Interferons (IFNs) are natural proteins produced by the cells of the immune systems of most animals in response to challenges by foreign agents such as viruses, bacteria, parasites and tumor cells. Interferons belong to the large class of glycoproteins known as cytokines.
Types of interferon
In humans, there are 3 major classes of interferon (IFN):
- The human type I IFNs consists of 13 different alpha isoforms (subtypes with slightly different specificities) - IFNA(1,2,4,5,6,7,8,10,13,14,16,17,21), and single beta - IFNB1, omega - IFNW1, epsilon - IFNE1 and kappa - IFNK isoforms. Homologous molecules are found in many species, including rats and mice (and most mammals) and have been identified in birds, reptiles, amphibians and fish species. In addition to these IFNs, IFN zeta (limitin) in mice,IFN nu in cats, IFN tau in ruminants and IFN delta in pigs have been identified. All type I IFNs bind to a specific cell surface receptor complex known as IFNAR consisting of IFNAR1 and IFNAR2 chains.
- The type II IFNs consists of IFN gamma - IFNG, its sole member. The mature IFNG ligand is an anti-parallel homodimer, and it binds to the IFNG receptor (IFNGR) complex, which is made up of two of each IFNGR1 and IFNGR2 subunits.
- The recently discovered 3rd class consists of IFN-lambda with 3 different isoforms - IL29. IL28A, IL28B and signal through a receptor complex consisting of IL10R2 and IFNLR1.
While there are evidence to suggest other signaling mechanisms exist, the JAK-STAT signaling pathway is the best-characterised and commonly accepted IFN signaling pathway.
In a majority of cases, the production of interferons is induced in response to microbes such as viruses and bacteria and their products (viral glycoproteins, viral RNA, bacterial endotoxin, flagella, CpG DNA), as well as mitogens? and other cytokines, for example interleukin 1, interleukin 2, interleukin-12, tumor necrosis factor and colony-stimulating factor, that are synthesised in the response to the appearance of various antigens in the body. Their metabolism and excretion take place mainly in the liver and kidneys. They hardly pass the placenta and the blood-brain barrier.
Interferon-alpha and -beta are produced by many cell types, including T-cells and B-cells, macrophages, fibroblasts, endothelial cells, osteoblasts and others, and are an important component of the anti-viral response. They stimulate both macrophages and NK cells. Interferons -alpha and -beta are also active against tumors.
Interferon-gamma is involved in the regulation of the immune and inflammatory responses; in humans, there is only one type of interferon-gamma. It is produced in activated T-cells and natural killer cells. Interferon-gamma has some anti-viral and anti-tumor effects, but these are generally weak; however, interferon-gamma potentiates the effects of interferon-alpha and interferon-beta. However, interferon-gamma must be released at the site of a tumor in very small doses; at this time, interferon-gamma is not very useful for treating cancer.
Interferon-gamma is also released by Th1 cells, and recruits leukocytes to a site of infection, resulting in increased inflammation. It also stimulates macrophages to kill bacteria that have been engulfed. The interferon-gamma released by Th1 cells is also important in regulating the Th2 response. As interferon-gamma is vitally implicated in the regulation of immune response, its production can lead to autoimmune disorders.
Interferon-omega is released by leukocytes at the site of viral infection or tumors.
Use in medicine
Interferon was scarce and expensive until 1980 when the interferon gene was inserted into bacteria using recombinant DNA technology, allowing mass cultivation and purification from bacterial cultures.
Interferon beta-1a is produced in mammalian cells.
Several different types of interferon are now approved for use in humans, and interferon therapy is used (in combination with chemotherapy and radiation) as a treatment for many types of systemic cancer. When used in the systemic therapy, IFN-α and IFN-γ are mostly administered by an intramuscular injection. The injection of interferons in the muscle, in the vein, or under skin is generally well-tolerated. The most frequent side-effects are flu-like symptoms: increased body temperature, feeling ill, fatigue, headache, muscle pain, and convulsion. Erythema, pain and hardness on the spot of injection are also frequently observed. Rarely, patients experience their hair falling out, dizziness and depression. All known effects are reversible and disappear a few days after the therapy has been finished.
Interferon-alpha was approved by the United States Food and Drug Administration (FDA) on February 25, 1991 as a treatment for hepatitis C.