ISSN:
1460-9568
Source:
Blackwell Publishing Journal Backfiles 1879-2005
Topics:
Medicine
Notes:
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.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1111/j.1460-9568.1998.00313.x
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