RESUMEN
Epigenetic modification, including histone modification, precisely controls target gene expression. The posttranscriptional regulation of the innate signaling-triggered production of inflammatory cytokines and type I interferons has been fully elucidated, whereas the roles of histone modification alteration and epigenetic modifiers in regulating inflammatory responses need to be further explored. Di/tri-methylation modifications of histone 3 lysine 79 (H3K79me2/3) have been shown to be associated with gene transcriptional activation. Disruptor of telomeric silencing-1-like (Dot1l) is the only known exclusive H3K79 methyltransferase and regulates the proliferation and differentiation of tumor cells. However, the roles of Dot1l and Dot1l-mediated H3K79 methylation in innate immunity and inflammatory responses remain unclear. Here, we found that H3K79me2/3 modification levels at the Il6 and Ifnb1 promoters, as well as H3K79me2 modification at the Tnfα promoter, were increased in macrophages activated by Toll-like receptor (TLR) ligands or virus infection. The innate signals upregulated Dot1l expression in macrophages and THP1 cells. Dot1l silencing or a Dot1l inhibitor preferentially suppressed the production of IL-6 and interferon (IFN)-ß but not of TNF-α in macrophages and THP1 cells triggered by TLR ligands or virus infection. Dot1l was recruited to the proximal promoter of the Il6 and Ifnb1 but not Tnfα gene and then mediated H3K79me2/3 modification at the Il6 and Ifnb1 promoters, consequently facilitating the transcription and expression of Il6 and Ifnb1. Thus, Dot1l-mediated selective H3K79me2/3 modifications at the Il6 and Ifnb1 promoters are required for the full activation of innate immune responses. This finding adds new insights into the epigenetic regulation of inflammatory responses and pathogenesis of autoimmune diseases.
Asunto(s)
N-Metiltransferasa de Histona-Lisina/inmunología , Histonas/inmunología , Inmunidad Innata , Interferón beta/inmunología , Interleucina-6/inmunología , Macrófagos/inmunología , Animales , Masculino , Metilación , RatonesRESUMEN
IL-6 plays important and pleiotropic roles in infection and inflammatory diseases, and its production needs to be tightly regulated. However, the epigenetic mechanism underlying Il6 gene transcription remains to be fully elucidated. Here, we report that lysine-specific demethylase 2b (KDM2B), which demethylates H3K4me3 and H3K36me2, is required in macrophages and dendritic cells for the induction of IL-6 but not TNF-α, IL-1, and IFN-ß. Compared to wild-type mice, KDM2B-deficient mice were more resistant to endotoxin shock and colitis, with a less severe inflammatory pathogenesis phenotype and decreased IL-6 production in sera. KDM2B selectively bound the Il6 promoter but did not alter histone demethylation; instead, KDM2B interacted with Brahma-related gene 1 (Brg1), the core ATPase subunit of SWI/SNF chromatin remodeling complexes, to facilitate chromatin accessibility of the Il6 promoter. Furthermore, KDM2B directly recruited RNA Polymerase II to further initiate and promote Il6 transcription. Thus, our finding identifies a novel nonclassical function of KDM2B in gene-specific transcription initiation and enhancement of Il6 independent of its demethylase activity and adds new insight into the specific epigenetic modification mechanism of inflammatory immune responses.
Asunto(s)
Ensamble y Desensamble de Cromatina , ADN Helicasas , Proteínas F-Box , Inflamación , Interleucina-6 , Histona Demetilasas con Dominio de Jumonji , Proteínas Nucleares , Factores de Transcripción , Humanos , Cromatina/metabolismo , Ensamble y Desensamble de Cromatina/genética , ADN Helicasas/metabolismo , Metilación de ADN/genética , Proteínas F-Box/metabolismo , Células HEK293 , Inmunidad Innata , Inflamación/genética , Inflamación/inmunología , Interleucina-6/biosíntesis , Histona Demetilasas con Dominio de Jumonji/deficiencia , Histona Demetilasas con Dominio de Jumonji/metabolismo , Proteínas Nucleares/metabolismo , Regiones Promotoras Genéticas , Unión Proteica/genética , ARN Polimerasa II/metabolismo , Factores de Transcripción/metabolismo , Activación Transcripcional/genética , Animales , RatonesRESUMEN
The transcription factor interferon regulatory factor 3 (IRF3) is essential for virus infection-triggered induction of type I interferons (IFN-I) and innate immune responses. IRF3 activity is tightly regulated by conventional posttranslational modifications (PTMs) such as phosphorylation and ubiquitination. Here, we identify an unconventional PTM of IRF3 that directly inhibits its transcriptional activity and attenuates antiviral immune response. We performed an RNA interference screen and found that lysine acetyltransferase 8 (KAT8), which is ubiquitously expressed in immune cells (particularly in macrophages), selectively inhibits RNA and DNA virus-triggered IFN-I production in macrophages and dendritic cells. KAT8 deficiency protects mice from viral challenge by enhancing IFN-I production. Mechanistically, KAT8 directly interacts with IRF3 and mediates IRF3 acetylation at lysine 359 via its MYST domain. KAT8 inhibits IRF3 recruitment to IFN-I gene promoters and decreases the transcriptional activity of IRF3. Our study reveals a critical role for KAT8 and IRF3 lysine acetylation in the suppression of antiviral innate immunity.
Asunto(s)
Histona Acetiltransferasas/metabolismo , Inmunidad Innata/inmunología , Factor 3 Regulador del Interferón/metabolismo , Estomatitis Vesicular/inmunología , Virus de la Estomatitis Vesicular Indiana/inmunología , Acetilación , Animales , Células Dendríticas/metabolismo , Células Dendríticas/virología , Femenino , Células HEK293 , Histona Acetiltransferasas/genética , Humanos , Factor 3 Regulador del Interferón/genética , Interferón Tipo I/metabolismo , Macrófagos/metabolismo , Macrófagos/virología , Masculino , Ratones , Ratones Endogámicos C57BL , Células RAW 264.7 , Interferencia de ARN , Activación Transcripcional , Transfección , Estomatitis Vesicular/virologíaRESUMEN
The cross-talk between cellular lipid metabolism and the innate immune responses remains obscure. In addition to presenting lipid antigens to Natural Killer T-cells (NKT cells), the Cluster of Differentiation 1D Glycoprotein (CD1d) might mediate reverse signaling in antigen-presenting cells (APCs). Here we found CD1d deficiency attenuated Toll-like receptor (TLR)-triggered inflammatory innate responses in macrophages and dendritic cells, protecting mice from endotoxin shock. TLR activation in macrophages induced metabolic changes of glycosphingolipids (GSLs), among which glycolipid isoglobotrihexosylceramide (iGb3) was rapidly produced. The endogenously generated iGb3 bound CD1d in endosomal compartments and then synergized with the initially activated TLR signal to induce Tyr332 phosphorylation of CD1d intracellular domain. This led to the recruitment and activation of proline-rich tyrosine kinase 2 (Pyk2). Pyk2 interacted with IκB kinase ß (IKKß) and TANK-binding kinase 1 (TBK1), and enhanced tyrosine phosphorylation of Tyr188/199 of IKKß and Tyr179 of TBK1 and thus, their activation to promote full activation of TLR signaling. Thus, intracellular CD1d reverse signaling, triggered by endogenous iGb3, amplifies inflammatory innate responses in APCs. Our findings identify a non-canonical function of CD1d reverse signaling activated by lipid metabolite in the innate immune response.
Asunto(s)
Antígenos CD1d/fisiología , Citocinas/inmunología , Células Dendríticas/inmunología , Globósidos/metabolismo , Monocitos/inmunología , Trihexosilceramidas/metabolismo , Animales , Presentación de Antígeno , Células HEK293 , Humanos , Inmunidad Innata , RatonesRESUMEN
The NLRP3 inflammasome has a fundamental role in host defence against microbial pathogens and its deregulation may cause diverse inflammatory diseases. NLRP3 protein expression is a rate-limiting step for inflammasome activation, thus its expression must be tightly controlled to maintain immune homeostasis and avoid detrimental effects. However, how NLRP3 expression is regulated remains largely unknown. In this study, we identify E3 ubiquitin ligase TRIM31 as a feedback suppressor of NLRP3 inflammasome. TRIM31 directly binds to NLRP3, promotes K48-linked polyubiquitination and proteasomal degradation of NLRP3. Consequently, TRIM31 deficiency enhances NLRP3 inflammasome activation and aggravates alum-induced peritonitis in vivo. Furthermore, TRIM31 deficiency attenuates the severity of dextran sodium sulfate (DSS)-induced colitis, an inflammatory bowel diseases model in which NLRP3 possesses protective roles. Thus, our research describes a mechanism by which TRIM31 limits NLRP3 inflammasome activity under physiological conditions and suggests TRIM31 as a potential therapeutic target for the intervention of NLRP3 inflammasome related diseases.
Asunto(s)
Proteínas Portadoras/metabolismo , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteínas Nucleares/metabolismo , Compuestos de Alumbre , Animales , Colitis/inducido químicamente , Sulfato de Dextran , Femenino , Interleucina-1beta/metabolismo , Lipopolisacáridos , Ratones Endogámicos C57BL , Ratones Noqueados , Peritonitis/inducido químicamente , Peritonitis/metabolismo , Poliubiquitina/metabolismo , Cultivo Primario de Células , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteínas de Motivos Tripartitos , Ubiquitina-Proteína Ligasas , UbiquitinaciónRESUMEN
Type I IFNs (IFN-α/ß) play crucial roles in the elimination of invading viruses. Multiple immune cells including macrophages recognize viral infection through a variety of pattern recognition receptors, such as Toll-like receptors (TLRs) and retinoic acid-inducible gene-I (RIG-I)-like receptors, and initiate type I IFN secretion and subsequent antiviral immune responses. However, the mechanisms by which host immune cells can produce adequate amounts of type I IFNs and then eliminate viruses effectively remain to be further elucidated. In the present study, we show that munc18-1-interacting protein 3 (Mint3) expression can be markedly induced during viral infection in macrophages. Mint3 enhances TLR3/4- and RIG-I-induced IRF3 activation and IFN-ß production by promoting K63-linked polyubiquitination of TNF receptor-associated factor 3 (TRAF3). Consistently, Mint3 deficiency greatly attenuated antiviral immune responses and increased viral replication. Therefore, we have identified Mint3 as a physiological positive regulator of TLR3/4 and RIG-I-induced IFN-ß production and have outlined a feedback mechanism for the control of antiviral immune responses.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteína 58 DEAD Box/metabolismo , Interacciones Huésped-Patógeno/inmunología , Interferón beta/genética , Receptor Toll-Like 3/metabolismo , Receptor Toll-Like 4/metabolismo , Virosis/etiología , Virosis/metabolismo , Proteínas Adaptadoras Transductoras de Señales/química , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Biomarcadores , Línea Celular , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Humanos , Factor 3 Regulador del Interferón/genética , Factor 3 Regulador del Interferón/metabolismo , Interferón beta/metabolismo , Macrófagos Peritoneales/inmunología , Macrófagos Peritoneales/metabolismo , Macrófagos Peritoneales/virología , Ratones , Ratones Noqueados , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Factor 3 Asociado a Receptor de TNF/metabolismo , UbiquitinaciónRESUMEN
Type I IFN production is tightly controlled by host to generate efficient viral clearance without harmful immunopathology or induction of autoimmune disorders. Epigenetic regulation of type I IFN production in innate immunity and inflammatory disorders remains to be fully understood. Several tumor suppressors have been shown to regulate immune response and inflammation. However, the non-classical functions of tumor suppressors in innate immunity and inflammatory diseases need further identification. Here we report retinoblastoma protein (Rb) deficiency selectively enhanced TLR- and virus-triggered production of IFN-ß which thus induced more IFN-α generation in the later phase of innate stimuli, but had no effect on the production of TNF, IL-6 and early phase IFN-α in macrophages. Rb1(fl/fl)Lyz2cre(+) Rb-deficient mice exhibited more resistant to lethal virus infection and more effective clearance of influenza virus. Rb selectively bound Ifnb1 enhancer region, but not the promoter of Ifna4, Tnf and Il6, by interacting with c-Jun, the component of IFN-ß enhanceosome. Then Rb recruited HDAC1 and HDAC8 to attenuate acetylation of Histone H3/H4 in Ifnb1 promoter, resulting in suppression of Ifnb1 transcription. Therefore, Rb selectively inhibits innate IFN-ß production by enhancing deacetylation of Ifnb1 promoter, exhibiting a previous unknown non-classical role in innate immunity, which also suggests a role of Rb in the regulation of type I IFN production in inflammatory or autoimmune diseases.
Asunto(s)
Acetilación , Inmunidad Innata/genética , Interferón beta/genética , Interferón beta/inmunología , Regiones Promotoras Genéticas , Proteína de Retinoblastoma/genética , Animales , Enfermedades Autoinmunes/genética , Elementos de Facilitación Genéticos , Epigénesis Genética , Femenino , Células HEK293 , Histona Desacetilasa 1/genética , Histona Desacetilasa 1/metabolismo , Histona Desacetilasas/genética , Histona Desacetilasas/metabolismo , Histonas/metabolismo , Humanos , Inflamación/genética , Interferón-alfa/metabolismo , Interferón beta/metabolismo , Interleucina-6/metabolismo , Macrófagos/metabolismo , Masculino , Ratones , Proteínas Proto-Oncogénicas c-jun/genética , Proteínas Proto-Oncogénicas c-jun/metabolismo , Células RAW 264.7 , Interferencia de ARN , ARN Interferente Pequeño , Proteína de Retinoblastoma/metabolismo , Receptores Toll-Like/metabolismo , Transcripción Genética , Factor de Necrosis Tumoral alfa/metabolismo , Virosis/inmunologíaRESUMEN
Neddylation is a posttranslational protein modification that conjugates ubiquitin-like protein neural precursor cell-expressed developmentally downregulated protein 8 (NEDD8) to target proteins and regulates diverse cellular processes. MLN4924, a novel NEDD8 activating enzyme inhibitor, which has emerged as a promising anticancer drug, has a multifaceted function by inhibiting the process of neddylation. However, the potential roles of MLN4924 and neddylation in IFN-ß production remain unknown. In this study, we show that MLN4924 inhibits TLR3/4- and retinoic acid-inducible gene-I-induced IFN-ß expression in different cells, whereas NEDD8 knockdown had no effects on IFN-ß expression. The ability of the MLN4924 to inhibit IFN-ß production was confirmed in vivo, as mice treated with MLN4924 exhibited decreased levels of IFN-ß upon LPS or polyinosinic-polycytidylic acid stimulation. Furthermore, we show that MLN4924 inhibits IFN regulatory factor 3 (IRF3) transcriptional activation and prevents IRF3 binding to IFN-ß promoter. Our findings suggest that MLN4924 inhibits TLR3/4- and retinoic acid-inducible gene-I-induced IFN-ß expression by preventing IRF3 binding to the IFN-ß promoter, with a neddylation-independent manner. Therefore, our results provide new insight into the mechanism of MLN4924 and may have significant implications for the treatment of MLN4924.
Asunto(s)
Ciclopentanos/farmacología , Interferón beta/biosíntesis , Pirimidinas/farmacología , Ubiquitinas/antagonistas & inhibidores , Animales , Línea Celular , Femenino , Humanos , Factor 3 Regulador del Interferón/genética , Factor 3 Regulador del Interferón/metabolismo , Interferón beta/genética , Macrófagos Peritoneales/efectos de los fármacos , Macrófagos Peritoneales/inmunología , Macrófagos Peritoneales/metabolismo , Ratones , Proteína NEDD8 , Fosforilación , Regiones Promotoras Genéticas , Unión Proteica , Transcripción Genética , Activación Transcripcional/efectos de los fármacos , Replicación Viral/efectos de los fármacosRESUMEN
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. The incidence of HCC is strikingly higher in males than in females. The remarkable gender disparity suggests an important role for sex hormones in HCC pathogenesis. Recently, estrogen has emerged as a protective factor in the development and progression of HCC, but whether it prevents and attenuates HCC, and the mechanism of protection, have not been elucidated. The present study shows that expression of estrogen receptor (ER) ß was significantly downregulated in HCC tissue compared with normal liver tissue; moreover, its expression level showed a significant negative correlation with disease progression and a positive correlation with the expression level of NLRP3 inflammasome components. In a previous study, we showed that loss of NLRP3 inflammasome in HCC tissue contributed to tumor progression, whereas the mechanism of its deregulation was not elucidated. In this study, we investigated the potential link between NLRP3 inflammasome and estrogen. Our data reveal that treatment with 17ß-estradiol (E2) significantly inhibited the malignant behavior of HCC cells through E2/ERß/MAPK pathway-mediated upregulation of the NLRP3 inflammasome. This study shows a novel link between ERß and the NLRP3 inflammasome in HCC progression, which provides a potentially valuable therapeutic strategy for treatment of HCC patients.
Asunto(s)
Carcinoma Hepatocelular/metabolismo , Proteínas Portadoras/metabolismo , Estradiol/metabolismo , Receptor beta de Estrógeno/metabolismo , Neoplasias Hepáticas/metabolismo , Carcinoma Hepatocelular/etiología , Regulación hacia Abajo , Femenino , Células Hep G2 , Humanos , Inflamasomas/metabolismo , Neoplasias Hepáticas/etiología , Sistema de Señalización de MAP Quinasas , Masculino , Persona de Mediana Edad , Proteína con Dominio Pirina 3 de la Familia NLRRESUMEN
TLR4 recruits TRIF-related adaptor molecule (TRAM, also known as TICAM2) as a sorting adaptor to facilitate the interaction between TLR4 and TRIF and then initiate TRIF-dependent IRF3 activation. However, the mechanisms by which TRAM links downstream molecules are not fully elucidated. In this study, we show that TRAM undergoes tyrosine phosphorylation upon TLR4 activation and that is required for TLR4-induced IRF3 activation. Protein tyrosine phosphatase nonreceptor type 4 (PTPN4), a protein tyrosine phosphatase, inhibits tyrosine phosphorylation and subsequent cytoplasm translocation of TRAM, resulting in the disturbance of TRAM-TRIF interaction. Consequently, PTPN4 specifically inhibits TRIF-dependent IRF3 activation and IFN-ß production in TLR4 pathway. Therefore, our results provide new insight into the TLR4 pathway and identify PTPN4 as a specific inhibitor of TRIF-dependent TLR4 pathway. Targeting PTPN4 would be beneficial for the development of new strategy to control TLR4-associated diseases without unwanted side effects.
Asunto(s)
Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 4/metabolismo , Receptores de Interleucina/metabolismo , Transducción de Señal , Receptor Toll-Like 4/metabolismo , Secuencia de Aminoácidos , Animales , Línea Celular , Femenino , Humanos , Factor 3 Regulador del Interferón/metabolismo , Interferón beta/biosíntesis , Macrófagos Peritoneales/metabolismo , Ratones , Modelos Moleculares , Datos de Secuencia Molecular , Fosforilación , Unión Proteica , Conformación Proteica , Receptores de Interleucina/química , Alineación de SecuenciaRESUMEN
Resistance to anoikis and Epithelial-mesenchymal transition (EMT) are two processes critically involved in cancer metastasis. In this study, we demonstrated that after anchorage deprival, hepatocellular carcinoma (HCC) cells not only resisted anoikis, but also exhibited EMT process. Microarray expression profiling revealed that expression of miR-424-5p was significantly decreased in anoikis-resistant HCC cells. Ectopic overexpression of miR-424-5p was sufficient to reverse resistance to anoikis, block EMT process and inhibit malignant behaviors of HCC cells. Target analysis showed that a potent ß-catenin inhibitor, ICAT/CTNNBIP1 was a direct target of miR-424-5p. Further study demonstrated that miR-424-5p reversed resistance to anoikis and EMT of HCCs by directly targeting ICAT and further maintaining the E-cadherin/ß-catanin complex on the cellular membrance. In vivo study further demonstrated that miR-424-5p significantly inhibited the tumorigenicity of HCC cells in nude mice. Clinical investigation demonstrated that miR-424-5p was significantly downregulated in HCC tissues compared with that of the non-cancerous liver tissues, and this decreased expression of miR-424-5p was significantly correlated with higher pathological grades and more advanced TNM stages. Therefore, aberrant expression of miR-424-5p is critically involved in resistance to anoikis and EMT during the metastatic process of HCC, and its downregulation significantly contributes to liver cancer progression.
Asunto(s)
Carcinoma Hepatocelular/genética , Transición Epitelial-Mesenquimal/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Neoplasias Hepáticas/genética , MicroARNs/genética , Proteínas Adaptadoras Transductoras de Señales , Animales , Cadherinas/genética , Carcinoma Hepatocelular/patología , Línea Celular , Línea Celular Tumoral , Progresión de la Enfermedad , Regulación hacia Abajo/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Células HEK293 , Células Hep G2 , Humanos , Hígado/patología , Neoplasias Hepáticas/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Persona de Mediana Edad , beta Catenina/genéticaRESUMEN
NLRP3 inflammasome is a multi-protein complex, which plays crucial roles in host defense against pathogens. The NLRP3 protein level is considered rate limiting for the activation of the inflammasome, thus its expression must be tightly controlled to maintain immune homeostasis. However, the molecular mechanisms that modulate NLRP3 expression, especially at the transcriptional level, remain largely unknown. In the present study, we show that aryl hydrocarbon receptor (AhR) activation inhibits NLRP3 expression, caspase-1 activation and subsequent IL-1ß secretion in peritoneal macrophages, whereas siRNA knockdown of AhR has opposite effects. AhR could bind to the xenobiotic response element (XRE) in the NLRP3 promoter and inhibit NLRP3 transcription. Furthermore, AhR activation suppresses Alum-induced peritonitis in vivo. Therefore, we identified AhR as a negative regulator of NLRP3 inflammasome activity by inhibiting the transcription of NLRP3 and suggested AhR as a potential target for the intervention of diseases with uncontrolled inflammasome activation.
Asunto(s)
Proteínas Portadoras/genética , Inflamasomas/genética , Macrófagos Peritoneales/inmunología , Peritonitis/genética , Receptores de Hidrocarburo de Aril/genética , Compuestos de Alumbre , Animales , Proteínas Portadoras/inmunología , Caspasa 1/genética , Caspasa 1/inmunología , Dimetilsulfóxido , Femenino , Regulación de la Expresión Génica , Inflamasomas/inmunología , Interleucina-1beta/genética , Interleucina-1beta/inmunología , Macrófagos Peritoneales/patología , Ratones , Ratones Endogámicos C57BL , Proteína con Dominio Pirina 3 de la Familia NLR , Peritonitis/inducido químicamente , Peritonitis/inmunología , Peritonitis/patología , Cultivo Primario de Células , Unión Proteica , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Receptores de Hidrocarburo de Aril/antagonistas & inhibidores , Receptores de Hidrocarburo de Aril/inmunología , Elementos de Respuesta , Transducción de Señal , Transcripción GenéticaRESUMEN
OBJECTIVE: NOD-like receptor family, pyrin domain containing 3 and 1 (NLRP3 and NLRP1) inflammasomes are molecular platforms that sense the damage or danger signals of cells. We investigated whether NLRP3/NLRP1 inflammasomes are involved in the pathogenesis and progression of systemic lupus erythematosus (SLE). METHODS: Expressions of inflammasome components at the mRNA and protein levels in the peripheral blood mononuclear cells (PBMC) from patients with SLE and healthy controls were investigated by quantitative real-time transcription PCR and Western blot, respectively. Correlations between NLRP3/NLRP1 inflammasome components' expression and clinical disease progression were investigated. Expressions of NLRP3/NLRP1 inflammasomes before and after treatment in the patients with SLE were also analyzed and compared. RESULTS: Our data showed that expressions of NLRP3/NLRP1 inflammasomes were significantly downregulated in PBMC from patients with SLE compared with PBMC from healthy controls. Further, expressions of NLRP3/NLRP1 inflammasomes were negatively correlated with the SLE Disease Activity Index, and regular glucocorticoid treatment significantly corrected this deregulation of these inflammasomes. Further analysis showed that type I interferon (IFN) level was significantly negatively correlated with expression of NLRP3/NLRP1 inflammasomes, which indicated that enhanced IFN-I level in patients with SLE was responsible, at least to a great degree, for the deregulation of inflammasomes. CONCLUSION: These results indicated deregulation of NLRP3/NLRP1 inflammasomes in patients with SLE, and suggested an important role for inflammasomes in the pathogenesis and progression of SLE.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteínas Portadoras/metabolismo , Inflamasomas/metabolismo , Vasculitis por Lupus del Sistema Nervioso Central/metabolismo , Adolescente , Adulto , Progresión de la Enfermedad , Femenino , Glucocorticoides/farmacología , Glucocorticoides/uso terapéutico , Humanos , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Vasculitis por Lupus del Sistema Nervioso Central/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Proteína con Dominio Pirina 3 de la Familia NLR , Proteínas NLR , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors worldwide, and it is always the consequence of chronic hepatitis and liver cirrhosis. The nucleotide-binding domain, leucine-rich family (NLR), pyrin-containing 3 (NLRP3) inflammasome has been shown to orchestrate multiple innate and adaptive immune responses. However, little is known about its role in cancer. This study was performed to investigate the role of the NLRP3 inflammasome in the development and progression of HCC. The expression of NLRP3 inflammasome components was analyzed in HCC tissues and corresponding non-cancerous liver tissues at both the mRNA and protein levels. Our data demonstrate that the expression of all of the NLRP3 inflammasome components was either completely lost or significantly downregulated in human HCC, and that the deficiency correlated significantly with advanced stages and poor pathological differentiation. In addition, our data provide an overview of the expression of NLRP3 inflammasome components in the multi-stage development of HCC and indicate a surprising link between deregulation of the NLRP3 inflammasome molecular platform and HCC progression. In conclusion, this study presents a dynamic expression pattern of NLRP3 inflammasome components in multi-stage hepatocarcinogenesis and demonstrates that deregulated expression of the inflammasome is involved in HCC progression.
Asunto(s)
Proteínas Portadoras/metabolismo , Hepatocitos/metabolismo , Inflamasomas/metabolismo , Neoplasias Hepáticas/metabolismo , Proteínas Portadoras/genética , Progresión de la Enfermedad , Femenino , Perfilación de la Expresión Génica , Histocitoquímica , Humanos , Neoplasias Hepáticas/química , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Proteína con Dominio Pirina 3 de la Familia NLR , Reacción en Cadena de la Polimerasa , Análisis de Matrices TisularesRESUMEN
Extracellular adenosine triphosphate (eATP) transduces purinergic signal and plays an important regulatory role in many biological processes, including tumor cell growth and cell death. A large amount of eATP exists in the fast-growing tumor center and inflammatory tumor microenvironment. Tumor cells could acquire anoikis resistance and anchorage independence in tumor microenvironment and further cause metastatic lesion. Whether such a high amount of eATP has any effect on the anchored and non-anchored tumor cells in tumor microenvironment has not been elucidated and is investigated in this study. Our data showed that autophagy helped hepatoma cells to maintain survival under the treatment of no more than 1 mM of eATP. Only when eATP concentration reached a relatively high level (2.5 mM), cell organelle could not be further maintained by autophagy, and apoptosis and cell death occurred. In hepatoma cells under treatment of 2.5 mM of eATP, an AMP-activated protein kinase (AMPK) pathway was dramatically activated while mTOR signaling pathway was suppressed in coordination with apoptosis. Further investigation showed that the AMPK/mTOR axis played a key role in tipping the balance between autophagy-mediated cell survival and apoptosis-induced cell death under the treatment of eATP. This work provides evidence to explain how hepatoma cells escape from eATP-induced cytotoxicity as well as offers an important clue to consider effective manipulation of cancer.