Interferons (IFNs, /ˌɪntərˈfɪərɒn/ IN-tər-FEER-on[1]) are a group of signaling proteins[2] made and released by host cells in response to the presence of several viruses.

IFNs belong to the large class of proteins known as cytokines, molecules used for communication between cells to trigger the protective defenses of the immune system that help eradicate pathogens.

[3] Interferons are named for their ability to "interfere" with viral replication[3] by protecting cells from virus infections.

[4] IFNs also have various other functions: they activate immune cells, such as natural killer cells and macrophages, and they increase host defenses by up-regulating antigen presentation by virtue of increasing the expression of major histocompatibility complex (MHC) antigens.

IFNs belonging to all three classes are important for fighting viral infections and for the regulation of the immune system.

[citation needed] All interferons share several common effects: they are antiviral agents and they modulate functions of the immune system.

In response to interferon, cells produce large amounts of an enzyme known as protein kinase R (PKR).

Another cellular enzyme, RNAse L—also induced by interferon action—destroys RNA within the cells to further reduce protein synthesis of both viral and host genes.

[13][14] They also limit viral spread by increasing p53 activity, which kills virus-infected cells by promoting apoptosis.

After binding dsRNA, this receptor activates the transcription factors IRF3 and NF-κB, which are important for initiating synthesis of many inflammatory proteins.

RNA interference technology tools such as siRNA or vector-based reagents can either silence or stimulate interferon pathways.

[22] A collection of known ISGs is available on Interferome, a curated online database of ISGs (www.interferome.org);[23] Additionally, STAT homodimers or heterodimers form from different combinations of STAT-1, -3, -4, -5, or -6 during IFN signaling; these dimers initiate gene transcription by binding to IFN-activated site (GAS) elements in gene promoters.

[22] Antiviral and antiproliferative effects specific to type I IFNs result from p38 MAP kinase signaling.

For example, interferon alpha induces RIG-G, which disrupts the CSN5-containing COP9 signalosome (CSN), a highly conserved multiprotein complex implicated in protein deneddylation, deubiquitination, and phosphorylation.

[24] RIG-G has shown the capacity to inhibit NF-κB and STAT3 signaling in lung cancer cells, which demonstrates the potential of type I IFNs.

The H5N1 influenza virus, also known as bird flu, has resistance to interferon and other anti-viral cytokines that is attributed to a single amino acid change in its Non-Structural Protein 1 (NS1), although the precise mechanism of how this confers immunity is unclear.

[40] Delayed IFN-I response contributes to the pathogenic inflammation (cytokine storm) seen in later stages of COVID-19 disease.

[41] Application of IFN-I prior to (or in the very early stages of) viral infection can be protective,[37] which should be validated in randomized clinical trials.

The most frequent adverse effects are flu-like symptoms: increased body temperature, feeling ill, fatigue, headache, muscle pain, convulsion, dizziness, hair thinning, and depression.

IFN therapy causes immunosuppression, in particular through neutropenia and can result in some infections manifesting in unusual ways.

[64] Interferons were first described in 1957 by Alick Isaacs and Jean Lindenmann at the National Institute for Medical Research in London;[65][66][67] the discovery was a result of their studies of viral interference.

Their experiments revealed that this interference was mediated by a protein released by cells in the heat-inactivated influenza virus-treated membranes.

For example, during research to produce a more efficient vaccine for smallpox, Yasu-ichi Nagano and Yasuhiko Kojima—two Japanese virologists working at the Institute for Infectious Diseases at the University of Tokyo—noticed inhibition of viral growth in an area of rabbit-skin or testis previously inoculated with UV-inactivated virus.

[69] Independently, Monto Ho, in John Enders's lab, observed in 1957 that attenuated poliovirus conferred a species specific anti-viral effect in human amniotic cell cultures.

[74][75] Tan's laboratory isolated sufficient amounts of human beta interferon to perform the first amino acid, sugar composition and N-terminal analyses.

A series of publications from the laboratories of Sidney Pestka and Alan Waldman between 1978 and 1981, describe the purification of the type I interferons IFN-α and IFN-β.

[83] Interferon was first synthesized manually at Rockefeller University in the lab of Dr. Bruce Merrifield, using solid phase peptide synthesis, one amino acid at a time.

The superinduced human beta interferon messenger RNA was prepared by Tan's lab for Cetus.