (all: 125-1000 µmol/l)]. DNCB and MBT increased a subset of IL-23 receptor+/IFN-γ receptor 1 (CD119)+ lymphocytes. DNCB, PPD, and MBT enhanced a subunit of the IL-4 receptor (CD124) and a memory marker (CD44) on lymphocytes. Remarkably, DNCB, PPD, and MBT raised IL-4 concentrations in coculture supernatants while IFN-γ levels decreased, which might point to Th2 activation in vitro. Coumarin, resorcinol, and non-sensitizers did not alter any of the tested surface markers or cytokines. IL-17 was not affected by any of the substances. Relative strength of sensitizers according to lymphocyte markers was DNCB > PPD > MBT, which corresponds to earlier results from the LCSA without lymphocyte endpoint, the murine local lymph node assay, and human data. This study is the first to prove the suitability of lymphocyte surface markers for sensitization testing and potency assessment.


Asunto(s)
Alérgenos/inmunología , Antígenos de Superficie/metabolismo , Citocinas/metabolismo , Dermatitis Alérgica por Contacto/inmunología , Alérgenos/toxicidad , Bioensayo , Técnicas de Cocultivo , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Humanos , Receptores de Hialuranos/metabolismo , Inmunización , Subunidad alfa del Receptor de Interleucina-4/metabolismo , Queratinocitos/efectos de los fármacos , Queratinocitos/inmunología , Linfocitos/inmunología , Receptores de Interferón/metabolismo , Piel/efectos de los fármacos , Piel/inmunología
8.
PLoS One ; 12(6): e0178705, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28594935

RESUMEN

Recent research shows bidirectional communication between the normal brain and the peripheral immune system. Glioma is a primary brain tumor characterized by systemic immunosuppression. To better understand gliomagenesis, we evaluated associations between 277 prediagnostic serum cytokines and glioma. We used glioma (n = 487) and matched control (n = 487) specimens from the Janus Serum Bank Cohort in Oslo, Norway. Conditional logistic regression allowed us to identify those cytokines that were individually associated with glioma. Next, we used heat maps to compare case to control Pearson correlation matrices of 12 cytokines modeled in an in silico study of the interaction between the microenvironment and the tumor. We did the same for case-control correlation matrices of lasso-selected cytokines and all 277 cytokines in the data set. Cytokines related to glioma risk (P ≤ .05) more than 10 years before diagnosis are sIL10RB, VEGF, beta-Catenin and CCL22. LIF was associated with decreased glioma risk within five years before glioma diagnosis (odds ratio (OR) = 0.47, 95% confidence interval (CI) = 0.23, 0.94). After adjustment for cytokines above, the previously observed interaction between IL4 and sIL4RA persisted (> 20 years before diagnosis, OR = 1.72, 95% CI = 1.20, 2.47). In addition, during this period, case correlations among 12 cytokines were weaker than were those among controls. This pattern was also observed among 30 lasso- selected cytokines and all 277 cytokines. We identified four cytokines and one interaction term that were independently related to glioma risk. We have documented prediagnostic changes in serum cytokine levels that may reflect the presence of a preclinical tumor.


Asunto(s)
Citocinas/sangre , Glioma/sangre , Adulto , Estudios de Casos y Controles , Femenino , Glioblastoma/sangre , Humanos , Interleucina-4/sangre , Subunidad alfa del Receptor de Interleucina-4/metabolismo , Modelos Logísticos , Masculino , Persona de Mediana Edad , Oportunidad Relativa
9.
PLoS Negl Trop Dis ; 11(6): e0005675, 2017 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-28651009

RESUMEN

There is currently no vaccine against parasitic nematodes and the knowledge on the mechanisms by which protective immunity against this class of parasites is achieved is continuously expanding. Nematode parasites trigger a host protective type 2 immune response via interleukin-4 receptor alpha (IL-4Rα). Despite this central role, it is not known whether IL-4Rα has a role in maintaining host type 2 immune responses following polarization. To determine the role of IL-4Rα after polarization, we used a recently established strain of rosaCreERT2-/+IL-4Rα-/Lox mice where il4rα gene deletion can be temporally controlled. We show that sustained expression of IL-4Rα is required for the maintenance of type 2 immune responses and protective immunity following interruption after polarization with Nippostrongylus brasiliensis primary infection. Moreover, we show by temporal deletion of IL-4Rα prior to secondary infection with N. brasiliensis that signaling via this receptor drives more efficient recall of type 2 immune responses and clearance of the parasites. Together, this study demonstrates that sustained IL-4Rα mediated signaling is required for the maintenance of anti-nematode type 2 immune responses, describing a novel function for IL-4Rα that is distinct from its role in immune polarization.


Asunto(s)
Subunidad alfa del Receptor de Interleucina-4/metabolismo , Nippostrongylus/inmunología , Infecciones por Strongylida/inmunología , Células Th2/inmunología , Animales , Modelos Animales de Enfermedad , Eliminación de Gen , Ratones , Ratones Noqueados
10.
BMC Immunol ; 18(1): 26, 2017 05 16.
Artículo en Inglés | MEDLINE | ID: mdl-28511637

RESUMEN

BACKGROUND: T-helper cell type 1 (Th1) polarization in chronic immune thrombocytopenia (cITP) has been reported at the protein and mRNA levels. We evaluated the impact of Th1/Th2 cytokine and cytokine receptor functional polymorphisms on both susceptibility to, and severity of, cITP. We analysed IFN-γ + 874 T/A, IFN-γR -611G/A, IL-4 -590C/T, and IL-4Rα Q576R polymorphisms in 126 cITP patients (male/female: 34/92; median age: 47.7 years) and 202 healthy control donors. Genotyping was determined by PCR and direct sequencing. The Th1/Th2 ratio was detected in peripheral blood mononuclear cells via flow cytometry. RESULTS: cITP patients had a higher frequency of the IL-4Rα 576 non-QQ genotype compared to healthy subjects (P = 0.04). cITP patients with the IFN-γ +874 non-AA genotype (high expression type) showed more severe thrombocytopenia than those with the AA genotype (P < 0.05). cITP patients had a significantly higher Th1/Th2 ratio than control patients (P < 0.01); this ratio was inversely correlated with platelet counts. Furthermore, patients with both IFN-γ +874 non-AA genotype (high expression type) and IFN-γR -611 non-AA genotype (high-function type) had a significantly higher Th1/Th2 ratio (P < 0.05). CONCLUSIONS: The cytokine polymorphisms affecting Th1/Th2 increase the susceptibility to, and severity of, chronic ITP.


Asunto(s)
Interferón gamma/genética , Subunidad alfa del Receptor de Interleucina-4/genética , Interleucina-4/genética , Púrpura Trombocitopénica Idiopática/genética , Receptores de Interferón/genética , Células TH1/inmunología , Células Th2/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Células Cultivadas , Niño , Preescolar , Enfermedad Crónica , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Interferón gamma/metabolismo , Interleucina-4/metabolismo , Subunidad alfa del Receptor de Interleucina-4/metabolismo , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Púrpura Trombocitopénica Idiopática/inmunología , Receptores de Interferón/metabolismo , Balance Th1 - Th2/genética , Adulto Joven
11.
J Immunol ; 198(10): 4166-4177, 2017 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-28396317

RESUMEN

Myeloid cells play a key role in tumor progression and metastasis by providing nourishment and immune protection, as well as facilitating cancer invasion and seeding to distal sites. Although advances have been made in understanding the biology of these tumor-educated myeloid cells (TEMCs), their intrinsic plasticity challenges our further understanding of their biology. Indeed, in vitro experiments only mimic the in vivo setting, and current gene-knockout technologies do not allow the simultaneous, temporally controlled, and cell-specific silencing of multiple genes or pathways. In this article, we describe the 4PD nanoplatform, which allows the in vivo preferential transfection and in vivo tracking of TEMCs with the desired RNAs. This platform is based on the conjugation of CD124/IL-4Rα-targeting peptide with G5 PAMAM dendrimers as the loading surface and can convey therapeutic or experimental RNAs of interest. When injected i.v. in mice bearing CT26 colon carcinoma or B16 melanoma, the 4PD nanoparticles predominantly accumulate at the tumor site, transfecting intratumoral myeloid cells. The use of 4PD to deliver a combination of STAT3- and C/EBPß-specific short hairpin RNA or miR-142-3p confirmed the importance of these genes and microRNAs in TEMC biology and indicates that silencing of both genes is necessary to increase the efficacy of immune interventions. Thus, the 4PD nanoparticle can rapidly and cost effectively modulate and assess the in vivo function of microRNAs and mRNAs in TEMCs.


Asunto(s)
Dendrímeros/metabolismo , Silenciador del Gen , Células Mieloides/metabolismo , Nanotecnología/métodos , Animales , Línea Celular Tumoral , Neoplasias del Colon , Dendrímeros/administración & dosificación , Subunidad alfa del Receptor de Interleucina-4/inmunología , Subunidad alfa del Receptor de Interleucina-4/metabolismo , Melanoma Experimental , Ratones , MicroARNs , Células Mieloides/inmunología , Nanopartículas/administración & dosificación , Nanopartículas/metabolismo , Nanotecnología/normas , Receptores de Interleucina-4/inmunología , Receptores de Interleucina-4/metabolismo
12.
Sci Rep ; 7: 40631, 2017 01 17.
Artículo en Inglés | MEDLINE | ID: mdl-28094779

RESUMEN

Infection with helminth parasites has been explored as a treatment for autoimmune and inflammatory diseases. As helminth antigens have potent immunomodulation properties capable of inducing regulatory programs in a variety of cell types, transferring cells treated with helminth antigens represents a novel extension to helminth therapy. Previous work determined that transfer of bone marrow-derived dendritic cells (DC) pulsed with a crude extract of the tapeworm Hymenolepis diminuta (HD) can suppress colitis in recipient mice. The present study explored the mechanism of disease suppression and the importance of interleukin (IL)-4 signaling. Transfer of HD-DCs suppressed dinitrobenzene sulfonic acid (DNBS)-induced colitis through activation of recipient IL-4 receptor-α. The transferred HD-DCs required IL-4Rα and the capacity to secrete IL-10 to drive IL-4 and IL-10 production and to suppress colitis in recipient mice. Treatment of DCs with IL-4 evokes an alternatively activated phenotype, but adoptive transfer of these cells did not affect the outcome of colitis. Collectively, these studies demonstrate the complexity between IL-4 and IL-10 in donor cells and recipient, and the requirement for parasite- and host-derived factors in this novel form of cell therapy. Thus IL-4Rα signaling is revealed as a pathway that could be exploited for helminth antigen cell-based therapy.


Asunto(s)
Antígenos Helmínticos/inmunología , Colitis/etiología , Colitis/metabolismo , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Subunidad alfa del Receptor de Interleucina-4/metabolismo , Transducción de Señal , Traslado Adoptivo , Animales , Biomarcadores , Colitis/patología , Colitis/terapia , Técnicas de Inactivación de Genes , Hymenolepis diminuta/inmunología , Inmunohistoquímica , Inmunomodulación , Inmunofenotipificación , Inmunoterapia , Interleucina-10/biosíntesis , Interleucina-4/biosíntesis , Lipopolisacáridos/inmunología , Ratones , Bazo/citología , Bazo/inmunología , Bazo/metabolismo
13.
J Orthop Res ; 35(6): 1290-1298, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-27504740

RESUMEN

Post-traumatic joint contracture was reported to be associated with elevated numbers of contractile myofibroblasts (MFs) in the healing capsule. During the physiological healing process, the number of MFs declines; however, in fibroconnective disorders, MFs persist. The manifold interaction of the cytokines regulating the appearance and persistence of MFs in the pathogenesis of joint contracture remains to be elucidated. The objective of our current study was to analyze the impact of the anti-inflammatory cytokine interleukin (IL)-4 on functional behavior of MFs. Cells were isolated from human joint capsule specimens and challenged with three different concentrations of IL-4 with or without its neutralizing antibody. MF viability, contractile properties, and the gene expression of both alpha-smooth muscle actin (α-SMA) and collagen type I were examined. Immunofluorescence staining revealed the presence of IL-4 receptor (R)-alpha (α) on the membrane of cultured MFs. The cytokine IL-4 promoted MF viability and enhanced MF modulated contraction of collagen gels. Moreover, IL-4 intervened in gene expression by up-regulation of α-SMA and collagen type I mRNA. These effects could be specifically lowered by the neutralizing IL-4 antibody. On the basis of our findings we conclude that the anti-inflammatory cytokine IL-4 specifically regulates viability and the contractile properties of MFs via up-regulating the gene expression of α-SMA and collagen type I. IL-4 may be a helpful target in developing anti-fibrotic therapeutics for post-traumatic joint contracture in human. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1290-1298, 2017.


Asunto(s)
Interleucina-4/fisiología , Cápsula Articular/citología , Miofibroblastos/fisiología , Actinas/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Colágeno Tipo I/metabolismo , Femenino , Humanos , Subunidad alfa del Receptor de Interleucina-4/metabolismo , Cápsula Articular/metabolismo , Masculino , Persona de Mediana Edad , Cultivo Primario de Células
14.
J Membr Biol ; 250(4): 393-406, 2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-27826635

RESUMEN

To quantitatively examine the effect of membrane organization on lateral diffusion, we studied fluorescent carbocyanine lipid analogues and EGFP-tagged, single-pass transmembrane proteins in systems of decreasing complexity: (i) the plasma membrane (PM) of living cells, (ii) paraformaldehyde/dithiothreitol-induced giant plasma membrane vesicles (GPMVs), and (iii) giant unilamellar vesicles (GUVs) under physiological buffer conditions. A truncated, signaling-deficient interleukin-4 receptor subunit, showing efficient accumulation in the plasma membrane, served as a model transmembrane protein. Two-dimensional diffusion coefficients (D) were determined by fluorescence correlation spectroscopy (FCS) either at fixed positions (single-point, spFCS) or while scanning a circular orbit (circular scanning, csFCS). Consistent with a different inclusion sizes in the membrane, lipids diffuse slightly faster than the single-spanning membrane proteins in both membrane systems, GUVs and GPMVs. In GPMVs lipids and proteins consistently experienced a fivefold larger viscosity than in GUVs, reflecting the significant fraction of plasma membrane-derived proteins partitioning into GPMVs. Lipid and protein diffusion in the PM was, respectively, 2 times and 4-5 times slower in comparison to GPMVs. This discrepancy was quantitatively confirmed by csFCS. The similarity of diffusion of receptors and lipids in GPMVs and GUVs and its significant difference in the plasma membrane suggest that protein domains as small as EGFP convey sensitivity to the actin cortex on various length scales.


Asunto(s)
Membrana Celular/metabolismo , Subunidad alfa del Receptor de Interleucina-4/metabolismo , Interleucina-4/metabolismo , Proteínas Recombinantes de Fusión/metabolismo , Liposomas Unilamelares/metabolismo , Carbocianinas/química , Membrana Celular/química , Colesterol/química , Colesterol/metabolismo , Difusión , Colorantes Fluorescentes/química , Expresión Génica , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Células HEK293 , Histidina/genética , Histidina/metabolismo , Humanos , Interleucina-4/genética , Subunidad alfa del Receptor de Interleucina-4/genética , Cinética , Oligopéptidos/genética , Oligopéptidos/metabolismo , Fosfatidilcolinas/química , Fosfatidilcolinas/metabolismo , Plásmidos/química , Plásmidos/metabolismo , Transporte de Proteínas , Proteínas Recombinantes de Fusión/genética , Espectrometría de Fluorescencia , Esfingomielinas/química , Esfingomielinas/metabolismo , Liposomas Unilamelares/química
15.
Oncotarget ; 7(52): 86836-86856, 2016 Dec 27.
Artículo en Inglés | MEDLINE | ID: mdl-27895317

RESUMEN

Radiotherapy induces the production of cytokines, thereby increasing aggressive tumor behavior. This radiation effect results in the failure of radiotherapy and increases the mortality rate in patients. We found that interleukin-4 (IL-4) and IL-4Rα (IL-4 receptor) are highly expressed in various human cancer cells subsequent to radiation treatment. In addition, IL-4 is highly overexpressed in metastatic carcinoma tissues compared with infiltrating carcinoma tissues. High expression of IL-4 in patients with cancer is strongly correlated with poor survival. The results of this study suggest that radiation-induced IL-4 contributes to tumor progression and metastasis. Radiation-induced IL-4 was associated with tumorigenicity and metastasis. IL-4 expression was downregulated by miR-340 and miR-429, which were decreased by ionizing radiation (IR). Radiation-regulated miR-340/429-IL4 signaling increased tumorigenesis and metastasis by inducing the production of Sox2, Vimentin, VEGF, Ang2, and MMP-2/9 via activating JAK, JNK, ß-catenin, and Stat6 in vitro and in vivo. Our study presents a conceptual advance in our understanding of the modification of tumor microenvironment by radiation and suggests that combining radiotherapy with genetic therapy to inhibit IL-4 may be a promising strategy for preventing post-radiation recurrence and metastasis in patients.


Asunto(s)
Neoplasias de la Mama/radioterapia , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , Interleucina-4/genética , MicroARNs/genética , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Células Cultivadas , Femenino , Células HEK293 , Humanos , Interleucina-4/metabolismo , Subunidad alfa del Receptor de Interleucina-4/genética , Subunidad alfa del Receptor de Interleucina-4/metabolismo , Células MCF-7 , Ratones Endogámicos BALB C , Ratones Desnudos , Interferencia de ARN , Transducción de Señal/genética , Transducción de Señal/efectos de la radiación , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , beta Catenina/genética , beta Catenina/metabolismo
16.
Tuberculosis (Edinb) ; 98: 139-48, 2016 05.
Artículo en Inglés | MEDLINE | ID: mdl-27156630

RESUMEN

OBJECTIVES: To characterize at high resolution DNA methylation changes of cytokines which occur in the genome of macrophages in association with Mycobacterium tuberculosis (MTB) infection METHODS: We studied the methylation profiles of THP-1 derived macrophage cells infected with clinical MTB strains [Beijing/W & non-Beijing/W lineage, sensitive (INH(S), RIF(S)) & resistant (INH(R), RIF(R)) strains] and of host macrophages from MTB infected cohorts (active & latent patients) with the human methylation CpG islands microarrays. RESULTS: Methylated modification on the promoter sequences of cytokines and their receptors were found to be associated with MTB infection in a strain- and host-dependent manner. Our epigenetic analyses revealed that infection with Beijing/W MTB strains enhanced IL6R, IL4R and IL17R hyper-methylations in infected macrophages. Validation of IL6R methylated sequence confirmed that MTB infection induced DNA methylation of CpG67 region in the IL6R promoter. In addition, studies on the human macrophage methylation profiles from the patient cohorts indicated that the methylation rate of IL17 family members and related genes were significantly altered in patients with active MTB infections. CONCLUSIONS: Our study offered novel insights into the epigenetic changes in the interaction of host macrophages in MTB infections and warrant further explorations into these changes in modulating the immune response in active and latent MTB infections.


Asunto(s)
Citocinas/genética , Metilación de ADN , Epigénesis Genética , Macrófagos/microbiología , Mycobacterium tuberculosis/patogenicidad , Receptores de Interleucina/genética , Tuberculosis/genética , Tuberculosis/microbiología , Estudios de Casos y Controles , Línea Celular , Islas de CpG , Citocinas/metabolismo , Interacciones Huésped-Patógeno , Humanos , Subunidad alfa del Receptor de Interleucina-4/genética , Subunidad alfa del Receptor de Interleucina-4/metabolismo , Tuberculosis Latente/genética , Tuberculosis Latente/metabolismo , Tuberculosis Latente/microbiología , Macrófagos/metabolismo , Regiones Promotoras Genéticas , Receptores de Interleucina/metabolismo , Receptores de Interleucina-17/genética , Receptores de Interleucina-17/metabolismo , Receptores de Interleucina-6/genética , Receptores de Interleucina-6/metabolismo , Tuberculosis/metabolismo
17.
Cell Rep ; 15(7): 1527-1541, 2016 05 17.
Artículo en Inglés | MEDLINE | ID: mdl-27160906

RESUMEN

Secondary lymphoid tissues provide specialized niches for the initiation of adaptive immune responses and undergo a remarkable expansion in response to inflammatory stimuli. Although the formation of B cell follicles was previously thought to be restricted to the postnatal period, we observed that the draining mesenteric lymph nodes (mLN) of helminth-infected mice form an extensive number of new, centrally located, B cell follicles in response to IL-4Rα-dependent inflammation. IL-4Rα signaling promoted LTα1ß2 (lymphotoxin) expression by B cells, which then interacted with CCL19 positive stromal cells to promote lymphoid enlargement and the formation of germinal center containing B cell follicles. Importantly, de novo follicle formation functioned to promote both total and parasite-specific antibody production. These data reveal a role for type 2 inflammation in promoting stromal cell remodeling and de novo follicle formation by promoting B cell-stromal cell crosstalk.


Asunto(s)
Formación de Anticuerpos/inmunología , Linfocitos B/metabolismo , Helmintiasis/inmunología , Helmintiasis/parasitología , Parasitosis Intestinales/inmunología , Parasitosis Intestinales/parasitología , Linfotoxina-alfa/metabolismo , Nematospiroides dubius/fisiología , Animales , Proliferación Celular , Quimiocina CCL19/metabolismo , Fibroblastos/metabolismo , Fibroblastos/patología , Subunidad alfa del Receptor de Interleucina-4/metabolismo , Ganglios Linfáticos/parasitología , Ganglios Linfáticos/patología , Receptor beta de Linfotoxina/metabolismo , Ratones Endogámicos C57BL , Transducción de Señal , Células del Estroma/patología , Linfocitos T/inmunología
18.
Oncol Rep ; 36(1): 131-6, 2016 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-27220374

RESUMEN

Gas (SF6)-filled microbubbles (MBs) were prepared by emulsion and solvent-evaporation method. The prepared MBs were further conjugated with doxorubicin (Dox)-loaded nano-sized liposome and peptide ligands to interleukin-4 receptor (IL4R) for targeting brain tumor cells. The final MB-liposome (Dox)-IL4R targeting peptide ligand [MB-Lipo (Dox)-IL4RTP] had a spherical structure with the mean size of 1,500 nm. The MB-Lipo (Dox)­IL4RTP exhibited cellular uptake in U87MG brain tumor cells (a brain tumor cell line expressing strongly IL4R) with frequency ultrasound energy suggesting that MB-Lipo (Dox)­IL4RTP provided effective targeting ability for brain tumor cells. In addition, WST-1 assay results showed that MB-Lipo (Dox)­IL4RTP inhibited the proliferation of U87MG cells IL4R­dependently. This was confirmed by western blotting of γH2AX, phospho (Ser15)-p53, p53 and p21 which are signal transduction proteins involved in DNA damage response and cell cycle arrest. Taken together, these results indicate that MB-Lipo (Dox)-IL4RTP represents a promising ultrasonic contrast agent for tumor-targeting ultrasonic imaging.


Asunto(s)
Neoplasias Encefálicas/tratamiento farmacológico , Doxorrubicina/análogos & derivados , Portadores de Fármacos/uso terapéutico , Subunidad alfa del Receptor de Interleucina-4/metabolismo , Microburbujas/uso terapéutico , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Daño del ADN/efectos de los fármacos , Daño del ADN/genética , Reparación del ADN/genética , Doxorrubicina/uso terapéutico , Histonas/metabolismo , Humanos , Liposomas/uso terapéutico , Péptidos/uso terapéutico , Polietilenglicoles/uso terapéutico , Proteína p53 Supresora de Tumor/metabolismo , Ultrasonografía
19.
Cell Transplant ; 25(10): 1863-1877, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-26980267

RESUMEN

Neural stem cells (NSCs) promote recovery from brain trauma, but neuronal replacement is unlikely the sole underlying mechanism. We hypothesize that grafted NSCs enhance neural repair at least partially through modulating the host immune response after traumatic brain injury (TBI). C57BL/6 mice were intracerebrally injected with primed human NSCs (hNSCs) or vehicle 24 h after a severe controlled cortical impact injury. Six days after transplantation, brain tissues were collected for Western blot and immunohistochemical analyses. Observations included indicators of microglia/macrophage activation, M1 and M2 phenotypes, axonal injury detected by amyloid precursor protein (APP), lesion size, and the fate of grafted hNSCs. Animals receiving hNSC transplantation did not show significant decreases of brain lesion volumes compared to transplantation procedures with vehicle alone, but did show significantly reduced injury-dependent accumulation of APP. Furthermore, intracerebral transplantation of hNSCs reduced microglial activation as shown by a diminished intensity of Iba1 immunostaining and a transition of microglia/macrophages toward the M2 anti-inflammatory phenotype. The latter was represented by an increase in the brain M2/M1 ratio and increases of M2 microglial proteins. These phenotypic switches were accompanied by the increased expression of anti-inflammatory interleukin-4 receptor α and decreased proinflammatory interferon-γ receptor ß. Finally, grafted hNSCs mainly differentiated into neurons and were phagocytized by either M1 or M2 microglia/macrophages. Thus, intracerebral transplantation of primed hNSCs efficiently leads host microglia/macrophages toward an anti-inflammatory phenotype that presumably contributes to stem cell-mediated neuroprotective effects after severe TBI in mice.


Asunto(s)
Lesiones Traumáticas del Encéfalo/terapia , Macrófagos/metabolismo , Microglía/metabolismo , Células-Madre Neurales/trasplante , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Antígeno B7-2/metabolismo , Encéfalo/patología , Lesiones Traumáticas del Encéfalo/metabolismo , Lesiones Traumáticas del Encéfalo/patología , Diferenciación Celular , Células Cultivadas , Humanos , Subunidad alfa del Receptor de Interleucina-4/genética , Subunidad alfa del Receptor de Interleucina-4/metabolismo , Lectinas Tipo C/metabolismo , Macrófagos/citología , Macrófagos/inmunología , Masculino , Lectinas de Unión a Manosa/metabolismo , Ratones , Ratones Endogámicos C57BL , Microglía/citología , Microglía/inmunología , Células-Madre Neurales/citología , Neuronas/citología , Neuronas/metabolismo , Fagocitosis , Fenotipo , Receptores de Superficie Celular/metabolismo , Receptores de IgG/metabolismo , Receptores de Interferón/genética , Receptores de Interferón/metabolismo
20.
Oncotarget ; 7(17): 23425-38, 2016 Apr 26.
Artículo en Inglés | MEDLINE | ID: mdl-26993600

RESUMEN

To evaluate the significance of interleukin 4 (IL-4) in tumor development, we compared B16F10 melanoma growth in IL-4-overespressing transgenic mice (IL-4 mice) and non-transgenic mice. In IL-4 mice, reduced tumor volume and weight were observed when compared with those of non-transgenic mice. Significant activation of DNA binding activity of STAT6, phosphorylation of STAT6 as well as IL-4, IL-4Rα and p21 expression were found in the tumor tissues of IL-4 mice compared to non-transgenic mice. Higher expression of IL-4, STAT6 and p21 in human melanoma tissue compared to normal human skin tissue was also found. Higher expression of apoptotic protein such as cleaved caspase-3, cleaved caspase-8, cleaved caspase-9, Bax, p53 and p21, but lower expression levels of survival protein such as Bcl-2 were found in the tumor of IL-4 mice. In vitro study, we found that overexpression of IL-4 significantly inhibited SK-MEL-28 human melanoma cell and B16F10 murine melanoma cell growth via p21-mediated activation of STAT6 pathway as well as increased expression of apoptotic cell death proteins. Moreover, p21 knockdown with siRNA abolished IL-4 induced activation of STAT6 and expression of p53 and p21 accompanied with reduced IL-4 expression as well as melanoma cell growth inhibition. Therefore, these results showed that IL-4 overexpression suppressed tumor development through p21-mediated activation of STAT6 pathways in melanoma models.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Subunidad alfa del Receptor de Interleucina-4/metabolismo , Interleucina-4/metabolismo , Melanoma/patología , Factor de Transcripción STAT6/metabolismo , Animales , Apoptosis , Biomarcadores de Tumor/genética , Proliferación Celular , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Modelos Animales de Enfermedad , Femenino , Humanos , Interleucina-4/genética , Subunidad alfa del Receptor de Interleucina-4/genética , Masculino , Melanoma/genética , Melanoma/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratones Transgénicos , Pronóstico , Factor de Transcripción STAT6/genética , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
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