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Interferons (IFNs) are natural cell-signaling proteins produced by the cells of the immune system of most vertebrates in response to challenges such as viruses, parasites and tumor cells. Interferons belong to the large class of glycoproteins known as cytokines. Interferons are produced by a wide variety of cells in response to the presence of double-stranded RNA, a key indicator of viral infection. Interferons assist the immune response by inhibiting viral replication within host cells, activating natural killer cells and macrophages, increasing antigen presentation to lymphocytes, and inducing the resistance of host cells to viral infection. It can be used as an antineoplastic drug

Types of interferonEdit

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

Signaling pathwayEdit

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.

Regulated genesEdit

Type I, II and III IFNs regulate approximately 2000 genes. Relatively little is known of these interferon regulated genes. INTERFEROME is a database of interferon regulated genes and attempts to bridge the gap in knowledge by identifying and integrating information on IRGs.

Natural function and synthesisEdit

Interferons in general have several effects in common. They are antiviral and possess antioncogenic properties, macrophage and natural killer cell 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 sites), 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 but they can cross the blood-brain barrier.

The therapeutically used forms are denoted by Greek letters indicating their origin: leukocytes, fibroblasts, and lymphocytes for interferon-alpha, -beta and -gamma, respectively.

Viral induction of interferonsEdit

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 B). 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, thousands of viruses will infect nearby cells. However, these cells have received interferon, which essentially warns these other cells of the virus. They then start producing large amounts of a protein known as protein kinase R (or PKR). If a virus infects a cell that has been “pre-warned” by interferon, the PKR is indirectly activated by the dsRNA, and begins transferring phosphate groups (phosphorylating) to a protein known as eIF-2, a eukaryotic translation initiation factor. After phosphorylation, eIF2 forms an inactive complex with eIF2B, thereby leading to reduced translation initiation and reduced protein synthesis. This inhibits viral replication and normal cell ribosome function, which may lead to killing both the virus and susceptible host cells. Various RNA species within the cell are degraded by activated RNAse L, another interferon-induced gene, thereby further reducing protein synthesis.

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.[2][3]

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.[2] Some of these side effects can be serious, severe and permanent.

Virus resistance to interferonsEdit

In a study of the blocking of interferon (IFN) by the Japanese Encephalitis Virus (JEV), a group of researchers infected human recombinant IFN-alpha with JEV, DEN-2, and PL406, which are all viruses, and found that some viruses have manifested methods of avoiding the IFN-alpha/beta response. These viruses therefore have the ability to carry on viral replication and production of new viruses as they normally would in the absence of IFN.[4] The ways that viruses find a way around the IFN response is through the inhibition of interferon signaling, production, and the blocking of the functions of IFN-induced proteins.[4]

It is not unusual to find viruses encoding for a multiple number of mechanisms to allow them to elude the IFN response at many different levels.[4] While doing the study with JEV, Lin and his coworkers found that IFN-alpha's inability to block JEV means that JEV may be able to block IFN-alpha signaling which in turn would prevent IFN from having STAT1, STAT2, ISGF3, and IRF-9 signaling.[4] DEN-2 also significantly reduces interferon ability to active JAK-STAT.[4] Some other viral gene products that have been found to have an effect on IFN signaling include EBNA-2, Polyomavirus large T antigen, EBV EBNA1, HPV E7, HCMV, and HHV8.[5] Several poxviruses encode a soluble IFN receptor homologue that acts as a decoy to inhibit the biological activity of IFN, and that activity is for IFN to bind to their cognate receptors on the cell surface to initiate a signaling cascade, known as the Janus kinase(JAK)-signal transducer and activation of transcription(Stat) pathways.[4] For example, a group of researchers found that the B18R protein, which acts as a type 1 IFN receptor and is produced by the vaccinia virus, inhibited IFN's ability to begin the phosphorylation of JAK1 which reduced the antiviral effect of IFN.[6]

Some viruses can encode proteins that bind to dsRNA. In a study where the researchers infected Human U cells with reovirus-sigma3 protein and then, using the Western blot test, they found that reovirus-sigma3 protein does bind to dsRNA.[7] Along with that, another study in which the researchers infected mouse L cells with vaccinia virus E3L found that E3L encodes the p25 protein that binds to dsRNA.[8] Without double stranded RNA (dsRNA), because it is bound to by the proteins, it is not able to create IFN-induced PKR and 2'-5' oligoadenylate-synthetase making IFN ineffective.[9] It was also found that JEV was able to inhibit IFN-alpha's ability to activate or create ISGs such as PKR.[4] PKR was not able to be found in the JEV infected cells and PKR RNA levels were found to be lower in those same infected cells, and this disruption of PKR can occur, for example, in cells infected with flavaviruses.[4]

The H5N1 influenza virus, also known as bird flu, has been shown to have resistance to interferon and other anti-viral cytokines. This is part of the reason for its high mortality rates in humans. It is resistant due to a single amino acid mutation in Non-Structural protein 1 (NS1), the precise mechanism of how this confers immunity is unclear (reference is Lethal H5N1 influenza viruses escape host anti-viral cytokine responses, Sang Heui Seo, Nature Med, 2002).

Pharmaceutical usesEdit

Vials of Interferon Image 3549-PH

Three vials filled with human leukocyte interferon.

UsesEdit

Just as their natural function, interferons have antiviral, antiseptic and antioncogenic properties when administered as drugs.

Interferon therapy is used (in combination with chemotherapy and radiation) as a treatment for many cancers.

More than half of hepatitis C patients treated with interferon respond with viral elimination (sustained virological response), better blood tests and better liver histology (detected on biopsy). There is some evidence that giving interferon immediately following infection can prevent chronic hepatitis C. However, people infected by HCV often do not display symptoms of HCV infection until months or years later making early treatment difficult.

Interferons (interferon beta-1a and interferon beta-1b ) are also used in the treatment and control of multiple sclerosis, an autoimmune disorder.

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. However, 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 any claims of good efficacy.[10]

Route of administrationEdit

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.

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.

Adverse effectsEdit

The most frequent adverse 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, in particular through neutropenia and can result in some infections manifesting in unusual ways.[11]

All known adverse effects are usually reversible and disappear a few days after the therapy has been finished.

TypesEdit

Several different types of interferon are now approved for use in humans.

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 multiple sclerosis. By an as-yet-unknown mechanism, interferon-beta inhibits the production of Th1 cytokines and the activation of monocytes.

HistoryEdit

While aiming to develop an improved vaccine for smallpox, two Japanese virologists, Yasu-ichi Nagano and Yasuhiko Kojima working at the Institute for Infectious Diseases 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 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”.[12] 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.[13][14]

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;[15] in this paper they coined the term ‘interferon’, and today that specific interfering agent is known as a ‘Type I interferon’.[16]

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 revaluation 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.[17]

As a drugEdit

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[18] or derived from yeast (e.g. Reiferon Retard is the first yeast derived interferon-alpha 2a).

Global sales ~ 5 billion US $. The second most successful pharmaceutical ever to come from genetic engineering.[How to reference and link to summary or text]


Pharmaceutical forms of interferons in the marketEdit

Generic name Trade name
Interferon alpha 2a Roferon A
Interferon alpha 2b§ Intron A
Human leukocyte Interferon-alpha (HuIFN-alpha-Le) Multiferon
Interferon beta 1a, liquid form Rebif
Interferon beta 1a, lyophilized Avonex
Interferon beta 1a, biogeneric (Iran) Cinnovex
Interferon beta 1b Betaseron / Betaferon
Pegylated interferon alpha 2a Pegasys
Pegylated interferon alpha 2a (Egypt) Reiferon Retard
Pegylated interferon alpha 2b PegIntron
Pegylated interferon alpha 2b plus ribavirin (Canada) Pegetron

§ also marketed in India as Reliferon, a product of Reliance Biopharmaceuticals

See alsoEdit


ReferencesEdit

  1. Liu YJ (2005). IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors. Annu Rev Immunol 23: 275–306.
  2. 2.0 2.1 Takaoka A, Hayakawa S, Yanai H, et al (2003). Integration of interferon-alpha/beta signalling to p53 responses in tumour suppression and antiviral defence. Nature 424 (6948): 516–23.
  3. Moiseeva O, Mallette FA, Mukhopadhyay UK, Moores A, Ferbeyre G (2006). DNA damage signaling and p53-dependent senescence after prolonged beta-interferon stimulation. Mol. Biol. Cell 17 (4): 1583–92.
  4. 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 Lin RJ, Liao CL, Lin E, Lin YL (2004 aaa). Blocking of the alpha interferon-induced Jak-Stat signaling pathway by Japanese encephalitis virus infection. J. Virol. 78 (17): 9285–94.
  5. Sen GC (2001). Viruses and interferons. Annu. Rev. Microbiol. 55: 255–81.
  6. Alcamí A, Symons JA, Smith GL (December 2000). The vaccinia virus soluble alpha/beta interferon (IFN) receptor binds to the cell surface and protects cells from the antiviral effects of IFN. J. Virol. 74 (23): 11230–9.
  7. Miller JE, Samuel CE (September 1992). Proteolytic cleavage of the reovirus sigma 3 protein results in enhanced double-stranded RNA-binding activity: identification of a repeated basic amino acid motif within the C-terminal binding region. J. Virol. 66 (9): 5347–56.
  8. Chang HW, Watson JC, Jacobs BL (June 1992). The E3L gene of vaccinia virus encodes an inhibitor of the interferon-induced, double-stranded RNA-dependent protein kinase. Proc. Natl. Acad. Sci. U.S.A. 89 (11): 4825–9.
  9. Minks MA, West DK, Benvin S, Baglioni C (October 1979). Structural requirements of double-stranded RNA for the activation of 2',5'-oligo(A) polymerase and protein kinase of interferon-treated HeLa cells. J. Biol. Chem. 254 (20): 10180–3.
  10. http://www.pathobiologics.org/ivphc/ref/iav121604.doc
  11. Bhatti Z, Berenson CS (2007). Adult systemic cat scratch disease associated with therapy for hepatitis C. BMC Infect Dis 7: 8.
  12. Nagano Y, Kojima Y (October 1954). Pouvoir immunisant du virus vaccinal inactivé par des rayons ultraviolets. C. R. Seances Soc. Biol. Fil. 148 (19-20): 1700–2.
  13. Nagano Y, Kojima Y (1958). Inhibition de l'infection vaccinale par un facteur liquide dans le tissu infecté par le virus homologue. C. R. Seances Soc. Biol. Fil. 152 (11): 1627–9.
  14. Watanabe Y (December 2004). Fifty years of interference. Nat. Immunol. 5 (12): 1193.
  15. Isaacs A, Lindenmann J (September 1957). Virus interference. I. The interferon. Proc. R. Soc. Lond., B, Biol. Sci. 147 (927): 258–67.
  16. Mergiran, TC. Worldbook Science Year, 1980
  17. International Society For Interferon And Cytokine Research, October 2005 Volume 12, No. 3.
  18. Nagata S, Taira H, Hall A, et al (March 1980). Synthesis in E. coli of a polypeptide with human leukocyte interferon activity. Nature 284 (5754): 316–20.


Further reading]Edit

  • Becker, D., Kritschmann, E., Floru, S., Shlomo-David, Y., & et al. (1990). Serum interferon in first psychotic attack: British Journal of Psychiatry Vol 157 Jul 1990, 136-138.
  • Cabrera Gomez, J. A., Reyes Gutierrez, B. R., Fernandez Lopez, O., Lois, M. M., & et al. (1990). Interferon: Its utilization with nine schizophrenic patients: Revista del Hospital Psiquiatrico de La Habana Vol 31(1) Jan-Mar 1990, 81-87.
  • Iivanainen, M., & et al. (1985). Memory and psychomotor impairment following high-dose interferon treatment in amyotrophic lateral sclerosis: Acta Neurologica Scandinavica Vol 72(5) Nov 1985, 475-480.
  • Segall, M. A., & Crnic, L. S. (1990). A test of conditioned taste aversion with mouse interferon-!a: Brain, Behavior, and Immunity Vol 4(3) Sep 1990, 223-231.



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