Interferons

Interferon (IFN) is a cytokine with antiviral properties (it interferes with viral infections) and various roles in immunoregulation. The different types are type I IFN (IFN-ɑ and IFN-β), type II IFN (IFN-ɣ), and type III IFN (IFN-ƛ). Type I IFNs have been extensively studied; these proteins bind to cell-surface receptors when triggered by a viral infection. After stimulation, pathways are activated to produce proteins (e.g., ribonuclease) that inhibit viral replication. An antiviral state is created in both infected and uninfected cells. Type I IFN also has antitumor properties. The antiviral activity of type II IFN (IFN-ɣ) is not as potent as that of type I, but IFN- ɣ is crucial in macrophage activation. The recently discovered IFN-ƛ is noted to have activity against intestinal viruses. With a wide range of biologic effects, interferons are used in therapy for malignancies, infections, and other immune-related conditions (e.g., multiple sclerosis).

Last update:

Table of Contents

Share this concept:

Share on facebook
Share on twitter
Share on linkedin
Share on reddit
Share on email
Share on whatsapp

Overview

Definition

Interferons are a group of proteins belonging to a class of signaling molecules known as cytokines and are released by a variety of cells during the inflammatory response.

General functions

  • Antiviral proteins (so named because they were found to interfere with viral replication) 
  • Important immunoregulatory proteins affecting cell growth, differentiation, gene transcription, and translation
Interferons

Interferons:
Interferons are cytokines that are released by cells infected with a virus, leukocytes, and other immune cells. To limit the infection, responses of cells to interferon include inhibition of protein synthesis, activation of immune cells, and induction of apoptosis.

Image: “Interferons” by OpenStax. License: CC BY 4.0

Types of Interferons

Type I interferons

  • Primarily includes interferon (IFN)-α and IFN-β
  • Most extensively studied
  • Produced by almost all cells, such as fibroblasts, leukocytes, and plasmacytoid dendritic cells (triggered by viral stimulation of pattern recognition receptors)
  • Functions:
    • Prevent viral replication inside cells (creating an antiviral state in both infected and uninfected cells)
    • Increases expression of class I MHC molecules on virus-infected cells
    • Possesses antitumor responses
    • Induces inhibition of angiogenesis
    • Regulates cell survival and apoptosis

Type II interferon

  • Also known as IFN-γ 
  • Produced by T lymphocytes, natural killer (NK) cells, and macrophages
  • IL-12 and IL-2 trigger release of IFN-γ from T cells.
  • Functions:
    • ​​Up-regulates class I and II MHC molecules and promotes the differentiation of naive helper T cells into Th1 cells
    • Important role in macrophage activation (↑ phagocytosis, ↑ microbial killing) and antigen presentation
    • Antiviral activity is not as potent as that for type I IFN.
Type IV hypersensitivity_dendritic cells are releasing IL-12-lpr

Dendritic cells release IL-12, which activates CD4 Th1 cells. These Th1 cells produce IL-2, stimulating production of more Th1 T-cell subsets. Th1 cells also release IFN-γ, which activates macrophages and activates fibroblasts to cause angiogenesis and fibrosis. If these macrophages are persistently stimulated by pathogens such as Mycobacterium and Schistosoma, granulomas are formed.

Image by Lecturio.

Type III interferon

  • More recently discovered
  • Also known as IFN-ƛ
  • Functions:
    • Mucosal immunity
    • Defense against intestinal viruses (e.g., rotavirus, norovirus)

Description of types of interferons

Table: Characteristics of types of interferons
Other designationChromosomal locationCell of origin
IFN-ɑIntron-A9p22Leukocytes
IFN-βIFN-b29p21Fibroblasts
IFN-ɣMacrophage activating factor: immune-interferon12q14Lymphocytes, macrophages, NK cells, dendritic cells
IFN-ƛIL-28A, IL-28B, IL-29, IFNA1419q13.13Epithelial cells

Effects of Interferons

Induction

  • Strong inducers of IFN include:
    • Type I IFN:
      • Viruses
      • Double-stranded RNA
    • Type II IFN:
      • Antigens, mitogens
      • Other interferons
      • Cytokines (e.g., IL-2)
      • NK receptors
    • Type III IFN: viruses
  • When induced (e.g., viral entry to a cell), the infected cell or an NK or a T cell produces IFN, sending signals to other cells.
  •  IFN binds to a specific cell-surface receptor in the uninfected cell:
    • Type I IFN (IFN-ɑ, IFN-β): both bind to the same receptors (IFNAR1 and IFNAR2)
    • IFN-ɣ: binds to IFGNR1 and IFNGR2
    • IFN-ƛ: binds to a set of receptors (which are shared with IL-10, IL-28A, IL-28B, and IL-29)

Effects

  • After binding to the receptor → JAK, STAT signaling pathways activated
  • Genes are instructed to produce proteins that inhibit viral replication. 
    • Ribonuclease: degrades mRNA
    • Protein kinase: inhibits protein synthesis (by phosphorylating eukaryotic initiation factor 2 (eIF-2))
    • Oligo(A) synthetase: Oligo(A) activates ribonuclease.
  • When the virus tries to infect the cell, the enzymes perform their functions.
  • The cell dies from the effects (without producing progeny virus), ultimately restricting the spread of infection.
  • IFNs have overlapping biologic effects during the early phase of infection, leading to:
    • Antiviral activity
    • Antiproliferative activity (other genes are also also down-regulated)
    • Immunoregulatory activity (immune cells such as macrophages are activated)
  • The IFNs also have unique functions that have differing effects (e.g.,  IFN-β is used for treatment of multiple sclerosis, whereas IFN-γ can exacerbate the condition).

Interferons and Diseases

Interferons as treatment

Table: Interferons as treatment
InterferonCondition(s) treated
Interferon-α
  • Hepatitis B and C
  • Papillomavirus (condylomata acuminata)
  • Hairy cell leukemia
  • Kaposi’s sarcoma
  • Recurrence of melanoma
  • Essential thrombocythemia
Interferon-βMultiple sclerosis
Interferon-γ
  • Chronic granulomatous disease (CGD)
  • Osteopetrosis

Evading interferons

  • Viruses have developed mechanisms of evading interferons by:
    • Inhibiting IFN synthesis
    • Inhibiting the effects of the antiviral proteins/enzymes
    • Blocking IFN signaling
    • Producing decoys to molecules that induce interferon signaling 
    • Encapsidating the genome
  • Some examples include:
    • Hepatitis B and HIV block IFN synthesis.
    • Hepatitis C reduces interferon-induced gene production.

Clinical Relevance

  • Viral hepatitis: viral infection of the liver that causes inflammation and damage. Interferon is used as part of the treatment of 2 primary hepatitis viruses: B and C. Management of acute hepatitis is typically supportive, whereas for chronic infection, options such as interferon and oral antiviral agents are available. Interferon-ɑ inhibits protein synthesis via antiviral proteins/enzymes. The medication can cause flu-like symptoms and elevated liver enzymes.
  • Multiple sclerosis (MS): chronic inflammatory autoimmune disease leading to demyelination of the CNS. The clinical presentation of MS varies depending on the site of lesions, but neurologic symptoms affecting vision, motor functions, sensation, and autonomic function are typically seen. Interferon-β is an option among disease-modifying therapies for relapsing MS. Flu-like symptoms and liver dysfunction are adverse effects.
  • Chronic granulomatous disease (CGD): genetic condition characterized by recurrent severe bacterial and fungal infections and granuloma formation. Defective nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (responsible for the respiratory burst) in neutrophils and macrophages leads to impaired phagocytosis. Infections commonly affect the lung, skin, lymph nodes, and liver. Prophylactic treatment includes IFN-ɣ. Side effects include fever and myalgias.
  • Hairy cell leukemia: rare, chronic B-cell leukemia characterized by the accumulation of small mature B lymphocytes that have hair-like projections visible on microscopy. The abnormal cells accumulate in the peripheral blood, bone marrow (causing fibrosis), and spleen. Interferon-ɑ is part of the treatment regimen, as it inhibits cell growth and interferes with oncogene and surface antigen expression.

References

  1. Bukowski, R.M., Tendler, C., Cutler, D., Rose, E., Laughlin, M.M., Statkevich, P. (2002). Treating cancer with PEG intron: pharmacokinetic profile and dosing guidelines for an improved interferon-alpha-2b formulation. Cancer 95:389–396.
  2. Baden L.R. (2018). Antiviral chemotherapy, excluding antiretroviral drugs. In: Jameson, J., Fauci, A.S., Kasper, D.L., Hauser, S.L., Longo, D.L., Loscalzo J. (Eds.). Harrison’s Principles of Internal Medicine, 20th ed. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2129&sectionid=192024526
  3. Castro, F., Cardoso, A., Gonçalves, R., Serre, K., Oliveira, M. (2018). Interferon-gamma at the crossroads of tumor immune surveillance or evasion. Frontiers in Immunology 9:847. https://www.frontiersin.org/article/10.3389/fimmu.2018.00847     
  4. Ferreira, V., Borba, H., Bonetti, A., Leonart, L., Pontarolo, R. (2018). Cytokines and interferons: types and functions, autoantibodies and cytokines https://www.intechopen.com/chapters/59914
  5. Kiladjian, J., Mesa, R., Hoffman, R. (2011). The renaissance of interferon therapy for the treatment of myeloid malignancies. Blood 117:4706–4715. https://doi.org/10.1182/blood-2010-08-258772
  6. Lasfar, A., Zloza, A., Cohen-Solal, K.A. (2016). IFN-lambda therapy: current status and future perspectives. Drug Discov Today. 21(1):167-171. 
  7. Lee, A., Ali, A. (2018). The dual nature of type I and type II interferons. Frontiers in Immunology 9:2061. https://www.frontiersin.org/article/10.3389/fimmu.2018.02061
  8. Levinson, W., Chin-Hong, P., Joyce, E.A., Nussbaum, J., Schwartz, B. (Eds.). (2020). Host defenses. Chapter 33 of Review of Medical Microbiology & Immunology: A Guide to Clinical Infectious Diseases, 16th ed. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2867&sectionid=242759604
  9. McNab, F., Mayer-Barber, K., Sher, A. et al. (2015). Type I interferons in infectious disease. Nat Rev Immunol 15:87–103. https://doi.org/10.1038/nri3787
  10. Riedel, S., Hobden, J.A., Miller, S., Morse, S.A., Mietzner, T.A., Detrick, B., Mitchell, T.G., Sakanari J.A., Hotez, P., Mejia, R. (Eds.). (2019). Immunology. Chapter 8 of Jawetz, Melnick, & Adelberg’s Medical Microbiology, 28th ed. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2629&sectionid=217769996
  11. Stubbs, S., Perez-Gracia, J., Rouzaut, A., Sanmamed, M., Le Bon, A.,  Melero, I. (2011). Direct effects of type I interferons on cells of the immune system. Clin Cancer Res 17:2619–2627. DOI: 10.1158/1078-0432.CCR-10-1114
  12. Taylor M.W. (2014) Interferons. In: Viruses and Man: A History of Interactions. Springer, Cham. https://doi.org/10.1007/978-3-319-07758-1_7
  13. Zhou, F. (2009). Molecular mechanisms of IFN-gamma to up-regulate MHC class I antigen processing and presentation. Int Rev Immunol 28:239–260.

Study on the Go

Lecturio Medical complements your studies with evidence-based learning strategies, video lectures, quiz questions, and more – all combined in one easy-to-use resource.

Learn even more with Lecturio:

Complement your med school studies with Lecturio’s all-in-one study companion, delivered with evidence-based learning strategies.

🍪 Lecturio is using cookies to improve your user experience. By continuing use of our service you agree upon our Data Privacy Statement.

Details