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  • Review Article
  • Published:

Immunomodulatory functions of type I interferons

Nature Reviews Immunology volume 12, pages 125–135 (2012)Cite this article

Subjects

Key Points

  • Interferons (IFNs) are widely expressed cytokines with strong antiviral properties. There are three main types of IFNs: type I IFNs, type II IFN and type III IFNs. In addition to their role in response to viruses, type I IFNs (mainly IFNα and IFNβ) are induced by bacterial infections.

  • The production of type I IFNs in response to bacterial ligands is mediated through Toll-like receptor (TLR)-dependent and -independent mechanisms. TLR3, TLR4, TLR7 and TLR9 have been linked to the production of type I IFNs. The TLR-independent pathways involve the cytoplasmic nucleic acid sensors retinoic-acid-inducible gene I (RIG-I), melanoma differentiation-associated gene 5 (MDA5), stimulator of interferon genes (STING) and DNA-dependent activator of IRFs (DAI).

  • Type I IFNs activate several Janus kinase (JAK)–signal transducer and activator of transcription (STAT) signalling pathways, which regulate the transcription of target genes. In addition to the classical JAK–STAT signalling pathways, type I IFNs activate other signalling cascades.

  • Type I IFNs mediate the regulatory functions of dendritic cells in the gut and the protective effect of TLR ligands in colonic injury.

  • Activation of type I IFN signalling has an important role in T helper cell differentiation and in the suppressive function of regulatory T cells.

  • Type I IFNs both negatively and positively regulate the activation of different types of inflammasome complex and the production of interleukin-1β.

  • In addition to their role as antiviral cytokines, type I IFNs have a wide range of immunomodulatory effects in response to bacterial infections.

  • Type I IFNs are implicated in different autoimmune and inflammatory conditions, although their role in each condition varies. Some autoimmune diseases are improved by the biological effects of type I IFNs, whereas others benefit from type I IFN inhibition.

Abstract

Interferon-α (IFNα) and IFNβ, collectively known as type I IFNs, are the major effector cytokines of the host immune response against viral infections. However, the production of type I IFNs is also induced in response to bacterial ligands of innate immune receptors and/or bacterial infections, indicating a broader physiological role for these cytokines in host defence and homeostasis than was originally assumed. The main focus of this Review is the underappreciated immunomodulatory functions of type I IFNs in health and disease. We discuss their function in the regulation of innate and adaptive immune responses, the response to bacterial ligands, inflammasome activation, intestinal homeostasis and inflammatory and autoimmune diseases.

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Figure 1: Signalling pathways activated by type I and type II IFNs.
Figure 2: Type I IFNs regulate inflammasome activation.
Figure 3: IL-1R1 signalling regulates type I IFN production.
Figure 4: Type I IFNs in human diseases.

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Acknowledgements

We thank S. Herdman for his editorial assistance. This work was supported by US National Institutes of Health grants AI068685, AI077989, AI095623 and DK35108; grants from the Crohn's and Colitis Foundation of America; and grant CP10/00417 from Instituto de Salud Carlos III, Madrid, Spain.

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Authors and Affiliations

  1. Division of Rheumatology, Department of Medicine, Allergy and Immunology, University of California San Diego, 9500 Gilman Drive, La Jolla, 92093-0663, California, USA

    José M. González-Navajas, Jongdae Lee & Eyal Raz

  2. Biomedical Research Center in Hepatic and Digestive Diseases (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain

    José M. González-Navajas

  3. Fundación para la Investigación en el Hospital General de Alicante, Alicante, Spain

    José M. González-Navajas

  4. Division of Biological Sciences, University of California San Diego, La Jolla, California, USA

    Michael David

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Glossary

Viral interference

The antagonistic or inhibitory effect induced by one virus or its components on the propagation of another virus.

IFN-stimulated genes

(ISGs). These genes contain promoters that are responsive to interferon (IFN) signalling, and they are responsible for the antiviral and immunomodulatory properties of IFNs. Over 400 such genes have been identified by microarray analyses. Some, such as RNA-activated protein kinase, ribonuclease L, MX1 (myxovirus resistance 1) and ISG15 (IFN-stimulated gene of 15 kDa), have well-documented antiviral activities, but the precise biological function of most of these genes is unknown.

Inflammasome

A cytosolic multiprotein complex that activates caspase 1 and regulates the release of IL-1β and IL-18 in response to exogenous pathogens and endogenous danger signals. This complex minimally consists of a danger-sensing initiator component and the effector component, which is mature caspase 1.

Coeliac disease

An immune-mediated enteropathy triggered by intolerance to dietary ingestion of glutamine- and proline-rich proteins, collectively known as gluten, which is present in wheat, barley, rye and other grains. This disease results in gastrointestinal symptoms such as diarrhoea, nutrient malabsorption and weight loss.

Multiple sclerosis

A chronic inflammatory disease of the central nervous system that causes the progressive destruction of the myelin sheaths around axons in any area of the brain, optic nerve and spinal cord. This results in slower nerve impulses.

Peyer's patches

Collections of lymphoid tissue that are located in the mucosa of the small intestine, with an outer epithelial layer that consists of specialized epithelial cells called M cells.

Systemic lupus erythematosus

(SLE). An autoimmune disease characterized by the presence of circulating immune complexes that contain antinuclear antibodies bound to self nucleic acids and other nuclear antigens.

Inflammatory bowel disease

(IBD). A chronic inflammatory condition that affects the intestinal tract. The proposed pathogenesis of IBD involves a complex model that includes abnormalities of innate immune function and their relationship with the commensal microbiota, inappropriate release of pro-inflammatory cytokines and other mediators, alterations of the intestinal epithelial barrier, and a cytokine imbalance that promotes the pro-inflammatory activity of adaptive immune cells.

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González-Navajas, J., Lee, J., David, M. et al. Immunomodulatory functions of type I interferons. Nat Rev Immunol 12, 125–135 (2012). https://doi.org/10.1038/nri3133

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