RESUMEN
Efficient IFN-alpha/beta gene induction in virus-infected cells is an event central to innate immunity, in which the transcription factor IRF-7 plays a critical role together with IRF-3. Unlike IRF-3, IRF-7 is short-lived and its gene expression is dependent on IFN-alpha/beta signalling; hence, the signal-dependent enhancement of IRF-7 gene induction during viral infection is essential for positive-feedback regulation of IFN-alpha/beta gene induction. Here, we provide evidence that constitutive, IRF-3/IRF-7-independent production of IFN-alpha/beta in uninfected cells is critical for setting the IRF-7 expression levels, determining whether or not the positive-feedback mechanism will operate effectively upon viral infection. In fact, spleen cells are more dependent than fibroblasts on this mechanism; the IFN-alpha/beta gene induction is impaired more severely by blocking the IRF-7 induction pathway than by introducing an IRF-3 null mutation. Thus, the constitutive IFN-alpha/beta signal provides a foundation for the IRF-7-mediated enhancement of its own production in response to virus infection.
Asunto(s)
Regulación de la Expresión Génica/inmunología , Interferón-alfa/genética , Interferón beta/genética , Linfocitos/inmunología , Virus de la Enfermedad de Newcastle/inmunología , Transcripción Genética , Animales , Células Cultivadas , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Embrión de Mamíferos , Fibroblastos/inmunología , Fibroblastos/fisiología , Fibroblastos/virología , Vectores Genéticos , Factor 3 Regulador del Interferón , Factor 7 Regulador del Interferón , Ratones , Ratones Noqueados , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Bazo/inmunología , Factores de Transcripción/deficiencia , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Transcripción Genética/inmunología , Activación Transcripcional , TransfecciónRESUMEN
During viral infection, interferon-alpha/beta (IFN-alpha/beta) and many IFN-inducible genes are induced to elicit antiviral responses of the host. Using cells with a gene disruption(s) for the IRF family of transcription factors, we provide evidence that these genes, containing similar IRF-binding cis-elements, are classified into distinct groups, based on the gene induction pathway(s). The IFN-beta gene induction is dependent on either IRF-3 or IRF-7, whereas induction of the IFN-alpha gene family is IRF-7-dependent. On the other hand, ISG15, ISG54 and IP-10 are induced by either IRF-3 or IFN stimulated gene factor 3 (ISGF3). We also show that another group of genes is totally dependent on ISGF3. Thus, during viral infection, a given gene responds either directly to a virus or virus-induced IFN-alpha/beta or both through distinct pathways. The differential utilization of these induction pathways for these genes during viral infection may reflect their distinct functional roles in the efficient antiviral response.
Asunto(s)
Proteínas de Unión al ADN/metabolismo , Regulación de la Expresión Génica/inmunología , Interferón-alfa/genética , Interferón beta/genética , Enfermedad de Newcastle/inmunología , Virus de la Enfermedad de Newcastle/inmunología , Factores de Transcripción/metabolismo , 2',5'-Oligoadenilato Sintetasa/genética , Animales , Proteínas Reguladoras de la Apoptosis , Secuencia de Bases , Sitios de Unión , Células Cultivadas , Quimiocina CXCL10 , Quimiocinas CXC/genética , Quimiocinas CXC/metabolismo , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Factor 3 Regulador del Interferón , Factor 7 Regulador del Interferón , Factor 3 de Genes Estimulados por el Interferón , Subunidad gamma del Factor 3 de Genes Estimulados por el Interferón , Ratones , Ratones Noqueados , Modelos Inmunológicos , Virus de la Enfermedad de Newcastle/genética , Proteínas de Unión al ARN , Factores de Transcripción/deficiencia , Factores de Transcripción/genética , Activación TranscripcionalRESUMEN
Induction of the interferon (IFN)-alpha/beta gene transcription in virus-infected cells is an event central to innate immunity. Mice lacking the transcription factor IRF-3 are more vulnerable to virus infection. In embryonic fibroblasts, virus-induced IFN-alpha/beta gene expression levels are reduced and the spectrum of the IFN-alpha mRNA subspecies altered. Furthermore, cells additionally defective in IRF-7 expression totally fail to induce these genes in response to infections by any of the virus types tested. In these cells, a normal profile of IFN-alpha/beta mRNA induction can be achieved by coexpressing both IRF-3 and IRF-7. These results demonstrate the essential and distinct roles of thetwo factors, which together ensure the transcriptional efficiency and diversity of IFN-alpha/beta genes for the antiviral response.
Asunto(s)
Proteínas de Unión al ADN/fisiología , Regulación de la Expresión Génica/inmunología , Interferón Tipo I/biosíntesis , Interferón Tipo I/genética , Virus de la Enfermedad de Newcastle/fisiología , Retroviridae/fisiología , Factores de Transcripción/fisiología , Animales , Proteínas de Unión al ADN/biosíntesis , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Regulación hacia Abajo/genética , Regulación hacia Abajo/inmunología , Embrión de Mamíferos , Femenino , Fibroblastos , Regulación de la Expresión Génica/genética , Marcación de Gen , Factor 3 Regulador del Interferón , Factor 7 Regulador del Interferón , Interferón Tipo I/deficiencia , Interferón Tipo I/fisiología , Interferón beta/genética , Interferón beta/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Virus de la Enfermedad de Newcastle/genética , Regiones Promotoras Genéticas/inmunología , ARN Mensajero/biosíntesis , Retroviridae/genética , Transducción de Señal/genética , Transducción de Señal/inmunología , Factores de Transcripción/biosíntesis , Factores de Transcripción/deficiencia , Factores de Transcripción/genética , Activación TranscripcionalRESUMEN
The interferon regulatory factor (IRF) family of transcription factors regulate the interferon (IFN) system, among which IRF-3 is involved in the virus-induced IFN-beta gene expression. Here we show that another member IRF-7 is critical for the IFN-alpha gene induction. Unlike the IRF-3 gene, the IRF-7 gene is induced by IFNs through activation of the ISGF3 transcription factor, and IRF-7 undergoes virus-induced nuclear translocation. In cells lacking p48, an essential component of IFN stimulated gene factor 3 (ISGF3), ectopic expression of IRF-7 but not IRF-3 can rescue the deficiency to induce IFN-alpha genes. These results indicate that IRF-7 is a key factor in the positive feedback regulation of IFN-alpha/beta production.
