A mechanism for selective induction of 2'-5' oligoadenylate synthetase, anti-viral state, but not MHC class I genes by interferon-beta in neurons.
Interferon-inducible expression of major histocompatibility class I genes has previously been found to be quantitatively and functionally deficient in neurons compared to other somatic cells or other neural cell types including astrocytes. This deficiency is a key component of neuronal immunoprivilege during viral infections of the CNS. To the contrary, in the present study, induction of functional antiviral state by IFN-beta in neurons compared to astrocytes was found to be highly efficient with respect to both viral replication and protection from cytopathic effects. A candidate antiviral state gene found to be efficiently induced in neurons by IFN-beta was the 2'-5'-oligoadenylate synthetase (OAS) gene. Unlike MHC class I genes, induction of OAS was comparable in neurons and astrocytes indicating differential expression in these neural cell types. Analysis of OAS gene promoter activity indicated that induction of the OAS gene by IFN-beta was dependent on a region containing the interferon stimulated responsive element (ISRE). In contrast, a construct containing the MHC class I-ISRE responsible for induction by IFN-beta in astrocytes was not responsive to IFN-beta in neurons. Therefore, transcription factor binding to the OAS- and MHC-ISREs was analyzed. While the OAS and MHC Class I site bound equal amounts of the transcriptional repressor IRF-2, the OAS-ISRE preferentially interacted with the transcriptional activator ISGF3 in response to IFN-beta. Further, unlike neurons, upregulation of MHC class I genes in astrocytes was related to binding of IRF-1 instead of IRF-2 to the MHC-ISRE. It is proposed that selective activation of anti-viral state genes compared to MHC class I genes by IFN-beta in neurons is mediated by preferential induction and binding of ISGF3 to anti-viral state gene ISREs but not the MHC-ISRE.
D015088:2',5'-Oligoadenylate Synthetase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D004686:Encephalomyocarditis virus / Q000502:physiology; D004742:Enhancer Elements, Genetic / Q000235:genetics; D004790:Enzyme Induction; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005805:Genes, MHC Class I / Q000235:genetics; D016899:Interferon-beta / Q000494:pharmacology*; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects