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A weak signal for strong responses: interferon-alpha/beta revisited

Key Points

  • Cells produce large amounts of type I interferons — IFN-α and IFN-β — in response to viral infection, and these interferons elicit strong antiviral activities in target cells. This event is an essential aspect of the innate immune system.

  • IFN-α/β binds to its receptor to activate the signalling pathway, involving the activation of the JAK family of protein tyrosine kinases, and STAT and interferon regulatory factor (IRF) families of transcription factors.

  • Very low levels of IFN-α/β are also produced in the absence of viral infection.

  • Although seemingly futile, this weak IFN-α/β signalling provides a foundation for enhancing its own pathway or other signalling pathways. Hence, it is analogous to 'revving up' the engine in car racing.

  • In fact, this spontaneous IFN-α/β signalling is crucial in enhancing its own pathway by inducing the expression of the transcription factor IRF-7, which activates the IFN-γ/β genes.

  • IFN-α/β signalling is also crucial for enhancing cellular responses to IFN-γ or interleukin-6.

  • Although weak, spontaneous IFN-α/β signalling also needs to be properly regulated, so as to maintain the homeostatic response of CD8+ T cells. The transcription factor IRF-2 is necessary to attenuate IFN-α/β signalling, and the absence of this factor causes a CD8+ T cell-mediated inflammatory skin disease.

  • The revving-up mechanism might be important for eliciting rapid and robust cellular responses to environmental changes, and may be extended to other biological systems.

Abstract

Biological systems have acquired adaptability and robustness against rapid environmental changes. A typical example is the immune system, which eradicates invading pathogens such as viruses. Interferons α and β, which are produced in response to viral infection, are essential components of this system but are also produced at low levels in the absence of infection. What is the purpose of the constitutive weak interferon-α/β signal?

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Figure 1: A constitutive, 'weak' signal might be crucial for the robust response of the cells.
Figure 2: Main features of the IFN-α/β signalling pathway.
Figure 3: A weak IFN-α/β signal is needed for its amplification during antiviral responses.
Figure 4: Signalling crosstalk between IFN-α/β and other cytokines to evoke strong responses to the latter.

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Acknowledgements

We are grateful to E. Barsoumian for critical reading of the manuscript, and M. Berridge and H. Rosen for their invaluable advice. This work is supported by a special grant for Advanced Research on Cancer from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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DATABASE LINKS

IFN-α

IFN-β

IFNAR-1

IFNAR-2

Jak1

Tyk2

Stat1

Stat2

ISGF3

IFNGR

IRF-3

IRF-7

Ifnar1

IL-6

IL-6 receptor

gp130

Jak2

Stat3

IFNGR-2

ErbB2

IRF-2

psoriasis

CSF-1

interleukin-10

PLC

FURTHER INFORMATION

Taniguchi lab

ENCYCLOPEDIA OF LIFE SCIENCES

Signal transduction in development: the JAK/STAT pathway

Glossary

INNATE IMMUNE RESPONSE

This is crucial during the early phase of host defence against infection by pathogens (such as bacteria and viruses), before the antigen-specific, adaptive immune response is induced.

NATURAL KILLER CELLS

A class of lymphocytes that are crucial in the innate immune response. They exert a cytotoxic activity on target cells (such as virus-infected cells) that is enhanced by cytokines such as interferons.

CD8+ T CELLS

One of the two major classes of T lymphocyte (the other being CD4+ T cells). CD8+ T cells exert cytolytic activity in an antigen-specific manner. They also produce various cytokines to regulate the immune system.

ADAPTIVE IMMUNE SYSTEM

In this host defence system, which evolved in vertebrates, T and B cells respond specifically to a given antigen. This type of immune response includes antibody production and killing of the pathogen-infected cells, and is regulated by cytokines such as IFN-α.

SH2 DOMAIN

(Src homology 2 domain). A protein motif that recognizes and binds tyrosine-phosphorylated sequences, and thereby has a key role in relaying cascades of signal transduction.

ACUTE-PHASE PROTEINS

Proteins for which plasma concentration changes largely owing to the level of their production by hepatocytes during inflammation.

PSORIASIS

A human chronic inflammatory skin disease characterized by abnormal growth and differentiation of keratinocytes. The involvement of T cells has been documented.

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Taniguchi, T., Takaoka, A. A weak signal for strong responses: interferon-alpha/beta revisited. Nat Rev Mol Cell Biol 2, 378–386 (2001). https://doi.org/10.1038/35073080

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