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, parasites and tumor cells. Proteins are large Organic compounds made of Amino acids arranged in a linear chain and joined together by Peptide bonds between the Carboxyl An immune system is a collection of mechanisms within an Organism that protects against Disease by identifying and killing Pathogens and Tumor Vertebrates are members of the Subphylum Vertebrata, Chordates with backbones or spinal columns The grouping sometimes includes A virus (from the Latin virus meaning Toxin or Poison) is a sub-microscopic infectious agent that is unable Parasitism is a type of symbiotic relationship between Organisms of different Species. See also Cancer A tumor or tumour is the name for a swelling or lesion formed by an abnormal growth of cells (termed neoplastic Interferons belong to the large class of glycoproteins known as cytokines. Not to be confused with Peptidoglycan. Glycoproteins are proteins that contain Oligosaccharide chains ( Glycans) covalently attached Cytokines are a category of signalling Proteins and Glycoproteins that like Hormones and Neurotransmitters, are used extensively in cellular Interferons are produced by a wide variety of cells in response to the presence of double-stranded RNA, a key indicator of viral infection. Ribonucleic acid ( RNA) is a Nucleic acid that consists of a long chain of Nucleotide units 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. When the antigen is presented to matching T and B cells, those cells multiply and strategically and specifically wipe out the foreign substance. That is why antigen presentation is so important to the immune response.
There are three major classes of interferons that have been described for humans according to the type of receptor through which they signal:
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. The recently classified type III Interferon group consists of three IFN-λ (lambda molecules called IFN-λ1 IFN-λ2 and IFN-λ3 (also called IL29, IL28A Interleukin 28 receptor alpha subunit is a subunit for the Interleukin-28 receptor. The JAK-STAT signaling pathway takes part in the regulation of cellular responses to Cytokines and Growth factors Employing Janus kinases (JAKs and
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. Macrophages ( Greek: "big eaters" from makros "large" + phagein "eat" ( Mø) are cells within the tissues that Natural killer cells (or NK cells) are a type of Cytotoxic Lymphocyte that constitute a major component of the Innate immune system. The major histocompatibility complex ( MHC) is a large genomic region or Gene family found in most Vertebrates It is the most gene-dense region Not to be confused with Peptidoglycan. Glycoproteins are proteins that contain Oligosaccharide chains ( Glycans) covalently attached T cells belong to a group of White blood cells known as Lymphocytes, and play a central role in Cell-mediated immunity. 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. CpG sites are regions of DNA where a Cytosine Nucleotide occurs next to a Guanine nucleotide in the linear sequence of bases Interleukin-1 (IL-1 is one of the first Cytokines ever described Interleukin-2 ( IL-2) is an Interleukin, a type of Cytokine Immune system signaling molecule that is instrumental in the body's natural response For Il-12 see also Ilyushin Il-12 Interleukin 12 ( IL-12) is an Interleukin that is naturally produced by Dendritic Tumor necrosis factor ( TNF, cachexin or cachectin and formally known as Tumor necrosis factor-alpha) is a Cytokine involved in systemic Colony-stimulating factors (CSFs are secreted Glycoproteins which bind to receptor proteins on the surfaces of Hemopoietic stem cells and thereby activate Intracellular 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 placenta is an Ephemeral organ present in placental Vertebrates, such as Eutherial Mammals and Sharks during Gestation The blood-brain barrier (BBB is a metabolic or cellular structure in the Central nervous system (CNS that restricts the passage of various chemical substances and microscopic
All classes of interferon are very important in fighting RNA virus infections. An RNA virus is a Virus that has RNA (ribonucleic acid as its Genetic material. 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. Ribonucleic acid ( RNA) is a Nucleic acid that consists of a long chain of Nucleotide units 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). TLR 3 is a member of the Toll-like receptor family of Pattern recognition receptors of the Innate immune system. Pattern recognition receptors, or PRR s are Proteins expressed by cells of the Immune system to identify molecules associated with microbial Pathogens Interferon regulatory factor 3, also known as IRF3, is an Interferon regulatory factor. 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. An RNA virus is a Virus that has RNA (ribonucleic acid as its Genetic material. However, these cells have received interferon, which essentially warns these other cells that there's a wolf in the flock of sheep. They then start producing large amounts of a protein known as protein kinase R (or PKR). Protein kinase R (Eukaryotic translation initiation factor 2-alpha kinase 2 is a protein protecting against Viral infections EIF2AK2 is its human Gene Protein kinase R (Eukaryotic translation initiation factor 2-alpha kinase 2 is a protein protecting against Viral infections EIF2AK2 is its human Gene If a virus infects a cell that has been “pre-warned” by interferon, 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 eIF-2, a eukaryotic translation initiation factor. Ribonucleic acid ( RNA) is a Nucleic acid that consists of a long chain of Nucleotide units Phosphorylation is the addition of a Phosphate (PO4 group to a Protein molecule or a small molecule Animals Plants fungi, and Protists are eukaryotes (juːˈkærɪɒt or -oʊt Organisms whose cells are organized into complex After phosphorylation, eIF2 has a reduced ability to initiate translation, the production of proteins coded by cellular mRNA. Messenger ribonucleic acid ( mRNA) is a molecule of RNA encoding a chemical "blueprint" for a Protein product 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. Ribosomes ( from ribo nucleic acid and "Greek soma ( meaning body") are complexes of RNA and Protein that 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. p53 (also known as protein 53 or tumor protein 53) is a Transcription factor encoded by the TP53 gene 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. Cyclin-dependent kinase inhibitor 1A (p21 Cip1, also known as CDKN1A, is a human Gene. 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. 
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. Chemotherapy, in its most general sense refers to treatment of disease by chemicals that kill cells specifically those of micro-organisms or Cancer. . Some of these side effects can be serious, severe and permanent.
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.  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. 
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.  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.  DEN-2 also significantly reduces interferon ability to active JAK-STAT. 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.  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.  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. 
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.  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.  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.  It was also found that JEV was able to inhibit IFN-alpha's ability to activate or create ISGs such as PKR.  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. 
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 immunity is unclear (reference is Lethal H5N1 influenza viruses escape host anti-viral cytokine responses, Sang Heui Seo, Nature Med, 2002).
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). Hepatitis C is a blood-borne infectious disease that is caused by the Hepatitis C virus ( HCV) affecting the Liver. A biopsy (in Greek: βίος life and όψη look/appearance is a Medical test involving the removal of cells or tissues There is some evidence that giving interferon immediately following infection can prevent chronic hepatitis C. Hepatitis C is a blood-borne infectious disease that is caused by the Hepatitis C virus ( HCV) affecting the Liver. 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. Interferon beta-1a is a drug in the Interferon family used to treat Multiple sclerosis (MS Interferon beta-1b (tradenames Betaferon, Betaseron (North America and Extavia) is a drug in the Interferon family used to treat Multiple sclerosis (abbreviated MS also known as disseminated sclerosis or encephalomyelitis disseminata) is an autoimmune condition in which the Autoimmunity is the failure of an organism to recognize its own constituent parts as self, which results in an immune response against its own cells and tissues
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. Acute viral nasopharyngitis or acute coryza, usually known as the common cold, is a highly contagious viral Infectious disease of the 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. 
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. Imidazoquinoline is a double cyclic organic molecule its derivatives and compounds are often used for antiviral and antiallergic creams 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.
The most frequent adverse effects are flu-like symptoms: increased body temperature, feeling ill, fatigue, headache, muscle pain, convulsion, dizziness, hair thinning, and depression. In Medicine, an adverse effect is a harmful and undesired effect resulting from a medication or other intervention such as Chemotherapy or Surgery. Erythema, pain and hardness on the spot of injection are also frequently observed. Erythema is redness of the Skin caused by Capillary congestion Interferon therapy causes immunosuppression, in particular though neutropenia and can result in some infections manifesting in unusual ways. Immunosuppression involves an act that reduces the activation or Efficacy of the Immune system. Neutropenia (adjective neutropenic) from Latin Prefix neutro- and Greek Suffix -πενία (deficiency is 
All known adverse effects are usually reversible and disappear a few days after the therapy has been finished.
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. PEGylation is the process of covalent attachment of poly(ethylene glycol polymer chains to another molecule normally a drug or therapeutic protein Poly( Ethylene glycol) (PEG also known as poly( Ethylene oxide) (PEO or polyoxyethylene (POE is the most commercially important type of polyether (Pegylated interferon-alpha-2b was approved in January 2001; pegylated interferon-alpha-2a was approved in October 2002. Pegylated Interferon alfa-2b is a treatment for Hepatitis C developed by Schering-Plough brand name is Peg Intron Pegylated interferon alfa-2a (40kD (commercial name PEGASYS) is an Antiviral drug discovered at the pharmaceutical company F ) 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. Ribavirin (Copegus Rebetol Ribasphere VilonaVirazole also generics from Sandoz Teva Warrick is an Anti-viral drug which is active against a number of DNA and S. and Western Europe).
Interferon-beta (Interferon beta-1a and Interferon beta-1b) is used in the treatment and control of multiple sclerosis. Interferon beta-1a is a drug in the Interferon family used to treat Multiple sclerosis (MS Interferon beta-1b (tradenames Betaferon, Betaseron (North America and Extavia) is a drug in the Interferon family used to treat Multiple sclerosis (abbreviated MS also known as disseminated sclerosis or encephalomyelitis disseminata) is an autoimmune condition in which the By an as-yet-unknown mechanism, interferon-beta inhibits the production of Th1 cytokines and the activation of monocytes.
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. A vaccine is a biological preparation which is used to establish or improve immunity to a particular disease Smallpox is an Infectious disease unique to humans caused by either of two virus variants named Variola major and Variola minor. Virology is the study of viruses and virus-like agents: their structure classification and evolution their ways to infect and exploit cells for virus reproduction The, abbreviated as, is a major Research university located in Tokyo, Japan. Inoculation is the placement of something to where it will grow or reproduce and is most commonly used in respect of the introduction of a serum Vaccine, or antigenic substance 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. Fractionation is a Separation process in which a certain quantity of a Mixture (solid liquid solute or suspension is divided up in a number of smaller quantities Homogenization (or homogenisation) is a term used in many fields such as Chemistry, Agricultural science, Food technology, Sociology The ultracentrifuge is a Centrifuge optimized for spinning a rotor at very high speeds capable of generating acceleration as high as 1000000 g (9800 km/s² They published these findings in 1954 in the French journal now known as “Journal de la Société de Biologie”.  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. Precipitation is the formation of a Solid in a Solution during a Chemical reaction. Antibodies (also known as immunoglobulins, abbreviated Ig) are Gamma globulin Proteins that are found in Blood or other Bodily 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. 
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. Alick Isaacs (17 July 1921 - 26 January 1967 was a British Virologist. The National Institute For Medical Research, commonly abbreviated to NIMR, is a large medical research facility situated in rural Mill Hill, on the outskirts of The Orthomyxoviridae (Derivation of name orthos is Greek for straight myxa is Greek for Mucus) are a family of RNA viruses that They published their results in 1957; in this paper they coined the term ‘interferon’, and today that specific interfering agent is known as a ‘Type I interferon’. 
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. French ( français,) is a Romance language spoken around the world by 118 million people as a native language and by about 180 to 260 million people In vivo ( Latin: within the living means that which takes place inside an organism. 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. 
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 or derived from yeast (e. History See also History of genetics The existence of genes was first suggested by Gregor Mendel (1822-1884 who in the 1860s studied inheritance The Bacteria ( singular: bacterium) are a large group of unicellular Microorganisms Typically a few Micrometres in length bacteria have Recombinant DNA is a form of synthetic DNA that is engineered through the combination or insertion of one or more DNA strands thereby combining DNA sequences Tillage is the agricultural preparation of the Soil by Ploughing ripping or turning it 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.
Pestka S. et al, Immun Rev, (2004) 202, pp. 8-32