Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 17 de 17
Filtrar
Más filtros











Base de datos
Intervalo de año de publicación
1.
Nat Immunol ; 20(3): 374, 2019 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-30733606

RESUMEN

In the version of this article initially published, the Supplementary Data file was an incorrect version. The correct version is now provided. The error has been corrected in the HTML and PDF version of the article.

2.
J Exp Med ; 215(11): 2737-2747, 2018 11 05.
Artículo en Inglés | MEDLINE | ID: mdl-30337469

RESUMEN

TPL-2 MAP 3-kinase promotes inflammation in numerous mouse disease models and is an attractive anti-inflammatory drug target. However, TPL-2-deficient (Map3k8 -/-) mice develop exacerbated allergic airway inflammation to house dust mite (HDM) compared with wild type controls. Here, we show that Map3k8D270A/D270A mice expressing kinase dead TPL-2 had an unaltered response to HDM, indicating that the severe airway inflammation observed in Map3k8 -/- mice is not due to blockade of TPL-2 signaling and rather reflects a TPL-2 adaptor function. Severe allergic inflammation in TPL-2-deficient mice was likely due to reduced levels of ABIN-2 (TNIP2), whose stability depends on TPL-2 expression. Tnip2E256K knock-in mutation, which reduced ABIN-2 binding to A20, augmented the HDM-induced airway inflammation, but did not affect TPL-2 expression or signaling. These results identify ABIN-2 as a novel negative regulator of allergic airway responses and importantly indicate that TPL-2 inhibitors would not have unwanted allergic comorbidities.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/inmunología , Regulación Enzimológica de la Expresión Génica/inmunología , Hipersensibilidad/inmunología , Quinasas Quinasa Quinasa PAM/inmunología , Sistema de Señalización de MAP Quinasas/inmunología , Proteínas Proto-Oncogénicas/inmunología , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Hipersensibilidad/genética , Hipersensibilidad/patología , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Quinasas Quinasa Quinasa PAM/genética , Sistema de Señalización de MAP Quinasas/genética , Ratones , Ratones Noqueados , Proteínas Proto-Oncogénicas/genética , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/genética , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/inmunología
3.
Nat Immunol ; 19(5): 497-507, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29662170

RESUMEN

The transcription factor c-Maf induces the anti-inflammatory cytokine IL-10 in CD4+ T cells in vitro. However, the global effects of c-Maf on diverse immune responses in vivo are unknown. Here we found that c-Maf regulated IL-10 production in CD4+ T cells in disease models involving the TH1 subset of helper T cells (malaria), TH2 cells (allergy) and TH17 cells (autoimmunity) in vivo. Although mice with c-Maf deficiency targeted to T cells showed greater pathology in TH1 and TH2 responses, TH17 cell-mediated pathology was reduced in this context, with an accompanying decrease in TH17 cells and increase in Foxp3+ regulatory T cells. Bivariate genomic footprinting elucidated the c-Maf transcription-factor network, including enhanced activity of NFAT; this led to the identification and validation of c-Maf as a negative regulator of IL-2. The decreased expression of the gene encoding the transcription factor RORγt (Rorc) that resulted from c-Maf deficiency was dependent on IL-2, which explained the in vivo observations. Thus, c-Maf is a positive and negative regulator of the expression of cytokine-encoding genes, with context-specific effects that allow each immune response to occur in a controlled yet effective manner.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Regulación de la Expresión Génica/inmunología , Redes Reguladoras de Genes/inmunología , Interleucina-2/biosíntesis , Proteínas Proto-Oncogénicas c-maf/inmunología , Animales , Interleucina-2/inmunología , Ratones
4.
Cell Host Microbe ; 22(4): 484-493.e5, 2017 Oct 11.
Artículo en Inglés | MEDLINE | ID: mdl-29024642

RESUMEN

Immunity to intestinal helminth infections has been well studied, but the mechanism of helminth killing prior to expulsion remains unclear. Here we identify epithelial-cell-derived phospholipase A2 group 1B (PLA2g1B) as a host-derived endogenous anthelmintic. PLA2g1B is elevated in resistant mice and is responsible for killing tissue-embedded larvae. Despite comparable activities of other essential type-2-dependent immune mechanisms, Pla2g1b-/- mice failed to expel the intestinal helminths Heligmosomoides polygyrus or Nippostrongylus brasiliensis. Expression of Pla2g1b by epithelial cells was dependent upon intestinal microbiota, adaptive immunity, and common-gamma chain-dependent signaling. Notably, Pla2g1b was downregulated in susceptible mice and inhibited by IL-4R-signaling in vitro, uncoupling parasite killing from expulsion mechanisms. Resistance was restored in Pla2g1b-/- mice by treating infective H. polygyrus L3 larvae with PLA2g1B, which reduced larval phospholipid abundance. These findings uncover epithelial-cell-derived Pla2g1b as an essential mediator of helminth killing, highlighting a previously overlooked mechanism of anti-helminth immunity.


Asunto(s)
Fosfolipasas A2 Grupo IB/inmunología , Mucosa Intestinal/inmunología , Nematospiroides dubius/inmunología , Nippostrongylus/inmunología , Fosfolípidos/metabolismo , Infecciones por Strongylida/inmunología , Inmunidad Adaptativa , Animales , Microbioma Gastrointestinal/inmunología , Fosfolipasas A2 Grupo IB/genética , Mucosa Intestinal/citología , Mucosa Intestinal/enzimología , Larva/inmunología , Ratones , Ratones Noqueados , Cultivo Primario de Células
5.
PLoS Pathog ; 13(7): e1006536, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-28759611

RESUMEN

TPL-2 (COT, MAP3K8) kinase activates the MEK1/2-ERK1/2 MAPK signaling pathway in innate immune responses following TLR, TNFR1 and IL-1R stimulation. TPL-2 contributes to type-1/Th17-mediated autoimmunity and control of intracellular pathogens. We recently demonstrated TPL-2 reduces severe airway allergy to house dust mite by negatively regulating type-2 responses. In the present study, we found that TPL-2 deficiency resulted in resistance to Heligmosomoides polygyrus infection, with accelerated worm expulsion, reduced fecal egg burden and reduced worm fitness. Using co-housing experiments, we found resistance to infection in TPL-2 deficient mice (Map3k8-/-) was independent of microbiota alterations in H. polygyrus infected WT and Map3k8-/-mice. Additionally, our data demonstrated immunity to H. polygyrus infection in TPL-2 deficient mice was not due to dysregulated type-2 immune responses. Genome-wide analysis of intestinal tissue from infected TPL-2-deficient mice identified elevated expression of genes involved in chemotaxis and homing of leukocytes and cells, including Ccl24 and alternatively activated genes. Indeed, Map3k8-/-mice had a significant influx of eosinophils, neutrophils, monocytes and Il4GFP+ T cells. Conditional knockout experiments demonstrated that specific deletion of TPL-2 in CD11c+ cells, but not Villin+ epithelial cells, LysM+ myeloid cells or CD4+ T cells, led to accelerated resistance to H. polygyrus. In line with a central role of CD11c+ cells, CD11c+ CD11b+ cells isolated from TPL-2-deficient mice had elevated Ccl24. Finally, Ccl24 neutralization in TPL-2 deficient mice significantly decreased the expression of Arg1, Retnla, Chil3 and Ear11 correlating with a loss of resistance to H. polygyrus. These observations suggest that TPL-2-regulated Ccl24 in CD11c+CD11b+ cells prevents accelerated type-2 mediated immunity to H. polygyrus. Collectively, this study identifies a previously unappreciated role for TPL-2 controlling immune responses to H. polygyrus infection by restricting Ccl24 production.


Asunto(s)
Quimiocina CCL24/inmunología , Quinasas Quinasa Quinasa PAM/inmunología , Nematospiroides dubius/inmunología , Proteínas Proto-Oncogénicas/inmunología , Infecciones por Strongylida/inmunología , Animales , Quimiocina CCL24/genética , Femenino , Humanos , Inmunidad Innata , Quinasas Quinasa Quinasa PAM/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Nematospiroides dubius/genética , Nematospiroides dubius/fisiología , Proteínas Proto-Oncogénicas/genética , Infecciones por Strongylida/enzimología , Infecciones por Strongylida/genética , Infecciones por Strongylida/parasitología , Células Th2/inmunología
6.
J Exp Med ; 214(6): 1809-1826, 2017 06 05.
Artículo en Inglés | MEDLINE | ID: mdl-28507062

RESUMEN

Immunity to intestinal helminth infections requires the rapid activation of T helper 2 cells (Th2 cells). However, simultaneous expansion of CD4+Foxp3+ regulatory T cells (T reg cells) impedes protective responses, resulting in chronic infections. The ratio between T reg and effector T cells can therefore determine the outcome of infection. The redifferentiation of T reg cells into Th cells has been identified in hyperinflammatory diseases. In this study, we asked whether ex-T reg Th2 cells develop and contribute to type-2 immunity. Using multigene reporter and fate-reporter systems, we demonstrate that a significant proportion of Th2 cells derive from Foxp3+ cells after Heligmosomoides polygyrus infection and airway allergy. Ex-Foxp3 Th2 cells exhibit characteristic Th2 effector functions and provide immunity to H. polygyrus Through selective deletion of Il4ra on Foxp3+ cells, we further demonstrate IL-4 is required for the development of ex-Foxp3 Th2 cells. Collectively, our findings indicate that converting T reg cells into Th2 cells could concomitantly enhance Th2 cells and limit T reg cell-mediated suppression.


Asunto(s)
Factores de Transcripción Forkhead/metabolismo , Inmunidad , Interleucina-4/metabolismo , Intestinos/inmunología , Intestinos/parasitología , Nematospiroides dubius/inmunología , Células Th2/inmunología , Traslado Adoptivo , Animales , Polaridad Celular , Perfilación de la Expresión Génica , Inmunidad/genética , Ratones Endogámicos C57BL , Receptores de Interleucina-4/metabolismo , Transducción de Señal , Infecciones por Strongylida/inmunología , Infecciones por Strongylida/parasitología , Linfocitos T Reguladores/inmunología
7.
J Allergy Clin Immunol ; 139(2): 655-666.e7, 2017 02.
Artículo en Inglés | MEDLINE | ID: mdl-27484038

RESUMEN

BACKGROUND: The molecular and cellular pathways driving the pathogenesis of severe asthma are poorly defined. Tumor progression locus 2 (TPL-2) (COT, MAP3K8) kinase activates the MEK1/2-extracellular-signal regulated kinase 1/2 MAP kinase signaling pathway following Toll-like receptor, TNFR1, and IL-1R stimulation. OBJECTIVE: TPL-2 has been widely described as a critical regulator of inflammation, and we sought to investigate the role of TPL-2 in house dust mite (HDM)-mediated allergic airway inflammation. METHODS: A comparative analysis of wild-type and Map3k8-/- mice was conducted. Mixed bone marrow chimeras, conditional knockout mice, and adoptive transfer models were also used. Differential cell counts were performed on the bronchoalveolar lavage fluid, followed by histological analysis of lung sections. Flow cytometry and quantitative PCR was used to measure type 2 cytokines. ELISA was used to assess the production of IgE, type 2 cytokines, and Ccl24. RNA sequencing was used to characterize dendritic cell (DC) transcripts. RESULTS: TPL-2 deficiency led to exacerbated HDM-induced airway allergy, with increased airway and tissue eosinophilia, lung inflammation, and IL-4, IL-5, IL-13, and IgE production. Increased airway allergic responses in Map3k8-/- mice were not due to a cell-intrinsic role for TPL-2 in T cells, B cells, or LysM+ cells but due to a regulatory role for TPL-2 in DCs. TPL-2 inhibited Ccl24 expression in lung DCs, and blockade of Ccl24 prevented the exaggerated airway eosinophilia and lung inflammation in mice given HDM-pulsed Map3k8-/- DCs. CONCLUSIONS: TPL-2 regulates DC-derived Ccl24 production to prevent severe type 2 airway allergy in mice.


Asunto(s)
Asma/inmunología , Quimiocina CCL24/metabolismo , Células Dendríticas/inmunología , Eosinófilos/inmunología , Pulmón/inmunología , Quinasas Quinasa Quinasa PAM/metabolismo , Neumonía/inmunología , Proteínas Proto-Oncogénicas/metabolismo , Animales , Antígenos Dermatofagoides/inmunología , Citocinas/metabolismo , Inmunoglobulina E/sangre , Quinasas Quinasa Quinasa PAM/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Proto-Oncogénicas/genética , Pyroglyphidae/inmunología , Transducción de Señal , Células Th2/inmunología
8.
PLoS Pathog ; 12(8): e1005783, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-27487182

RESUMEN

Persistent TH2 cytokine responses following chronic helminth infections can often lead to the development of tissue pathology and fibrotic scarring. Despite a good understanding of the cellular mechanisms involved in fibrogenesis, there are very few therapeutic options available, highlighting a significant medical need and gap in our understanding of the molecular mechanisms of TH2-mediated immunopathology. In this study, we found that the Map3 kinase, TPL-2 (Map3k8; Cot) regulated TH2-mediated intestinal, hepatic and pulmonary immunopathology following Schistosoma mansoni infection or S. mansoni egg injection. Elevated inflammation, TH2 cell responses and exacerbated fibrosis in Map3k8-/-mice was observed in mice with myeloid cell-specific (LysM) deletion of Map3k8, but not CD4 cell-specific deletion of Map3k8, indicating that TPL-2 regulated myeloid cell function to limit TH2-mediated immunopathology. Transcriptional and metabolic assays of Map3k8-/-M2 macrophages identified that TPL-2 was required for lipolysis, M2 macrophage activation and the expression of a variety of genes involved in immuno-regulatory and pro-fibrotic pathways. Taken together this study identified that TPL-2 regulated TH2-mediated inflammation by supporting lipolysis and M2 macrophage activation, preventing TH2 cell expansion and downstream immunopathology and fibrosis.


Asunto(s)
Diferenciación Celular/inmunología , Lipólisis/inmunología , Quinasas Quinasa Quinasa PAM/inmunología , Macrófagos/inmunología , Proteínas Proto-Oncogénicas/inmunología , Schistosoma mansoni/inmunología , Esquistosomiasis mansoni/inmunología , Células Th2/inmunología , Animales , Diferenciación Celular/genética , Fibrosis , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Lipólisis/genética , Quinasas Quinasa Quinasa PAM/genética , Macrófagos/patología , Ratones , Ratones Noqueados , Proteínas Proto-Oncogénicas/genética , Esquistosomiasis mansoni/genética , Esquistosomiasis mansoni/patología , Células Th2/patología
9.
Proc Natl Acad Sci U S A ; 113(5): E568-76, 2016 Feb 02.
Artículo en Inglés | MEDLINE | ID: mdl-26787865

RESUMEN

There is a paucity of new therapeutic targets to control allergic reactions and forestall the rising trend of allergic diseases. Although a variety of immune cells contribute to allergy, cytokine-secreting αß(+)CD4(+) T-helper 2 (TH2) cells orchestrate the type-2-driven immune response in a large proportion of atopic asthmatics. To identify previously unidentified putative targets in pathogenic TH2 cells, we performed in silico analyses of recently published transcriptional data from a wide variety of pathogenic TH cells [Okoye IS, et al. (2014) Proc Natl Acad Sci USA 111(30):E3081-E3090] and identified that transcription intermediary factor 1 regulator-alpha (Tif1α)/tripartite motif-containing 24 (Trim24) was predicted to be active in house dust mite (HDM)- and helminth-elicited Il4(gfp+)αß(+)CD4(+) TH2 cells but not in TH1, TH17, or Treg cells. Testing this prediction, we restricted Trim24 deficiency to T cells by using a mixed bone marrow chimera system and found that T-cell-intrinsic Trim24 is essential for HDM-mediated airway allergy and antihelminth immunity. Mechanistically, HDM-elicited Trim24(-/-) T cells have reduced expression of many TH2 cytokines and chemokines and were predicted to have compromised IL-1-regulated signaling. Following this prediction, we found that Trim24(-/-) T cells have reduced IL-1 receptor (IL-1R) expression, are refractory to IL-1ß-mediated activation in vitro and in vivo, and fail to respond to IL-1ß-exacerbated airway allergy. Collectively, these data identify a previously unappreciated Trim24-dependent requirement for IL-1R expression on TH2 cells and an important nonredundant role for T-cell-intrinsic Trim24 in TH2-mediated allergy and antihelminth immunity.


Asunto(s)
Hipersensibilidad/inmunología , Proteínas Nucleares/fisiología , Receptores de Interleucina-1/metabolismo , Células Th2/inmunología , Factores de Transcripción/fisiología , Animales , Helmintos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas Nucleares/genética , Células Th2/metabolismo , Factores de Transcripción/genética
10.
PLoS Pathog ; 11(7): e1004994, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-26147567

RESUMEN

Parasitic helminths establish chronic infections in mammalian hosts. Helminth/Plasmodium co-infections occur frequently in endemic areas. However, it is unclear whether Plasmodium infections compromise anti-helminth immunity, contributing to the chronicity of infection. Immunity to Plasmodium or helminths requires divergent CD4+ T cell-driven responses, dominated by IFNγ or IL-4, respectively. Recent literature has indicated that Th cells, including Th2 cells, have phenotypic plasticity with the ability to produce non-lineage associated cytokines. Whether such plasticity occurs during co-infection is unclear. In this study, we observed reduced anti-helminth Th2 cell responses and compromised anti-helminth immunity during Heligmosomoides polygyrus and Plasmodium chabaudi co-infection. Using newly established triple cytokine reporter mice (Il4gfpIfngyfpIl17aFP635), we demonstrated that Il4gfp+ Th2 cells purified from in vitro cultures or isolated ex vivo from helminth-infected mice up-regulated IFNγ following adoptive transfer into Rag1-/- mice infected with P. chabaudi. Functionally, Th2 cells that up-regulated IFNγ were transcriptionally re-wired and protected recipient mice from high parasitemia. Mechanistically, TCR stimulation and responsiveness to IL-12 and IFNγ, but not type I IFN, was required for optimal IFNγ production by Th2 cells. Finally, blockade of IL-12 and IFNγ during co-infection partially preserved anti-helminth Th2 responses. In summary, this study demonstrates that Th2 cells retain substantial plasticity with the ability to produce IFNγ during Plasmodium infection. Consequently, co-infection with Plasmodium spp. may contribute to the chronicity of helminth infection by reducing anti-helminth Th2 cells and converting them into IFNγ-secreting cells.


Asunto(s)
Coinfección/inmunología , Interferón gamma/metabolismo , Interleucina-12/inmunología , Malaria/inmunología , Infecciones por Strongylida/inmunología , Células Th2/inmunología , Traslado Adoptivo , Animales , Separación Celular , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Interferón gamma/inmunología , Activación de Linfocitos/inmunología , Ratones , Ratones Noqueados , Nematospiroides dubius/inmunología , Plasmodium chabaudi/inmunología , Reacción en Cadena de la Polimerasa
11.
Proc Natl Acad Sci U S A ; 111(30): E3081-90, 2014 Jul 29.
Artículo en Inglés | MEDLINE | ID: mdl-25024218

RESUMEN

Allergic diseases, orchestrated by hyperactive CD4(+) Th2 cells, are some of the most common global chronic diseases. Therapeutic intervention relies upon broad-scale corticosteroids with indiscriminate impact. To identify targets in pathogenic Th2 cells, we took a comprehensive approach to identify the microRNA (miRNA) and mRNA transcriptome of highly purified cytokine-expressing Th1, Th2, Th9, Th17, and Treg cells both generated in vitro and isolated ex vivo from allergy, infection, and autoimmune disease models. We report here that distinct regulatory miRNA networks operate to regulate Th2 cells in house dust mite-allergic or helminth-infected animals and in vitro Th2 cells, which are distinguishable from other T cells. We validated several miRNA (miR) candidates (miR-15a, miR-20b, miR-146a, miR-155, and miR-200c), which targeted a suite of dynamically regulated genes in Th2 cells. Through in-depth studies using miR-155(-/-) or miR-146a(-/-) T cells, we identified that T-cell-intrinsic miR-155 was required for type-2 immunity, in part through regulation of S1pr1, whereas T-cell-intrinsic miR-146a was required to prevent overt Th1/Th17 skewing. These data identify miR-155, but not miR-146a, as a potential therapeutic target to alleviate Th2-medited inflammation and allergy.


Asunto(s)
Helmintiasis Animal/inmunología , Hipersensibilidad/inmunología , MicroARNs/inmunología , Células Th2/inmunología , Animales , Perfilación de la Expresión Génica , Helmintiasis Animal/genética , Helmintiasis Animal/patología , Hipersensibilidad/genética , Hipersensibilidad/patología , Ratones , Ratones Noqueados , MicroARNs/genética , Pyroglyphidae/inmunología , Receptores de Lisoesfingolípidos/genética , Receptores de Lisoesfingolípidos/inmunología , Receptores de Esfingosina-1-Fosfato , Células TH1/inmunología , Células TH1/patología , Células Th17/inmunología , Células Th17/patología , Células Th2/patología
12.
J Biol Chem ; 287(28): 23479-88, 2012 Jul 06.
Artículo en Inglés | MEDLINE | ID: mdl-22613713

RESUMEN

Inflammation characterized by the expression and release of cytokines and chemokines is implicated in the development and progression of atherosclerosis. Oxidatively modified low density lipoproteins, central to the formation of atherosclerotic plaques, have been reported to signal through Toll-like receptors (TLRs), TLR4 and TLR2, in concert with scavenger receptors to regulate the inflammatory microenvironment in atherosclerosis. This study evaluates the role of low density lipoproteins (LDL) and oxidatively modified LDL (oxmLDL) in the expression and release of proinflammatory mediators IκBζ, IL-6, IL-1ß, TNFα, and IL-8 in human monocytes and macrophages. Although standard LDL preparations induced IκBζ along with IL-6 and IL-8 production, this inflammatory effect was eliminated when LDL was isolated under endotoxin-restricted conditions. However, when added with TLR4 and TLR2 ligands, this low endotoxin preparation of oxmLDL suppressed the expression and release of IL-1ß, IL-6, and TNFα but surprisingly spared IL-8 production. The suppressive effect of oxmLDL was specific to monocytes as it did not inhibit LPS-induced proinflammatory cytokines in human macrophages. Thus, TLR ligand contamination of LDL/oxmLDL preparations can complicate interpretations of inflammatory responses to these modified lipoproteins. In contrast to providing a proinflammatory function, oxmLDL suppresses the expression and release of selected proinflammatory mediators.


Asunto(s)
Citocinas/metabolismo , Lipoproteínas LDL/farmacología , Macrófagos/efectos de los fármacos , Monocitos/efectos de los fármacos , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 4/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Antígenos CD36/metabolismo , Células Cultivadas , Citocinas/genética , Relación Dosis-Respuesta a Droga , Citometría de Flujo , Expresión Génica/efectos de los fármacos , Humanos , Proteínas I-kappa B , Immunoblotting , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Lipopéptidos/farmacología , Lipopolisacáridos/farmacología , Macrófagos/citología , Macrófagos/metabolismo , Monocitos/citología , Monocitos/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/efectos de los fármacos , Factores de Tiempo , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo
13.
J Clin Cell Immunol ; Suppl 12: 11, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-24116341

RESUMEN

Significant advances in our understanding of the signalling events during T cell development and differentiation have been made in the past few decades. It is clear that ligation of the T cell receptor (TCR) triggers a series of proximal signalling cascades regulated by an array of protein kinases. These orchestrated and highly regulated series of events, with differential requirements of particular kinases, highlight the disparities between αß+CD4+ T cells. Throughout this review we summarise both new and old studies, highlighting the role of Tec and MAPK in T cell development and differentiation with particular focus on T helper 2 (TH2) cells. Finally, as the allergy epidemic continues, we feature the role played by TH2 cells in the development of allergy and provide a brief update on promising kinase inhibitors that have been tested in vitro, in pre-clinical disease models in vivo and into clinical studies.

14.
Blood ; 117(10): 2855-63, 2011 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-21224476

RESUMEN

Interferon-γ (IFN-γ) production by natural killer (NK) cells and cytotoxic lymphocytes is a key component of innate and adaptive immune responses. Because inhibitor of κB-ζ (IκBζ), a Toll-like receptor (TLR)/interleukin-1 receptor (IL-1R) inducible transcription factor, regulates IFN-γ production in KG-1 cells, we tested IκBζ's role in the classic lymphocyte pathway of IL-12/IL-18-induced IFN-γ. Upon stimulation with IL-12/IL-18, monocyte-depleted human peripheral blood lymphocytes expressed the 79-kDa form of IκBζ and released IFN-γ. CD56(+) NK cells were shown to be the IκBζ-producing lymphocyte subpopulation, which also released abundant IFN-γ in response to IL-12/IL-18. Importantly, IκBζ was undetectable in CD56(-) lymphocytes where IFN-γ release was 10-fold lower. In addition, small interfering RNA knockdown of IκBζ suppressed IFN-γ expression in CD56(+) cells. The association of IκBζ with the IFN-γ promoter was documented by chromatin immunoprecipitation. IFN-γ promoter activity from IκBζ overexpression was confirmed by luciferase reporter assay. Finally, IκBζ coprecipitated with p65 and p50 NF-κB in NK cells in response to IL-12/IL-18, suggesting that IκBζ's effects on IFN-γ promoter activity are coregulated by NF-κB. These results suggest that IκBζ functions as an important regulator of IFN-γ in human NK cells, further expanding the class of IκBζ-modulated genes.


Asunto(s)
Regulación de la Expresión Génica/inmunología , Interferón gamma/biosíntesis , Interleucina-12/metabolismo , Interleucina-18/metabolismo , Células Asesinas Naturales/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Ensayo de Inmunoadsorción Enzimática , Expresión Génica , Regulación de la Expresión Génica/genética , Humanos , Proteínas I-kappa B , Immunoblotting , Inmunoprecipitación , Interferón gamma/genética , Interferón gamma/inmunología , Interleucina-12/genética , Interleucina-12/inmunología , Interleucina-18/inmunología , Células Asesinas Naturales/inmunología , Proteínas Nucleares/genética , Proteínas Nucleares/inmunología , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena de la Polimerasa , ARN Interferente Pequeño
15.
J Immunol ; 183(8): 5358-68, 2009 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-19783680

RESUMEN

IL-6 is a pleiotropic cytokine implicated in the pathogenesis of disorders such as sepsis and cancer. We noted that human monocytes are excellent producers of IL-6 as compared with monocyte-derived macrophages. Because macrophages from molecule containing ankyrin repeats induced by LPS (MAIL) knockout animals have suppressed IL-6 production, we hypothesized that regulation of MAIL is key to IL-6 production in humans and may explain the differences between human monocytes and macrophages. To test this hypothesis fresh human monocytes and monocyte-derived macrophages were compared for MAIL expression in response to LPS. LPS-induced monocyte MAIL expression was highly inducible and transient. Importantly for our hypothesis MAIL protein expression was suppressed during differentiation of monocytes to macrophages. Of note, the human MAIL protein detected was the 80 kDa MAIL-L form and human MAIL showed nuclear localization. Human MAIL-L bound to p50 subunit of the NF-kappaB and increased IL-6 luciferase promoter activity in a cEBPbeta, NF-kappaB, and AP-1-dependent fashion. Like the differences in MAIL induction, monocytes produced 6-fold more IL-6 compared with macrophages (81.7 +/- 29.7 vs 12.6 +/- 6.8 ng/ml). Furthermore, suppression of MAIL by small interfering RNA decreased the production of IL-6 significantly in both THP-1 cells and in primary monocytes. Costimulation of monocytes with LPS and muramyl dipeptide induced an enhanced IL-6 response that was suppressed by siMAIL. Our data suggests that MAIL is a key regulator of IL-6 production in human monocytes and plays an important role in both TLR and NOD-like receptor ligand induced inflammation.


Asunto(s)
Interleucina-6/biosíntesis , Macrófagos/inmunología , Monocitos/inmunología , Proteínas Nucleares/metabolismo , Acetilmuramil-Alanil-Isoglutamina/farmacología , Proteínas Adaptadoras Transductoras de Señales , Adyuvantes Inmunológicos/farmacología , Línea Celular , Células Cultivadas , Técnicas de Silenciamiento del Gen , Humanos , Proteínas I-kappa B , Interleucina-1beta/farmacología , Interleucina-6/inmunología , Lipopolisacáridos/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Monocitos/efectos de los fármacos , Subunidad p50 de NF-kappa B/inmunología , Subunidad p50 de NF-kappa B/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/inmunología , Regiones Promotoras Genéticas/inmunología , ARN Interferente Pequeño/inmunología , ARN Interferente Pequeño/metabolismo , Factor de Transcripción AP-1/inmunología , Factor de Transcripción AP-1/metabolismo , Factor de Necrosis Tumoral alfa/farmacología
16.
PLoS One ; 4(8): e6776, 2009 Aug 26.
Artículo en Inglés | MEDLINE | ID: mdl-19707556

RESUMEN

IkappaBzeta is a novel member of the IkappaB family of NFkappaB regulators, which modulates NFkappaB activity in the nucleus, rather than controlling its nuclear translocation. IkappaBzeta is specifically induced by IL-1beta and several TLR ligands and positively regulates NFkappaB-mediated transcription of genes such as IL-6 and NGAL as an NFkappaB binding co-factor. We recently reported that the IL-1 family cytokines, IL-1beta and IL-18, strongly synergize with TNFalpha for IFNgamma production in KG-1 cells, whereas the same cytokines alone have minimal effects on IFNgamma production. Given the striking similarities between the IL-1R and IL-18R signaling pathways we hypothesized that a common signaling event or gene product downstream of these receptors is responsible for the observed synergy. We investigated IkappaBzeta protein expression in KG-1 cells upon stimulation with IL-1beta, IL-18 and TNFalpha. Our results demonstrated that IL-18, as well as IL-1beta, induced moderate IkappaBzeta expression in KG-1 cells. However, TNFalpha synergized with IL-1beta and IL-18, whereas by itself it had a minimal effect on IkappaBzeta expression. NFkappaB inhibition resulted in decreased IL-1beta/IL-18/TNFalpha-stimulated IFNgamma release. Moreover, silencing of IkappaBzeta expression led to a specific decrease in IFNgamma production. Overall, our data suggests that IkappaBzeta positively regulates NFkappaB-mediated IFNgamma production in KG-1 cells.


Asunto(s)
Interferón gamma/biosíntesis , Proteínas Nucleares/fisiología , Proteínas Adaptadoras Transductoras de Señales , Western Blotting , Línea Celular , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Humanos , Proteínas I-kappa B , Reacción en Cadena de la Polimerasa , ARN Interferente Pequeño
17.
Cytokine ; 44(2): 234-41, 2008 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-18805021

RESUMEN

Although much is known about classic IFNgamma inducers, little is known about the IFNgamma inducing capability of inflammasome-activated monocytes. In this study, supernatants from LPS/ATP-stimulated human monocytes were analyzed for their ability to induce IFNgamma production by KG-1 cells. Unexpectedly, monocyte-derived IFN inducing activity was detected, but it was completely inhibited by IL-1beta, not IL-18 blockade. Moreover, size-fractionation of the monocyte conditioned media dramatically reduced the IFNgamma inducing activity of IL-1beta, suggesting that IL-1beta requires a cofactor to induce IFNgamma production in KG-1 cells. Because TNFalpha is known to synergize with IL-1beta for various gene products, it was studied as the putative IL-1beta synergizing factor. Although recombinant TNFalpha (rTNFalpha) alone had no IFNgamma inducing activity, neutralization of TNFalpha in the monocyte conditioned media inhibited the IFNgamma inducing activity. Furthermore, rTNFalpha restored the IFNgamma inducing activity of the size-fractionated IL-1beta. Finally, rTNFalpha synergized with rIL-1beta, as well as with rIL-1alpha and rIL-18, for KG-1 IFNgamma release. These studies demonstrate a synergistic role between TNFalpha and IL-1 family members in the induction of IFNgamma production and give caution to interpretations of KG-1 functional assays designed to detect functional IL-18.


Asunto(s)
Interferón gamma/inmunología , Interleucina-1beta/inmunología , Monocitos/inmunología , Factor de Necrosis Tumoral alfa/inmunología , Caspasa 1/metabolismo , Inhibidores de Caspasas , Células Cultivadas , Humanos , Interleucina-18/inmunología , Lipopolisacáridos/inmunología , Lipopolisacáridos/farmacología , Monocitos/citología , Monocitos/efectos de los fármacos
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA