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1.
Nat Immunol ; 10(12): 1267-74, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19881508

RESUMEN

Nod2 belongs to the nucleotide-binding oligomerization domain receptor (NLR) family of proteins, which function as intracellular pathogen sensors in innate immune cells. Nod2 deficiency results in an impaired immune response to bacterial pathogens. However, how this protein promotes host defense against intracellular parasites is unknown. Here we found that Nod2(-/-) mice had less clearance of Toxoplasma gondii and lower interferon-gamma (IFN-gamma) production. Reconstitution of T cell-deficient mice with Nod2(-/-) T cells followed by T. gondii infection demonstrated a T cell-intrinsic defect. Nod2(-/-) CD4(+) T cells had poor helper T cell differentiation, which was associated with impaired production of interleukin 2 (IL-2) and nuclear accumulation of the transcription factor subunit c-Rel. Our data demonstrate a T cell-intrinsic role for Nod2 signaling that is critical for host defense against T. gondii.


Asunto(s)
Proteína Adaptadora de Señalización NOD2/inmunología , Linfocitos T/inmunología , Toxoplasma/inmunología , Toxoplasmosis/inmunología , Animales , Diferenciación Celular , Colitis/inmunología , Colitis/patología , Interferón gamma/biosíntesis , Interferón gamma/inmunología , Interleucina-2/biosíntesis , Interleucina-2/inmunología , Ratones , Ratones Noqueados , Proteína Adaptadora de Señalización NOD2/deficiencia , Transducción de Señal , Tasa de Supervivencia , Linfocitos T/citología , Toxoplasmosis/metabolismo
2.
J Biol Chem ; 291(25): 13014-27, 2016 Jun 17.
Artículo en Inglés | MEDLINE | ID: mdl-27056325

RESUMEN

Covalent modification of histones is a fundamental mechanism of regulated gene expression in eukaryotes, and interpretation of histone modifications is an essential feature of epigenetic control. Bromodomains are specialized binding modules that interact with acetylated histones, linking chromatin recognition to gene transcription. Because of their ability to function in a domain-specific fashion, selective disruption of bromodomain:acetylated histone interactions with chemical probes serves as a powerful means for understanding biological processes regulated by these chromatin adaptors. Here we describe the discovery and characterization of potent and selective small molecule inhibitors for the bromodomains of CREBBP/EP300 that engage their target in cellular assays. We use these tools to demonstrate a critical role for CREBBP/EP300 bromodomains in regulatory T cell biology. Because regulatory T cell recruitment to tumors is a major mechanism of immune evasion by cancer cells, our data highlight the importance of CREBBP/EP300 bromodomain inhibition as a novel, small molecule-based approach for cancer immunotherapy.


Asunto(s)
Proteína de Unión a CREB/antagonistas & inhibidores , Proteína p300 Asociada a E1A/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Linfocitos T Reguladores/efectos de los fármacos , Acetilación/efectos de los fármacos , Proteína de Unión a CREB/química , Proteína de Unión a CREB/metabolismo , Diferenciación Celular/efectos de los fármacos , Línea Celular , Células Cultivadas , Proteína p300 Asociada a E1A/química , Proteína p300 Asociada a E1A/metabolismo , Factores de Transcripción Forkhead/metabolismo , Histonas/metabolismo , Humanos , Simulación del Acoplamiento Molecular , Estructura Terciaria de Proteína/efectos de los fármacos , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/metabolismo , Transcriptoma/efectos de los fármacos
3.
Eur J Immunol ; 44(12): 3669-79, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25229885

RESUMEN

Anaphylatoxin C5a released upon complement activation is associated with both acute and chronic inflammations such as gout. The pathogenesis of gout was identified as uric acid crystal deposition in the joints that activates inflammasome, leading to IL-1ß release. However, little is known about the interaction between complement activation and monosodium urate/uric acid (MSU) crystal-induced inflammasome activation or IL-1ß production. Here, we report that MSU crystal-induced proinflammatory cytokines/chemokines in human whole blood is predominantly regulated by C5a through its interaction with C5a receptor. C5a induces pro-IL-1ß and IL-1ß production in human primary monocytes, and potentiates MSU or cholesterol crystals in IL-1ß production. This potentiation is caspase-1 dependent and requires intracellular Ca(2+) mobilization, K(+) efflux, and cathepsin B activity. Our results provide insight into the role of C5a as an endogenous priming signal that is required for the initiation of uric acid crystal-induced IL-1ß production. C5a could potentially be a therapeutic target together with IL-1ß antagonists for the treatment of complement-dependent and inflammasome-associated diseases.


Asunto(s)
Antioxidantes/farmacología , Señalización del Calcio/efectos de los fármacos , Complemento C5a/inmunología , Interleucina-1beta/inmunología , Monocitos/inmunología , Ácido Úrico/farmacología , Antioxidantes/efectos adversos , Calcio/inmunología , Señalización del Calcio/inmunología , Caspasa 1/inmunología , Femenino , Humanos , Inflamasomas/inmunología , Masculino , Monocitos/patología , Potasio/inmunología , Ácido Úrico/efectos adversos
4.
Eur J Immunol ; 40(3): 611-5, 2010 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-20201013

RESUMEN

Members of the Nod-like receptor family and the adaptor ASC assemble into multiprotein platforms, termed inflammasomes, to mediate the activation of caspase-1 and subsequent secretion of IL-1beta and IL-18. Recent studies have identified microbial and endogenous molecules as well as possible mechanisms involved in inflammasome activation.


Asunto(s)
Infecciones Bacterianas/inmunología , Inflamación/microbiología , Complejos Multiproteicos/inmunología , Micosis/inmunología , Virosis/inmunología , Animales , Apoptosis/inmunología , Proteínas Adaptadoras de Señalización CARD , Proteínas del Citoesqueleto/inmunología , Humanos , Inflamación/inmunología , Interleucina-1beta/inmunología , Proteínas Adaptadoras de Señalización NOD/inmunología , Transducción de Señal/inmunología
5.
Eur J Immunol ; 40(3): 764-9, 2010 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-19950187

RESUMEN

Cerebral malaria is the most severe complication of Plasmodium falciparum infection in humans and the pathogenesis is still unclear. Using the P. berghei ANKA infection model of mice, we investigated a potential involvement of Nlrp3 and the inflammasome in the pathogenesis of cerebral malaria. Nlrp3 mRNA expression was upregulated in brain endothelial cells after exposure to P. berghei ANKA. Although beta-hematin, a synthetic compound of the parasites heme polymer hemozoin, induced the release of IL-1beta in macrophages through Nlrp3, we did not obtain evidence for a role of IL-1beta in vivo. Nlrp3 knock-out mice displayed a delayed onset of cerebral malaria; however, mice deficient in caspase-1, the adaptor protein ASC or the IL-1 receptor succumbed as WT mice. These results indicate that the role of Nlrp3 in experimental cerebral malaria is independent of the inflammasome and the IL-1 receptor pathway.


Asunto(s)
Encéfalo/inmunología , Proteínas Portadoras/inmunología , Malaria Cerebral/inmunología , Complejos Multiproteicos/inmunología , Animales , Encéfalo/microbiología , Encéfalo/patología , Separación Celular , Modelos Animales de Enfermedad , Endotelio Vascular/inmunología , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Inflamación/inmunología , Interleucina-1beta/biosíntesis , Interleucina-1beta/inmunología , Activación de Linfocitos , Malaria Cerebral/metabolismo , Malaria Cerebral/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína con Dominio Pirina 3 de la Familia NLR , Plasmodium berghei , ARN Mensajero/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Linfocitos T/inmunología
6.
Curr Opin Immunol ; 20(4): 377-82, 2008 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-18585455

RESUMEN

The nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) (nucleotide-binding domain leucine-rich repeat containing) family of proteins has been demonstrated to function as regulators of innate immune response against microbial pathogens. Stimulation of NOD1 and NOD2, two prototypic NLRs, results in the activation of MAPK and NF-kappaB. On the other hand, a different set of NLRs induces caspase-1 activation through the assembly of an inflammasome. This review discusses recent findings regarding the signaling pathways utilized by NLR proteins in the control of caspase-1 and NF-kappaB activation, as well as the nonredundant role of NLRs in pathogen clearance. The review also covers advances regarding the cellular localization of these proteins and the implications this may have on pathogen sensing and signal transduction.


Asunto(s)
Bacterias/inmunología , Proteína Adaptadora de Señalización NOD1/metabolismo , Proteína Adaptadora de Señalización NOD2/metabolismo , Transducción de Señal , Animales , Bacterias/metabolismo , Caspasa 1/inmunología , Caspasa 1/metabolismo , Humanos , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , FN-kappa B/metabolismo , Proteína Adaptadora de Señalización NOD1/química , Proteína Adaptadora de Señalización NOD1/inmunología , Proteína Adaptadora de Señalización NOD2/química , Proteína Adaptadora de Señalización NOD2/inmunología
7.
J Immunol ; 183(9): 5823-9, 2009 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-19812205

RESUMEN

Macrophages play a crucial role in the innate immune response against the human pathogen Streptococcus pyogenes, yet the innate immune response against the bacterium is poorly characterized. In the present study, we show that caspase-1 activation and IL-1beta secretion were induced by live, but not killed, S. pyogenes, and required expression of the pore-forming toxin streptolysin O. Using macrophages deficient in inflammasome components, we found that both NLR family pyrin domain-containing 3 (Nlrp3) and apoptosis-associated speck-like protein (Asc) were crucial for caspase-1 activation and IL-1beta secretion, but dispensable for pro-IL-1beta induction, in response to S. pyogenes infection. Conversely, macrophages deficient in the essential TLR adaptors Myd88 and Trif showed normal activation of caspase-1, but impaired induction of pro-IL-1beta and secretion of IL-1beta. Notably, activation of caspase-1 by TLR2 and TLR4 ligands in the presence of streptolysin O required Myd88/Trif, whereas that induced by S. pyogenes was blocked by inhibition of NF-kappaB. Unlike activation of the Nlrp3 inflammasome by TLR ligands, the induction of caspase-1 activation by S. pyogenes did not require exogenous ATP or the P2X7R. In vivo experiments revealed that Nlrp3 was critical for the production of IL-1beta but was not important for survival in a mouse model of S. pyogenes peritoneal infection. These results indicate that caspase-1 activation in response to S. pyogenes infection requires NF-kappaB and the virulence factor streptolysin O, but proceeds independently of P2X7R and TLR signaling.


Asunto(s)
Proteínas Portadoras/metabolismo , Mediadores de Inflamación/fisiología , FN-kappa B/metabolismo , Receptores Purinérgicos P2/fisiología , Transducción de Señal/inmunología , Streptococcus pyogenes/inmunología , Estreptolisinas/fisiología , Receptores Toll-Like/fisiología , Animales , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/fisiología , Proteínas Portadoras/genética , Proteínas Portadoras/fisiología , Caspasa 1/metabolismo , Células Cultivadas , Modelos Animales de Enfermedad , Mediadores de Inflamación/metabolismo , Interleucina-1beta/biosíntesis , Interleucina-1beta/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Complejos Multiproteicos/genética , Complejos Multiproteicos/metabolismo , Complejos Multiproteicos/fisiología , FN-kappa B/fisiología , Proteína con Dominio Pirina 3 de la Familia NLR , Peritonitis/inmunología , Peritonitis/microbiología , Peritonitis/mortalidad , Precursores de Proteínas/biosíntesis , Precursores de Proteínas/metabolismo , Receptores Purinérgicos P2/deficiencia , Receptores Purinérgicos P2/genética , Receptores Purinérgicos P2X7 , Transducción de Señal/genética , Infecciones Estreptocócicas/inmunología , Infecciones Estreptocócicas/metabolismo , Infecciones Estreptocócicas/mortalidad , Streptococcus pyogenes/genética , Estreptolisinas/deficiencia , Estreptolisinas/metabolismo , Análisis de Supervivencia
8.
J Leukoc Biol ; 83(5): 1249-57, 2008 May.
Artículo en Inglés | MEDLINE | ID: mdl-18252870

RESUMEN

Macrophages play major roles in the onset of immune responses and inflammation by inducing a variety of cytokines such as TNF and IFN-beta. The pathogen-associated molecular pattern, polyinosinic-polycytidylic acid [poly(I:C)], and LPS were used to study type-I IFN and TNF responses in human macrophages. Additionally, activation of the key signaling pathways, IFN-regulatory factor 3 (IRF3) and NF-kappaB, were studied. We found that TNF production occurred rapidly after LPS stimulation. LPS induced a strong IFN-beta mRNA response within a short time-frame, which subsided at 8 h. The IFN-stimulated genes (ISGs), ISG56 and IFN-inducible protein 10, were strongly induced by LPS. These responses were associated with NF-kappaB and IRF3 activation, as shown by IRF3 dimerization and by nuclear translocation assays. poly(I:C), on the other hand, induced a strong and long-lasting (>12 h) IFN-beta mRNA and protein response, particularly when transfected, whereas only a protracted TNF response was observed when poly(I:C) was transfected. However, these responses were induced in the absence of detectable IRF3 and NF-kappaB signaling. Thus, in human macrophages, poly(I:C) treatment induces a distinct cytokine response when compared with murine macrophages. Additionally, a robust IFN-beta response can be induced in the absence of detectable IRF3 activation.


Asunto(s)
Factor 3 Regulador del Interferón/fisiología , Interferón Tipo I/genética , Interferón beta/genética , Lipopolisacáridos/farmacología , Macrófagos/fisiología , FN-kappa B/fisiología , Poli I-C/farmacología , Factor de Necrosis Tumoral alfa/fisiología , Proteínas Adaptadoras Transductoras de Señales , Animales , Humanos , Macrófagos/efectos de los fármacos , Ratones , Monocitos/citología , Monocitos/efectos de los fármacos , Monocitos/fisiología , Proteínas de Unión al ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/efectos de los fármacos , Especificidad de la Especie , Factores de Transcripción/genética
9.
J Interferon Cytokine Res ; 27(9): 751-5, 2007 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-17892396

RESUMEN

Induction of interferon-beta (IFN-beta) gene expression is a tightly regulated process, and a plethora of studies identified the signal transduction pathway TANK-binding kinase-1 (TBK-1)/IFN regulatory factor-3 (IRF-3) as essential to the induction of IFN-beta gene expression. Data regarding the role of p38 and JNK are rare, however. We investigated the contribution of these kinases to IFN-beta expression in human macrophages treated with poly(I:C), lipopolysaccharide (LPS), Sendai virus, or vesicular stomatitis virus (VSV). We found that all the stimuli induced IFN-beta mRNA, albeit to a different extent. Whereas LPS and VSV induced the phosphorylation of p38 and JNK, neither poly(I:C) nor Sendai virus led to the detection of phosphospecific signals. When inhibiting p38, a VSV-triggered IFN-beta mRNA response was inhibited, whereas inhibiting JNK suppressed an LPS-triggered response, but only when macrophages were primed with IFN-gamma. Neither poly(I:C)-induced nor Sendai virus-induced IFN-beta mRNA expression was affected when p38 and JNK were inhibited. Collectively, the data show that the contribution of p38 and JNK to the expression of IFN-beta occurs in a stimulation-specific manner in human macrophages.


Asunto(s)
Interferón beta/genética , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Macrófagos/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Expresión Génica , Humanos , Inductores de Interferón , Interferón gamma/metabolismo , Lipopolisacáridos/inmunología , Activación de Macrófagos , Poli I-C/inmunología , ARN Mensajero/metabolismo , Virus Sendai/inmunología , Virus de la Estomatitis Vesicular Indiana/inmunología
10.
Cell Host Microbe ; 9(6): 496-507, 2011 Jun 16.
Artículo en Inglés | MEDLINE | ID: mdl-21669398

RESUMEN

Secondary bacterial infection is a common sequela to viral infection and is associated with increased lethality and morbidity. However, the underlying mechanisms remain poorly understood. We show that the TLR3/MDA5 agonist poly I:C or viral infection dramatically augments signaling via the NLRs Nod1 and Nod2 and enhances the production of proinflammatory cytokines. Enhanced Nod1 and Nod2 signaling by poly I:C required the TLR3/MDA5 adaptors TRIF and IPS-1 and was mediated by type I IFNs. Mechanistically, poly I:C or IFN-ß induced the expression of Nod1, Nod2, and the Nod-signaling adaptor Rip2. Systemic administration of poly I:C or IFN-ß or infection with murine norovirus-1 promoted inflammation and lethality in mice superinfected with E. coli, which was independent of bacterial burden but attenuated in the absence of Nod1/Nod2 or Rip2. Thus, crosstalk between type I IFNs and Nod1/Nod2 signaling promotes bacterial recognition, but induces harmful effects in the virally infected host.


Asunto(s)
Infecciones por Caliciviridae/complicaciones , Infecciones por Caliciviridae/inmunología , Infecciones por Escherichia coli/inmunología , Infecciones por Escherichia coli/mortalidad , Proteína Adaptadora de Señalización NOD1/inmunología , Proteína Adaptadora de Señalización NOD2/inmunología , Transducción de Señal , Animales , Infecciones por Caliciviridae/genética , Células Cultivadas , Citocinas/genética , Citocinas/inmunología , Escherichia coli/fisiología , Infecciones por Escherichia coli/etiología , Infecciones por Escherichia coli/genética , Femenino , Humanos , Macrófagos/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína Adaptadora de Señalización NOD1/genética , Proteína Adaptadora de Señalización NOD2/genética , Norovirus/fisiología , Poli I-C/inmunología
11.
Cell Host Microbe ; 7(1): 50-61, 2010 Jan 21.
Artículo en Inglés | MEDLINE | ID: mdl-20114028

RESUMEN

Although whole-parasite vaccine strategies for malaria infection have regained attention, their immunological mechanisms of action remain unclear. We find that immunization of mice with a crude blood stage extract of the malaria parasite Plasmodium falciparum elicits parasite antigen-specific immune responses via Toll-like receptor (TLR) 9 and that the malarial heme-detoxification byproduct, hemozoin (HZ), but not malarial DNA, produces a potent adjuvant effect. Malarial and synthetic (s)HZ bound TLR9 directly to induce conformational changes in the receptor. The adjuvant effect of sHZ depended on its method of synthesis and particle size. Although natural HZ acts as a TLR9 ligand, the adjuvant effects of synthetic HZ are independent of TLR9 or the NLRP3-inflammasome but are dependent on MyD88. The adjuvant function of sHZ was further validated in a canine antiallergen vaccine model. Thus, HZ can influence adaptive immune responses to malaria infection and may have therapeutic value in vaccine adjuvant development.


Asunto(s)
Adyuvantes Inmunológicos/farmacología , Hemoproteínas/farmacología , Vacunas contra la Malaria/inmunología , Malaria Falciparum/prevención & control , Plasmodium falciparum/inmunología , Receptor Toll-Like 9/agonistas , Animales , Anticuerpos Antiprotozoarios/sangre , Proteínas Portadoras/genética , Proteínas Portadoras/inmunología , Hipersensibilidad/prevención & control , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factor 88 de Diferenciación Mieloide/deficiencia , Factor 88 de Diferenciación Mieloide/inmunología , Proteína con Dominio Pirina 3 de la Familia NLR , Ovalbúmina/inmunología , Unión Proteica , Conformación Proteica , Receptor Toll-Like 9/deficiencia
12.
J Immunol ; 179(2): 1166-77, 2007 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-17617610

RESUMEN

Listeria monocytogenes is a prototypic bacterium for studying innate and adaptive cellular immunity as well as host defense. Using human monocyte-derived macrophages, we report that an infection with a wild-type strain, but not a listeriolysin O-deficient strain, of the Gram-positive bacterium L. monocytogenes induces expression of IFN-beta and a bioactive type I IFN response. Investigating the activation of signaling pathways in human macrophages after infection revealed that a wild-type strain and a hemolysin-deficient strain of L. monocytogenes activated the NF-kappaB pathway and induced a comparable TNF response. p38 MAPK and activating transcription factor 2 were phosphorylated following infection with either strain, and IFN-beta gene expression induced by wild-type L. monocytogenes was reduced when p38 was inhibited. However, neither IFN regulatory factor (IRF) 3 translocation to the nucleus nor posttranslational modifications and dimerizations were observed after L. monocytogenes infection. In contrast, vesicular stomatitis virus and LPS triggered IRF3 activation and signaling. When IRF3 was knocked down using small interfering RNA, a L. monocytogenes-induced IFN-beta response remained unaffected whereas a vesicular stomatitis virus-triggered response was reduced. Evidence against the possibility that IRF7 acts in place of IRF3 is provided. Thus, we show that wild-type L. monocytogenes induced an IFN-beta response in human macrophages and propose that this response involves p38 MAPK and activating transcription factor 2. Using various stimuli, we show that IRF3 is differentially activated during type I IFN responses in human macrophages.


Asunto(s)
Factor 3 Regulador del Interferón/inmunología , Interferón Tipo I/inmunología , Listeriosis/inmunología , Activación de Macrófagos/inmunología , Macrófagos/inmunología , Factor de Transcripción Activador 2/inmunología , Factor de Transcripción Activador 2/metabolismo , Toxinas Bacterianas , Western Blotting , Células Cultivadas , Electroforesis en Gel de Poliacrilamida , Ensayo de Cambio de Movilidad Electroforética , Ensayo de Inmunoadsorción Enzimática , Técnica del Anticuerpo Fluorescente , Proteínas de Choque Térmico/deficiencia , Proteínas Hemolisinas/deficiencia , Humanos , Factor 3 Regulador del Interferón/metabolismo , Interferón Tipo I/metabolismo , Interferón beta/inmunología , Interferón beta/metabolismo , Listeria monocytogenes/inmunología , Macrófagos/metabolismo , FN-kappa B/inmunología , FN-kappa B/metabolismo , Fagosomas/metabolismo , ARN Interferente Pequeño , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/inmunología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
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