Synergistic stimulation of MHC class I and IRF‐1 gene expression by IFN‐γ and TNF‐α in oligodendrocytes

Abstract

In order to understand the molecular basis of the synergistic action of interferon gamma (IFN-gamma) and tumour necrosis factor alpha (TNF-alpha) 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-gamma nor TNF-alpha was capable of inducing MHC-CRE binding activity when administrated alone. Following the exposure of oligodendrocytes to IFN-gamma, TNF-R1 expression was transcriptionally induced by the binding of signal transducer and activator of transcription (STAT-1) homodimers to the IFN-gamma activated site (GAS) present in the gene promoter. The upregulation of TNF-R1 allowed TNF-alpha to induce the binding of nuclear factor-kappaB (NF-kappaB) to the MHC-CRE site. With respect to ICS element, IFN-gamma induced IRF-1 binding, that was further enhanced upon co-treatment with TNF-alpha. The existence of a synergism between IFN-gamma and TNF-alpha in stimulating IRF-1 expression at the transcriptional level was supported by IRF-1 promoter analysis: IFN-gamma directly induced the binding of STAT-1 homodimers to the GAS element, while NF-kappaB binding to the kappaB sequence was activated by TNF-alpha only after IFN-gamma treatment. This transcriptional regulation of IRF-1 gene by IFN-gamma and TNF-alpha 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.

Enhanced growth inhibition of metastatic lung tumors by intravenous injection of ATRA-cationic liposome/IL-12 pDNA complexes in mice

“…TNFR1 expression is upregulated by ATRA and ATRA-cationic liposome/IL-12 pDNA complexes in mice P Charoensit et al cytokines such as interferon-g and IL-1b. 22,37,38 Therefore, ATRA-cationic liposome/IL-12 pDNA complexes may produce synergistic effects on TNFR1 upregulation. To date, the upregulation of TNFR1 by ATRA has been reported in human lung cancer cells; 22 however, there have been no reports in mouse colon26 cells.…”

Cerebral Endothelial Activation and Signal Transduction Mechanisms during Inflammation and Infectious Disease

“…13 In support of this, Deckert-Schluter et al 8 also demonstrated that TNF mRNA was not induced in the IFN-␥-deficient mice with Toxoplasma encephalitis. A recent study suggesting that induction of TNFR1 by IFN-␥ facilitates the actions of TNF-␣ at the transcription level shows the importance of this finding in oligodendrocytes, 14 although it is not unlikely that brain endothelial cells may respond in a similar manner. Agresti et al 14 demonstrated that neither IFN-␥ nor TNF-␣ was capable of inducing MHC class I regulatory element (MHC-CRE) binding activity when administered alone.…”

15 Periventrikuläre Leukomalazie

“…Einfluss von IFN-γ auf Oligodendrocyten-Vorläuferzellen potenzierenden Effekt von TNF-α feststellen konnten [Agresti et al, 1998;Andrews et al, 1998] [Boehm et al, 1997]. Aber auch Makrophagen [Munder et al, 1998], B-Zellen [Yoshimoto et al, 1997] und CD8a+ dendritische Zellen [Ohteki et al, 1999] können nach Aktivierung IFN-γ produzieren.…”

“…Die Signalweiterleitung beider Cytokine könnte dann zu einer erhöhten Aktivierung des MHC Klasse I Genes führen [Agresti et al, 1998]. In einer Reihe von demyelinisierenden Krankheiten wurde eine anormale Expression dieses Genes beobachtet [Traugott 1987;Traugott and Lebon 1988].…”

“…Bei der diffusen Komponente der PVL sind Bach et al, 1996] und auch der Synergismus von IFN-γ und TNF-α ist in Ansätzen erforscht [Agresti et al, 1998]. Eine Untersuchung, ob und inwieweit die Apoptose durch Inhibitoren der einzelnen Signalwege gehemmt werden kann, ist dabei von großem Interesse.…”