Interferon

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Interferons (IFNs) are natural proteins produced by the cells of the immune system of most vertebrates 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. Interferons assist the immune response by inhibiting viral replication within other cells of the body.

Contents 1 History 2 Types of interferon 3 The signaling pathway of interferons 4 Sources and functions of interferons 5 Viral induction of interferons 6 Virus Resistance to Interferons 7 Pharmaceutical uses 8 See also 9 References 10 Further reading

[edit] History

Whilst aiming to develop an improved vaccine for smallpox, two Japanese virologists, Yasu-ichi Nagano and Yasuhiko Kojima working at the then Institute for Infection Disease at the University of Tokyo, noticed that rabbit-skin or testis previously inoculated with UV-inactivated virus exhibited inhibition of viral growth when re-infected at the same site with live virus. They hypothesised that this was due to some “facteur inhibiteur” (inhibitory factor), and began to characterise it by fractionation of the UV-irradiated viral homogenates using an ultracentrifuge. They published these findings in 1954 in the French journal now known as “Journal de la Société de Biologie”.^[1] While this paper demonstrated that the activity could be separated from the virus particles, it could not reconcile the antiviral activity demonstrated in the rabbit skin experiments, with the observation that the same supernatant led to the production of antiviral antibodies in mice. A further paper in 1958, involving triple-ultracentrifugation of the homogenate demonstrated that the inhibitory factor was distinct from the virus particles, leading to trace contamination being ascribed to the 1954 observations.^[2][3]

Meanwhile, the British virologist Alick Isaacs and the Swiss researcher Jean Lindenmann, at the National Institute for Medical Research in London, noticed an interference effect caused by heat-inactivated influenza virus on the growth of live influenza virus in chicken egg membranes in a nutritive solution chorioallantoic membrane. They published their results in 1957;^[4] in this paper they coined the term ‘interferon’, and today that specific interfering agent is known as a ‘Type I interferon’.^[5]

Nagano’s work was never fully appreciated in the scientific community; possibly because it was printed in French, but also because his in vivo system was perhaps too complex to provide clear results in the characterisation and purification of interferon. As time passed, Nagano became aware that his work had not been widely recognised, yet did not actively seek reevaluation of his status in field of interferon research. As such, the majority of the credit for discovery of the interferon goes to Isaacs and Lindenmann, with whom there is no record of Nagano ever having made personal contact.^[6]

[edit] Types of interferon

There are three major classes of interferons that have been described for humans according to the type of receptor through which they signal:

• Interferon type I: All type I IFNs bind to a specific cell surface receptor complex known as the IFN-α receptor (IFNAR) that consists of IFNAR1 and IFNAR2 chains.

• Interferon type II: Binds to IFNGR.

• Interferon type III: Signal through a receptor complex consisting of IL10R2 (also called CRF2-4) and IFNLR1 (also called CRF2-12)

[edit] The signaling pathway of interferons

While there is evidence to suggest other signaling mechanisms exist, the JAK-STAT signaling pathway is the best-characterised and commonly accepted IFN signaling pathway.

[edit] Sources and functions of interferons

Interferons in general have several effects in common. They are antiviral and possess antioncogenic properties, macrophage and natural killer lymphocyte activation, and enhancement of major histocompatibility complex glycoprotein classes I and II, and thus presentation of foreign (microbial) peptides to T cells. 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, bacterial 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 rarely pass the placenta and the blood-brain barrier.

[edit] Viral induction of interferons

All classes of interferon are very important in fighting RNA virus infections. However, their presence also accounts for some of the host symptoms, such as sore muscles and fever. They are secreted when abnormally large amounts of dsRNA are found in a cell. dsRNA is normally present in very low quantities. The dsRNA acts like a trigger for the production of interferon (via Toll Like Receptor 3 (TLR 3) a pattern recognition receptor of the innate immune system which leads to activation of the transcription factor IRF3 and late phase NF kappa Beta). The gene that codes for this cytokine is switched on in an infected cell, and the interferon synthesized and secreted to surrounding cells.

As the original cell dies from the cytolytic RNA virus, these thousands of viruses will infect nearby cells. However, these cells have received interferon, which essentially warns these other cells that there's a wolf in the pack of sheep. They then start producing large amounts of a protein known as protein kinase R (or PKR). If a virus chooses to infect a cell that has been “pre-warned” by interferon, it is like charging into a hail of bullets for the virus. The PKR is indirectly activated by the dsRNA (actually by 2'-5' oligoadenylate produced by the 2'-5' oligoadenylate-synthetase which is produced due to TLR3 activation), and begins transferring phosphate groups (phosphorylating) to a protein known as eIF2, a eukaryotic translation initiation factor. After phosphorylation, eIF2 has a reduced ability to initiate translation, the production of proteins coded by cellular mRNA. This prevents viral replication, but also inhibits normal cell ribosome function, killing both the virus and the host cell if the response is active for a sufficient amount of time. All RNA within the cell is also degraded, preventing the mRNA from being translated by eIF2 if some of the eIF2 failed to be phosphorylated.

Furthermore, interferon leads to upregulation of MHC I and therefore to increased presentation of viral peptides to cytotoxic CD8 T cells, as well as to a change in the proteasome (exchange of some beta subunits by b1i, b2i, b5i - then known as the immunoproteasome) which leads to increased production of MHC I compatible peptides.

Interferon can cause increased p53 activity in virus infected cells. It acts as an inducer and causes increased production of the p53 gene product. This promotes apoptosis, limiting the ability of the virus to spread. Increased levels of transcription are observed even in cells which are not infected, but only infected cells show increased apoptosis. This increased transcription may serve to prepare susceptible cells so they can respond quickly in the case of infection. When p53 is induced by viral presence, it behaves differently than it usually does. Some p53 target genes are expressed under viral load, but others, especially those that respond to DNA damage, aren’t. One of the genes that is not activated is p21, which can promote cell survival. Leaving this gene inactive would help promote the apoptotic effect. Interferon enhances the apoptotic effects of p53, but it is not strictly required. Normal cells exhibit a stronger apoptotic response than cells without p53. ^[7][8]

Additionally, interferon has been shown to have therapeutic effect against certain cancers. It is probable that one mechanism of this effect is p53 induction. This could be useful clinically: Interferons could supplement or replace chemotherapy drugs that activate p53 but also cause unwanted side effects.^[9]

[edit] Virus Resistance to Interferons

Subversion of the interferon response is essential for virus survival, replication and transmission. Most viruses have developed mechanisms to counteract the effects of interferon. These strategies include:

• Inhibition of interferon signalling
• Inhibition of interferon synthesis
• Disruption of the function of interferon-induced proteins

Most viruses encode specific viral proteins in order to antagonize the interferon response. Several viruses interfere with the JAK-STAT signalling pathway to inhibit interferon signalling. For example Epstein-Barr viruses encode EBNA-2 and the large T antigen of polyomaviruses can block interferon-induced signalling. Some viruses have developed decoy receptors which can bind interferon preventing it from binding to its cognate cellular receptor and stimulating an antiviral response. For example vaccinia viruses produce the B18R protein which is a soluble receptor that can specifically bind type I IFN and sequester it.^[10] Furthermore a number of viruses encode proteins that bind to dsRNA, thereby preventing the synthesis of interferon as well as the activation of PKR and 2’-5’ oligoadenylate-synthetase. The reovirus σ3 protein, the vaccinia virus E3L protein and the influenza virus NS1 protein are all examples of virus encoded proteins that can perform such a function. In addition some viruses can activate a cellular inhibitor of PKR that results in the degradation of PKR and this disruption of PKR activity can occur for example in cells infected with polioviruses.^[11]

[edit] Pharmaceutical uses

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.^{[citation needed]} 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 cancers. 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, convulsion, dizziness, hair thinning, and depression. Erythema, pain and hardness on the spot of injection are also frequently observed. Interferon therapy causes immunosuppression and can result in some infections manifesting in unusual ways.^[12]

All known effects are usually reversible and disappear a few days after the therapy has been finished. However, there are some serious side effects and the patient is advised to read the accompanying pamphlet.

More than half of hepatitis C patients treated with interferon respond with better blood tests and better liver biopsies. There is some evidence that giving interferon immediately following infection can prevent hepatitis C; however, people infected by hepatitis C often do not display symptoms of HCV until months or years later.

More recently, the FDA approved pegylated interferon-alpha, in which polyethylene glycol is added to make the interferon last longer in the body. (Pegylated interferon-alpha-2b was approved in January 2001; pegylated interferon-alpha-2a was approved in October 2002.) The pegylated form is injected once weekly, rather than three times per week for conventional interferon-alpha. Used in combination with the antiviral drug ribavirin, pegylated interferon produces sustained cure rates of 75% or better in people with genotype 2 or 3 hepatitis C (which is easier to treat) but still less than 50% in people with genotype 1 (which is most common in the U.S. and Western Europe).

Interferon-beta (Interferon beta-1a and Interferon beta-1b) is used in the treatment and control of the neurological disorder multiple sclerosis. By an as-yet-unknown mechanism, interferon-beta inhibits the production of Th1 cytokines and the activation of monocytes.

Administered intranasally in very low doses, interferon is extensively used in Eastern Europe and Russia as a method to prevent and treat viral respiratory diseases such as cold and flu. It is claimed that the treatment can lower the risk of infection by as much as 60-70%.^{[citations needed]} Mechanisms of such action of interferon are not well understood; it is thought that doses must be larger by several orders of magnitude to have any effect on the virus. Consequently, most Western scientists are skeptical of these claims.^[13] Interferon alpha can also be induced with small imidazoquinoline molecules by activation of TLR7 receptor. Aldara (Imiquimod) cream works with this mechanism to induce IFN alpha and IL12 and approved by FDA to treat Actinic Keratosis, Superficial Basal Cell Carcinoma, and External Genital Warts.

[edit] See also

• Immunotherapy
• Immunosuppression
• Immunosuppressive drug
• PEGASYS
• ATC code L03#L03AB Interferons

[edit] References

1. ^ Nagano, Y. and Kojima,Y. (1954) “Pouvoir immunisant du virus vaccinal inactivé par des rayons ultraviolets” C.R. Seans. Soc. Biol.Fil 148:1700-1702
2. ^ Nagano, Y. and Kojima,Y. (1958) “Pouvoir immunisant du virus vaccinal inactivé par des rayons ultraviolets” C.R. Seans. Soc. Biol.Fil 152:1672-1629
3. ^ Wantanabe, Y. (2004) “Fifty Years of Interference”. Nature Immunology; 5(12):1193
4. ^ Isaacs, A and Lindenmann J. 1957 "Virus Interference. I. The interferon" J. Proc. Roy. Soc. Lond. B Biol. Sci. 147;258-267
5. ^ Mergiran, TC. Worldbook Science Year, 1980
6. ^ International Society For Interferon And Cytokine Research, October 2005 Volume 12, No. 3.
7. ^ http://www.nature.com/nature/journal/v424/n6948/pdf/nature01850.pdf
8. ^ http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16436515
9. ^ http://www.nature.com/nature/journal/v424/n6948/pdf/nature01850.pdf
10. ^ Levy, DE. and Garcia-Sastre, A. (2001). "The virus battles: IFN induction of the antiviral state and mechanisms of viral evasion.". Cytokine Growth Factor Rev 12 (2-3): 143-156. PMID 11325598. 
11. ^ Samuel, CE. (2001). "Antiviral actions of interferons". Clin Microbiol Rev 14 (4): 778-809. PMID 11585785. 
12. ^ Bhatti Z, Berenson CS (2007). "Adult systemic cat scratch disease associated with therapy for hepatitis C". BMC Infect Dis 7: 8. PMID 17319959. 
13. ^ http://www.pathobiologics.org/ivphc/ref/iav121604.doc

[edit] Further reading

• Hall, Steven S. (1997) A Commotion in the Blood. New York, New York: Henry Holt and Company. ISBN 0-8050-5841-9
• Information on Interferon and how it relates to hepatitis c

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