ReviewThe interferon-α/β system in antiviral responses: a multimodal machinery of gene regulation by the IRF family of transcription factors
Introduction
In The Analects of Confucius the Master said “If you understand it, say you understand it. If you don't understand it, say you don't understand it. That is knowledge” (quoted in [1]).
Interferon-α and interferon-β (IFN-α/β) and their genes were the first cytokines to be discovered, and analysis of the IFN-α/β system during the past two decades has always been at the forefront of cytokine research 2., 3., 4., 5., 6., 7.. Perhaps surprisingly, our knowledge of how the IFN-α/β system is regulated, and how it contributes to the immune and other biological systems, is still expanding.
IFN-α/β are produced en masse upon viral infection in many different cell types, and they directly exert their antiviral function in two ways: one is to elicit antiviral activity from the target cells and the other is to induce apoptosis in infected cells, at least for some viruses 2., 3., 6., 8., 9.. Thus, the inhibition of viral replication and the selective induction of apoptosis in virally infected cells constitute the first line of defense of the immune system against viruses. In addition to this direct action, virus-induced IFN-α/β are also known to contribute indirectly to the antiviral response by affecting cells of the immune system. For example, it has been known for a long time that IFN-α/β are crucial in the activation of NK cells and macrophages 10., 11., 12..
More recently, attention has been focused on the role of IFN-α/β as the key cytokines that link the innate and adaptive immune systems 13., 14••.. Thus, IFN-α/β directly affect the fate of the CD8+-T-cell proliferation and survival [15], and they may be the key cytokines that induce effective B-cell responses 16., 17•.. In this context, it is interesting to note that IFN-α/β are also induced by nonviral, pathogen-associated molecules, such as lipopolysaccharide (LPS) and unmethylated DNA 18., 19..
In this review, we shall avoid reiterating the well-known, multi-functional aspects of IFN-α/β in antiviral responses 2., 3., 6., 8., but instead shall present a unique overview of the gene induction mechanisms that operate in the IFN-α/β system during viral infection. We also present our view on how a host has achieved these mechanisms, with the caveat that we may not, therefore, be following the teaching of the Master.
Section snippets
Transcriptional regulation in the IFN-α/β system
Whereas there is only one IFN-β gene, there are many members of the IFN-α gene family, including pseudogenes in man and mice, which are all located on the same chromosome (9p in humans and 4q in mice) 3., 20.. During viral infection, transcriptional induction of the IFN-α/β genes is achieved through activation of two transcription factors of the IFN regulatory factor (IRF) family, namely IRF-3 and IRF-7 (21., 22., 23•.; and see below). The virus-induced IFN-α/β transmit signals to induce
‘Revving-up the cellular engine’ by weak IFN-α/β signalling
The induction of IFN-α/β genes by viruses involves IRF-3 and IRF-7, and expression of the latter is dependent on ISGF3 activated by IFN-α/β. Briefly, viral infections result in phosphorylation of the constitutively expressed IRF-3 at its carboxy-terminal region, converting it to its active form 37., 38.. This phosphorylated IRF-3 then undergoes nuclear translocation, interacts with coactivators CBP and p300, and primarily activates the IFN-β promoter 48., 49., 50., 51., 52..
Once IFN-β is
The IFN-α/β system and IRFs: a view of their evolution
We have discussed the significance of spontaneous IFN-α/β gene expression in the context of what we proposed as the ‘revving-up model’ [61••]. In fact, weak IFN-α/β signalling also provides a foundation for cells to respond efficiently to other cytokines 62., 63.. Although it has long been known that IFN-α/β are produced in the absence of viral infection 3., 64., 65., 66., their production mechanism under this condition is poorly understood. In fibroblasts, IFN-α/β expression is observed even
Conclusions
The discovery and functional analyses of the IRF family of transcription factors provided new insights into the long-sought molecular mechanism by which efficient induction of IFN-α/β genes can be achieved. In fact, the unique auto-amplification mechanism of the IFN-α/β genes, mediated by IRF-3 and IRF-7, may have implications regarding to the evolution of the families of the IFN-α/β genes and IRF genes, during the acquisition of the robust host defense system against viruses.
As for future
Acknowledgements
We are grateful to E Barsoumian for critical reading of the manuscript. Our work is supported by grants for Advanced Research on Cancer from the Ministry of Education, Culture, Sports, Science and Technology of Japan, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, and the Welfide Medicinal Research Foundation.
References and recommended reading
Papers of particular interest, published within the annual period of review,have been highlighted as:
• of special interest
•• of outstanding interest
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