Difference between revisions of "Interferon" - New World Encyclopedia

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'''Interferons''' (IFNs) are natural [[protein]]s produced by the cells of the [[immune system]] of most [[vertebrate]]s in response to challenges by foreign agents such as [[virus]]es, [[bacterium|bacteria]], [[parasite]]s and [[tumor]] cells. Interferons belong to the large class of [[glycoproteins]] known as [[cytokine]]s. Interferons assist the immune response by inhibiting viral replication within other cells of the body.
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==History==
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While aiming to develop an improved [[vaccine]] for [[smallpox]], two Japanese [[virology|virologists]], [[Yasu-ichi Nagano]] and [[Yasuhiko Kojima]] working at the then Institute for Infectious Diseases at the [[University of Tokyo]], noticed that rabbit-skin or testis previously [[inoculate]]d 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 [[homogenate]]s using an [[ultracentrifuge]]. They published these findings in 1954 in the French journal now known as “[[Journal de la Société de Biologie]]”.<ref>Nagano, Y. and Y. Kojima. 1954. Pouvoir immunisant du virus vaccinal inactivé par des rayons ultraviolets. ''C.R. Seances Soc. Biol. Fil''. 148:1700-1702</ref> 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.<ref>Nagano, Y. and 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. 152:1627-1629</ref><ref> Watanabe, Y. (2004) “Fifty Years of Interference.” Nature Immunology 5(12):1193</ref>
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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;<ref>Isaacs, A and Lindenmann, J. (1957) "Virus Interference. I. The interferon"  Proc. Roy. Soc. Lond. B Biol. Sci. 147;258-267</ref> in this paper they coined the term ‘interferon’, and today that specific interfering agent is known as a ‘Type I interferon’.<ref>Mergiran, TC. ''Worldbook Science Year'', 1980</ref>
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Nagano’s work was never fully appreciated in the scientific community; possibly because it was printed in [[French language|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.<ref>International Society For Interferon And Cytokine Research, October 2005 Volume 12, No. 3.</ref>
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==Types of interferon==
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There are three major classes of interferons that have been described for humans according to the type of receptor through which they signal:
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* [[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.
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* [[Interferon type II]]: Binds to [[IFNGR]].
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* [[Interferon type III]]: Signal through a receptor complex consisting of IL10R2 (also called CRF2-4) and IFNLR1 (also called CRF2-12)
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==The signaling pathway of interferons==
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While there is evidence to suggest other signaling mechanisms exist, the [[JAK-STAT pathway|JAK-STAT]] signaling pathway is the best-characterised and commonly accepted IFN signaling pathway.
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==Sources and functions of interferons==
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Interferons in general have several effects in common. They are antiviral and possess antioncogenic properties, [[macrophage]] and [[natural killer cell|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-alpha|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]].
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==Viral induction of interferons==
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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 [[RNA#Double-stranded RNA|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.
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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 [[RNA#Double-stranded RNA|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 ([[phosphorylation|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 and 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.
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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.
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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.<ref name="Takaoka">{{cite journal |author=Takaoka A, Hayakawa S, Yanai H, ''et al'' |title=Integration of interferon-alpha/beta signalling to p53 responses in tumour suppression and antiviral defence |journal=Nature |volume=424 |issue=6948 |pages=516-23 |year=2003 |pmid=12872134 |doi=10.1038/nature01850 |url=http://www.nature.com/nature/journal/v424/n6948/pdf/nature01850.pdf}}</ref><ref>{{cite journal |author=Moiseeva O, Mallette FA, Mukhopadhyay UK, Moores A, Ferbeyre G |title=DNA damage signaling and p53-dependent senescence after prolonged beta-interferon stimulation |journal=Mol. Biol. Cell |volume=17 |issue=4 |pages=1583-92 |year=2006 |pmid=16436515 |doi=10.1091/mbc.E05-09-0858}}</ref>
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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.<ref name="Takaoka"> </ref>.Some of these side effects can be serious, severe and permanent.
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==Virus resistance to interferons==
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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 that give them a way around the IFN-alpha/beta response.  The viruses need to master these methods so they can have the ability to carry on viral replication and production of new viruses.<ref name="Lin">{{cite journal |author=Lin RJ, Liao CL, Lin E, Lin YL |title=Blocking of the alpha interferon-induced Jak-Stat signaling pathway by Japanese encephalitis virus infection |journal=J. Virol. |volume=78 |issue=17 |pages=9285-94 |year=2004 aaa|pmid=15308723 |doi=10.1128/JVI.78.17.9285-9294.2004}}</ref> 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.<ref name="Lin"> </ref>
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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.<ref name="Lin"> </ref> While doing the study with JEV, Lin and his coworkers found that with 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.<ref name="Lin"> </ref> DEN-2 also significantly reduces interferon ability to active JAK-STAT.<ref name="Lin"> </ref>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.<ref>Sen, Ganes C. "Viruses and Interferons." ''Annual Review Microbiology v.55:255-281''. 16 December 2003.</ref> "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 recepors on the cell surface to iniate a signaling cascade, known as the Janus kinase(JAK)-signal transducer and activation of transcription(Stat) pathways.<ref name="Lin"> </ref> For example, in a study done by a group of researcher, they found that the B18R protein, which acts as a type 1 IFN receptor and is produced by the vaccinia virus, it was found that the B18R protein inhibited IFN's ability to begin the phosphorylation of JAK1 which reduced the antiviral effect of IFN.<ref>Alcami', Antonio et al. "The Vaccinia Virus Soluble Alpha/Beta Interferon (IFN) Receptor Binds to the Cell Surface and Protects Cells from the Antiviral Effects of IFN." ''Journal of Virology:11230-11239''. 13 September 2000.</ref>
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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 reaovirus-sigma3 protein does bind to dsRNA.<ref>Miller, Jeffrey E., and Samuel, Charles E. "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." ''Journal of Virology v.66(9):5347-5356.'' 8 June 1992.</ref> 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.<ref>Chang, H et al. "The E3L Gene of Vaccinia Virus Encodes an Inhibitor of the Interferon-Induced, Double-Stranded RNA-Dependent Protein Kinase." Proceedings of the National Academy of Sciences v.89:4825-4829. 28 February 1992. </ref> 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.<ref>Minks, Michael A. et al. "Structural Requirements of Double-stranded RNA for the Activation of 2',5'-Oligo(A) Polymerase and Protein Kinase of Interferon-treated HeLa Cells." ''The Journal of Biological Chemistry v254(20):10180-10183.'' 16 May 1979. </ref>  It was also found that JEV was able to inhibit IFN-alpha's ability to activate or create ISGs such as PKR.<ref name="Lin"> </ref> 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.<ref name="Lin"> </ref>
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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-Structual protein 1 (NS1), the precise mechanism of how this confers immuninity is unclear (reference is Lethal H5N1 influenza viruses escape host anti-viral cytokine responses, Sang Heui Seo, Nature Med,  2002).
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==Pharmaceutical uses==
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[[Image:Vials of Interferon Image 3549-PH.jpg|thumb|left|200px|Three vials filled with human leukocyte interferon. ]]
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Interferon was scarce and expensive until 1980 when the interferon [[gene]] was inserted into [[bacterium|bacteria]] using [[recombinant DNA technology]], allowing mass [[cultivation]] and purification from bacterial cultures.{Nagata, S., Taira, H., Hall, A., Johnstrud,
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L., et al. 1980. Synthesis in E. coli
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of a polypeptide with human leukocyte
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interferon activity. Nature (London)
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284 : 315-21)}  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.
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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.<ref>{{cite journal | title=Adult systemic cat scratch disease associated with therapy for hepatitis C | author=Bhatti Z, Berenson CS | journal=BMC Infect Dis | year=2007 | volume=7 | pages=8 | id=PMID 17319959 }}</ref>
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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 {{Fact|date=April 2007}}.
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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.
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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).
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Interferon-beta ([[Interferon beta-1a]] and [[Interferon beta-1b]]) is used in the treatment and control of the neurological disorder [[multiple sclerosis]].(Auto Immune) By an as-yet-unknown mechanism, interferon-beta inhibits the production of Th1 cytokines and the activation of monocytes.
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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 [[Common cold|cold]] and [[flu]]. It is claimed that the treatment can lower the risk of infection by as much as 60-70%.{{Facts|date=February 2007}} 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.<ref>http://www.pathobiologics.org/ivphc/ref/iav121604.doc</ref>
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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.
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==Pharmaceutical forms of interferons in the market==
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*[[Rebif]], liquid form of Interferon beta 1a
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*[[Avonex]], lyophilized form of Interferon beta 1a
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*[[Cinnovex]], generic/biosimilar form of Interferon beta 1a (Avonex)
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*[[Betaseron]], Interferon beta 1b
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*[[Roferon A]]. regular Interferon-alpha2a
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*[[Intron-A]], regular Interferon-alpha2b
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*[[Pegasys]], Pegylated Interferon alpha 2a
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*[[Berlex]], Interferon beta 1b
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*[[PegIntron]], Pegylated Interferon alpha 2b
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*[[Reiferon Etard]] , pegylated Interferon alpha 2a
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==See also==
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*[[Immunotherapy]]
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*[[Immunosuppression]]
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*[[Immunosuppressive drug]]
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*[[PEGASYS]]
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*[[CinnoVex]]
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*[[ATC code L03#L03AB Interferons]]
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*[[PEGylation]]
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==References==
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{{Reflist|2}}
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{{Antivirals}}
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{{Cytokines}}
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{{Interferons}}
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[[Category:Cytokines]]
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[[Category:Antivirals]]
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{{Credit|162462423}}

Revision as of 03:35, 7 October 2007

Template:Cleanup 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.

History

While aiming to develop an improved vaccine for smallpox, two Japanese virologists, Yasu-ichi Nagano and Yasuhiko Kojima working at the then 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”.[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]

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)

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.

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 but they can cross the blood-brain barrier.

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 and 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.[7].Some of these side effects can be serious, severe and permanent.

Virus resistance to interferons

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 that give them a way around the IFN-alpha/beta response. The viruses need to master these methods so they can have the ability to carry on viral replication and production of new viruses.[9] 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.[9]

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.[9] While doing the study with JEV, Lin and his coworkers found that with 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.[9] DEN-2 also significantly reduces interferon ability to active JAK-STAT.[9]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.[10] "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 recepors on the cell surface to iniate a signaling cascade, known as the Janus kinase(JAK)-signal transducer and activation of transcription(Stat) pathways.[9] For example, in a study done by a group of researcher, they found that the B18R protein, which acts as a type 1 IFN receptor and is produced by the vaccinia virus, it was found that the B18R protein inhibited IFN's ability to begin the phosphorylation of JAK1 which reduced the antiviral effect of IFN.[11]

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 reaovirus-sigma3 protein does bind to dsRNA.[12] 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.[13] 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.[14] It was also found that JEV was able to inhibit IFN-alpha's ability to activate or create ISGs such as PKR.[9] 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.[9]

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-Structual protein 1 (NS1), the precise mechanism of how this confers immuninity is unclear (reference is Lethal H5N1 influenza viruses escape host anti-viral cytokine responses, Sang Heui Seo, Nature Med, 2002).

Pharmaceutical uses

Three vials filled with human leukocyte interferon.

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.{Nagata, S., Taira, H., Hall, A., Johnstrud, L., et al. 1980. Synthesis in E. coli of a polypeptide with human leukocyte interferon activity. Nature (London) 284 : 315-21)} 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.[15]

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 [citation needed].

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.(Auto Immune) 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%. 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.[16] 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.

Pharmaceutical forms of interferons in the market

  • Rebif, liquid form of Interferon beta 1a
  • Avonex, lyophilized form of Interferon beta 1a
  • Cinnovex, generic/biosimilar form of Interferon beta 1a (Avonex)
  • Betaseron, Interferon beta 1b
  • Roferon A. regular Interferon-alpha2a
  • Intron-A, regular Interferon-alpha2b
  • Pegasys, Pegylated Interferon alpha 2a
  • Berlex, Interferon beta 1b
  • PegIntron, Pegylated Interferon alpha 2b
  • Reiferon Etard , pegylated Interferon alpha 2a

See also

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

References
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  1. ↑ Nagano, Y. and Y. Kojima. 1954. Pouvoir immunisant du virus vaccinal inactivé par des rayons ultraviolets. C.R. Seances Soc. Biol. Fil. 148:1700-1702
  2. ↑ Nagano, Y. and 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. 152:1627-1629
  3. ↑ Watanabe, Y. (2004) “Fifty Years of Interference.” Nature Immunology 5(12):1193
  4. ↑ Isaacs, A and Lindenmann, J. (1957) "Virus Interference. I. The interferon" 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. ↑ 7.0 7.1 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.
  8. ↑ 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.
  9. ↑ 9.0 9.1 9.2 9.3 9.4 9.5 9.6 9.7 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.
  10. ↑ Sen, Ganes C. "Viruses and Interferons." Annual Review Microbiology v.55:255-281. 16 December 2003.
  11. ↑ Alcami', Antonio et al. "The Vaccinia Virus Soluble Alpha/Beta Interferon (IFN) Receptor Binds to the Cell Surface and Protects Cells from the Antiviral Effects of IFN." Journal of Virology:11230-11239. 13 September 2000.
  12. ↑ Miller, Jeffrey E., and Samuel, Charles E. "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." Journal of Virology v.66(9):5347-5356. 8 June 1992.
  13. ↑ Chang, H et al. "The E3L Gene of Vaccinia Virus Encodes an Inhibitor of the Interferon-Induced, Double-Stranded RNA-Dependent Protein Kinase." Proceedings of the National Academy of Sciences v.89:4825-4829. 28 February 1992.
  14. ↑ Minks, Michael A. et al. "Structural Requirements of Double-stranded RNA for the Activation of 2',5'-Oligo(A) Polymerase and Protein Kinase of Interferon-treated HeLa Cells." The Journal of Biological Chemistry v254(20):10180-10183. 16 May 1979.
  15. ↑ Bhatti Z, Berenson CS (2007). Adult systemic cat scratch disease associated with therapy for hepatitis C. BMC Infect Dis 7: 8. PMID 17319959.
  16. ↑ http://www.pathobiologics.org/ivphc/ref/iav121604.doc


Template:Antivirals

Cell signaling: cytokines
Autocrine motility factor - Chemokine - Hematopoietic (Stem cell factor, Colony-stimulating factor) - Hepatocyte growth factor - Interferon - Interleukin - Leukemia inhibitory factor - Lymphokine (Lymphotoxin, Transfer factor) - Monokine - Oncostatin M - Osteopontin - TGF beta - Tumor necrosis factor
Cytokines: interferons
Interferon type I
Interferon beta-1a - Interferon beta-1b - Pegylated interferon alfa-2a - Pegylated interferon alfa-2b
Interferon type II
Interferon-gamma
Interferon type III
Interleukin 28 - Interleukin 29

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