ISSN:
1460-9568
Quelle:
Blackwell Publishing Journal Backfiles 1879-2005
Thema:
Medizin
Notizen:
In order to understand the molecular basis of the synergistic action of interferon γ (IFN-γ) and tumour necrosis factor α (TNF-α) on rat oligodendrocyte development, we studied some aspects of the signalling pathways involved in the regulation of the major histocompatibility complex (MHC) class I and the interferon regulatory factor 1 (IRF-1) gene expression. Two well-defined inducible enhancers of the MHC class I gene promoter, the MHC class I regulatory element (MHC-CRE) and the interferon consensus sequence (ICS), were analysed. Neither IFN-γ nor TNF-α was capable of inducing MHC-CRE binding activity when administrated alone. Following the exposure of oligodendrocytes to IFN-γ, TNF-R1 expression was transcriptionally induced by the binding of signal transducer and activator of transcription (STAT-1) homodimers to the IFN-γ activated site (GAS) present in the gene promoter. The upregulation of TNF-R1 allowed TNF-α to induce the binding of nuclear factor-κB (NF-κB) to the MHC-CRE site. With respect to ICS element, IFN-γ induced IRF-1 binding, that was further enhanced upon co-treatment with TNF-α. The existence of a synergism between IFN-γ and TNF-α in stimulating IRF-1 expression at the transcriptional level was supported by IRF-1 promoter analysis: IFN-γ directly induced the binding of STAT-1 homodimers to the GAS element, while NF-κB binding to the κB sequence was activated by TNF-α only after IFN-γ treatment. This transcriptional regulation of IRF-1 gene by IFN-γ and TNF-α was confirmed at the mRNA level. The synergism demonstrated in the present study highlights the importance of cytokine interactions in magnifying their biological effects during brain injury and inflammation.
Materialart:
Digitale Medien
URL:
http://dx.doi.org/10.1111/j.1460-9568.1998.00313.x
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