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.
- Antiviral proteins (so named because they were found to interfere with viral replication)
- Important immunoregulatory proteins affecting cell growth, differentiation, gene transcription, and translation
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)
- 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.
- 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 III interferon
- More recently discovered
- Also known as IFN-ƛ
- Mucosal immunity
- Defense against intestinal viruses (e.g., rotavirus, norovirus)
Description of types of interferons
|Other designation||Chromosomal location||Cell of origin|
|IFN-ɣ||Macrophage activating factor: immune-interferon||12q14||Lymphocytes, macrophages, NK cells, dendritic cells|
|IFN-ƛ||IL-28A, IL-28B, IL-29, IFNA14||19q13.13||Epithelial cells|
Effects of Interferons
- Strong inducers of IFN include:
- Type I IFN:
- Double-stranded RNA
- Type II IFN:
- Antigens, mitogens
- Other interferons
- Cytokines (e.g., IL-2)
- NK receptors
- Type III IFN: viruses
- Type I IFN:
- 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)
- 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
- 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.
- 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.
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