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. They belong to the large class of glycoproteins known as cytokines and 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 T lymphocytes, and increasing the resistance of host cells to viral infection. There are 3 known classes of interferons; type I, type II and type III. All classes are very important in fighting viral infections. Their presence also accounts for some of the host symptoms to infections, such as sore muscles and fever.

Contents 1 Types of interferon 2 Function 3 Induction of interferons 4 Signaling pathway 5 Virus resistance to interferons 6 Interferon therapy 6.1 Diseases 6.2 Drug formulations 7 History 7.1 As a drug 8 Miscellaneous facts 9 See also 10 References

[edit] Types of interferon

Based on the type of receptor through which they signal, human interferons have been classified into three major types.

• 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. The type I interferons present in humans are IFN-α, IFN-β and IFN-ω.^[1]

• Interferon type II: Binds to IFNGR. In humans this is IFN-γ.

• Interferon type III: Signal through a receptor complex consisting of IL10R2 (also called CRF2-4) and IFNLR1 (also called CRF2-12). Acceptance of this classification is less universal than that of type I and type II, and unlike the other two, it is not currently included in Medical Subject Headings.^[2]

[edit] Function

All interferons share several common effects. They are antiviral agents and can fight tumors. These activities are co-ordinated by IFN-mediated activation of certain immune cells, such as macrophages and natural killer cells, and by enhancing cell surface expression of important immune molecules -- including major histocompatibility complex classes I and II, which display foreign (microbial) peptides for activation of T cells. Production of hundreds of other proteins that play a role in combating viruses, and known collectively as interferon-stimulated genes (ISGs), is also induced by interferons.^[3][4]

As an infected cell dies from a cytolytic virus, thousands of viral particles will infect nearby cells. However, the infected cell releases interferon and warns these other cells of the presence of the virus. These neighboring cells, in response, produce large amounts of an enzyme known as protein kinase R (PKR). If a virus infects a cell that has been “pre-warned” by interferon, the PKR begins transferring phosphate groups (phosphorylating) to a protein known as eIF-2, a eukaryotic translation initiation factor, which forms an inactive complex with another protein called eIF2B to reduce translation initiation and protein synthesis. This prevents both viral replication and normal cell ribosome function, potentially killing both the virus and susceptible host cells. Following PKR activation, another cellular enzyme, RNAse L is also induced. This enzyme destroys all RNA within the cells thereby further reducing protein synthesis of both viral and host genes.

Another function of interferon is to upregulate major histocompatibility complex molecules, MHC I and MHC II, and increase immunoproteasome activity. Higher MHC I expression increases presentation of viral peptides to cytotoxic T cells, while the immunoproteasome produces peptides compatible for loading onto the MHC I molecule, to increase killing of infected cells by T cells. Higher MHC II expression increases presentation of viral peptides to helper T cells, which release cytokines that signal to and co-ordinate the activity of other cells of the immune system.

Interferon can increase p53 activity in virus infected cells promoting cell death by apoptosis and limiting the ability of the virus to spread.^[5][6] The effect of IFN on p53 is also linked to its protective role against against certain cancers.^[5]

[edit] Induction of interferons

Production of interferons predominantly occurs in response to microbes, such as viruses and bacteria, and their products. Binding of molecules uniquely found in microbes—viral glycoproteins, viral RNA, bacterial endotoxin (lipopolysaccharide), bacterial flagella, CpG motifs -- by pattern recognition receptors, such as membrane bound Toll like receptors or the cytoplasmic receptors RIG-I or MDA5, can trigger release of IFNs. Toll Like Receptor 3 (TLR3) is important for inducing interferon in response to the presence of double-stranded RNA viruses; the ligand for this receptor is double-stranded RNA (dsRNA). After binding dsRNA, this receptor activates the transcription factors IRF3 and NF-κB, which are important for initiating synthesis of many inflammatory proteins. Release of IFN from cells is also induced by mitogens. Other cytokines, such as interleukin 1, interleukin 2, interleukin-12, tumor necrosis factor and colony-stimulating factor, can also enhance interferon production.^[7]

[edit] Signaling pathway

By interacting with their specific receptors, IFNs activate signal transducer and activator of transcription (STAT) complexes; these are transcription factors that regulate the expression of certain immune system genes. Type I and type II IFNs activate the same STATs and unique STATs in a type dependent manner.^[8] STAT activation initiates the classical Janus kinase-STAT (JAK-STAT) signaling pathway, which is the most well defined signaling pathway for all IFNs.^[8] The JAKs are associated with IFN receptors and phosphorylate both STAT1 and STAT2 following receptor engagement with IFN. As a result, an IFN-stimulated gene factor 3 (ISGF3) complex forms—this contains STAT1, STAT2 and a third transcription factor called IRF9 -- which moves into the cell nucleus to initiate gene transcription. This complex binds to specific sequences in the promoter of a gene called IFN-stimulated response elements (ISREs) to induce transcription of that gene.^[8] Additionally, STAT homodimers or heterodimers form from different combinations of STAT-1, -3, -4, -5, or -6 during IFN signaling; these dimers initiate gene transcription by binding to IFN-activated site (GAS) elements in gene promoters.^[8] Type I IFNs can induce expression of genes with either ISRE or GAS elements, but gene induction by type II IFN can only occur in the presence of a GAS element.^[8]

IFNs can activate several other signaling cascades in addition to the JAK-STAT pathway. Both type I and type II IFNs activate a member of the CRK family of adaptor proteins called CRKL, a nuclear adaptor for STAT5 that also regulates signaling through the C3G/Rap1 pathway.^[8] Type I IFNs further activate p38 mitogen-activated protein kinase (MAP kinase) to induce type I IFN-dependent gene transcription.^[8] p38 MAP kinase signaling is also associated with antiviral and antiproliferative effects that are associated with type I IFNs. The phosphatidylinositol 3-kinase (PI3K) signaling pathway is also regulated by both type I and type II IFNs. PI3K activates P70-S6 Kinase 1, an enzyme that increases protein synthesis and cell proliferation; phosphorylates of ribosomal protein s6, which is involved in protein synthesis; and phosphorylates a translational repressor protein called eukaryotic translation-initiation factor 4E-binding protein 1 (EIF4EBP1) in order to deactivate it.^[8]

[edit] Virus resistance to interferons

Many viruses have evolved mechanisms to resist interferon activity. They circumvent the IFN response by blocking downstream signaling events that occur after the cytokine binds to its receptor, by preventing further IFN production, and by inhibiting the functions of proteins that are induced by IFN.^[9] Viruses that inhibit IFN signaling include Japanese Encephalitis Virus (JEV), dengue type 2 virus (DEN-2) and viruses of the herpesvirus family, such as human cytomegalovirus (HCMV) and Kaposi's sarcoma-associated herpesvirus (KSHV or HHV8).^[9][10] Viral proteins proven to affect IFN signaling include EBV nuclear antigen 1 (EBNA1) and EBV nuclear antigen 2 (EBNA-2) from Epstein-Barr virus, the large T antigen of Polyomavirus, the E7 protein of Human papillomavirus (HPV), and the B18R protein of vaccinia virus.^[10][11] Reducing IFN-α activity may prevent signaling via STAT1, STAT2, or IRF9 (as with JEV infection) or through the JAK-STAT pathway (as with DEN-2 infection).^[9] Several poxviruses encode soluble IFN receptor homologs—like the B18R protein of the vaccinia virus—that bind to and prevent IFN interacting with its cellular receptor, impeding communication between this cytokine and its target cells.^[11] Some viruses can encode proteins that bind to double-stranded RNA (dsRNA) to prevent the activity of RNA-dependent protein kinases; this is the mechanism reovirus adopts using its sigma 3 (σ3) protein, and vaccinia virus employs using the gene product of its E3L gene, p25.^[12][13][14] The ability of interferon to induce protein production from interferon stimulated genes (ISGs) can also be affected. Production of protein kinase R, for example, can be disrupted in cells infected with JEV or flaviviruses.^[9] Some viruses escape the anti-viral activities of interferons by gene (and thus protein) mutation. The H5N1 influenza virus, also known as bird flu, has resistance to interferon and other anti-viral cytokines that is attributed to a single amino acid change in its Non-Structural Protein 1 (NS1), although the precise mechanism of how this confers immunity is unclear.^[15]

[edit] Interferon therapy

[edit] Diseases

The immune effects of interferons have been exploited to treat several diseases. Agents that activate the immune system, such as small imidazoquinoline molecules that activate TLR7, can induce IFN-α. Imidazoquinoline is the main ingredient of Aldara (Imiquimod) cream, a treatment approved in the United States by the Food and Drug Administration (FDA) for actinic keratosis, superficial basal cell carcinoma, papilloma and external genital warts.^[16] Synthetic IFNs are also made, and administered as antiviral, antiseptic and anticarcinogenic drugs, and to treat some autoimmune diseases.

Interferon beta-1a and interferon beta-1b are used to treat and control multiple sclerosis, an autoimmune disorder. This treatment is effective for slowing disease progression and activity in relapsing-remitting multiple sclerosis and reducing attacks in secondary progressive multiple sclerosis.^[17]

Interferon therapy is used (in combination with chemotherapy and radiation) as a treatment for many cancers.^[16] This treatment is most effective for treating hematological malignancy; leukemia and lymphomas including hairy cell leukemia, chronic myeloid leukemia, nodular lymphoma, cutaneous T-cell lymphoma.^[16] Patients with recurrent melanomas receive recombinant IFN-α2b.^[18]

Both hepatitis B and hepatitis C are treated with IFN-α, often in combination with other antiviral drugs.^[19][20] Those treated with interferon have a sustained virological response and can eliminate hepatitis virus. Biopsies show reductions in liver damage and cirrhosis. Some evidence shows giving interferon immediately following infection can prevent chronic hepatitis C, although diagnosis early in infection is difficult since physical symptoms are sparse in early hepatitis C infection. Control of chronic hepatitis C by IFN is associated with reduced hepatocellular carcinoma.^[21]

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.^[22]

When used in the systemic therapy, IFNs are mostly administered by an intramuscular injection. The injection of IFNs in the muscle, in the vein, or under skin is generally well tolerated. 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. IFN therapy causes immunosuppression, in particular through neutropenia and can result in some infections manifesting in unusual ways.^[23]

[edit] Drug formulations

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Pharmaceutical forms of interferons

Generic name	Trade name
Interferon alpha 2a	Roferon A
Interferon alpha 2b	Intron A/Reliferon
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

Several different types of interferon are now approved for use in humans. Multiferon^TM(HuIFN-alpha-Le) was being used in 14 EU countries by March 10^th 2009. The human subtype Interferon Alpha (HuIFN-alpha-Le) is approved for Adjuvant treatment of high-risk patients with cutaneous melanoma, stages IIb-III^[24], after 2 initial cycles of dacarbazine (DTIC)^[25]. The approval is based on the study performed in Germany ^[26] 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).

[edit] History

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”.^[27] 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.^[28][29]

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;^[30] in this paper they coined the term ‘interferon’, and today that specific interfering agent is known as a ‘Type I interferon’.^[31]

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.^[32]

[edit] As a drug

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^[33] or derived from yeast (e.g. Reiferon Retard is the first yeast derived interferon-alpha 2a).

[edit] Miscellaneous facts

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• Interferon is species-specific: the substance prepared from infected eggs protected only chicken cells from virus infection, while the similar substance prepared from mice protected only mouse cells.
• Produced by many cells in the human body by a receptor dependent feedback mechanism.
• Interferons are part of the "first-wave" immune response of the innate immune system, acting within hours, whereas antibody production takes days.^{[citation needed]}
• In general, exposure of human cells to viruses or double stranded RNAs induces the production of IFN-a, IFN-b, and IFN-o species.
• For the most part, the IFN-alpha species are not glycosylated, although some contain carbohydrates.
• The IFN-alpha family represents a family of related and homologous proteins, each exhibiting a unique activity profile. Each IFN-a species seems to exhibit a distinct profile of activities [antiviral, antiproliferative, and stimulation of cytotoxic activities of natural killer (NK) cells and T cells]
• The IFNs and IFN-like molecules signal through the Jak-Stat pathway. The receptor for the Type I IFNs consists of two chains, IFN-aR1 and IFN-aR2c. The ligand INF-alpha is a monomer that binds to the two-chain complex of IFN-aR1 and INF-aR2c.
• Within each subtype of mammalian Type I IFN, there is additional variability in gene duplication. The IFN-a genes are duplicated to a much greater extent than any other subtype of Type I IFN. This observation in conjunction with the observation that the IFN-a subtypes generally possess the highest specific antiviral activity imply that physiologically, the body likely uses IFN-a as the primary antiviral defense protein and that the major function of IFN-a is defense.
• STRUCTURE: The Type I IFNs consist of five a-helices (labeled A–E) which are linked by one overhand loop (AB loop) and three shorter segments (BC, CD, and DE loops). Helices A, B, C, and E are arranged in an antiparallel fashion to form a left-handed four-helix bundle. The AB loop contains short segments of 3_10 helix and is best described in three segments labeled AB1, AB2, and AB3. In all Type I IFNs, the AB1 loop encircles and is linked to helix E by a disulfide bond. An additional disulfide bond is observed in most IFN-a subtypes but not IFN-b, which connects the N-terminus of the molecule to helix C. The AB loop is critical for high-affinity IFNAR2 binding and suggest that sequence differences in this region may hold the key to differences in biological activity between the different IFN-a subtypes.
• The IFNs were the first of the proteins we now recognize as members of the Class II cytokine family.
• IFNa2 contain 165 amino acids; according to circular dichroism measurements ~68% of the residues adopt helical conformation.INFa2 is composed of five a-helices, labeled A–E, linked by one long overhand connection (AB loop) and three short segments (BC, CD and DE loops). The topology of the molecule resembles the classical up-up-down-down four-helixbundle motif; helices A, B, C, and E comprise the helix bundle.
• Type I IFNs are stable at acidic pH (pH 2) and are represented by two major subtypes, the fibroblast or beta interferon (IFN-b) and the leukocyte or alpha family of interferons (IFN-a).The only known interferon of type II is IFN-g, which is produced exclusively by lymphocytes.

[edit] See also

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

[edit] References

v • d • e DNA virus Antivirals (primarily J05, also S01AD and D06BB) Baltimore I Herpesvirus DNA synthesis inhibitor TK activated Purine analogue guanine (Aciclovir#/Valaciclovir, Ganciclovir/Valganciclovir, Penciclovir/Famciclovir) adenine (Vidarabine, Cytarabine) Pyrimidine analogue uridine (Idoxuridine, Trifluridine, Edoxudine) thymine (Brivudine) Not TK activated Foscarnet Other Docosanol · early protein (Fomivirsen) · Tromantadine HPV/MC Imiquimod/Resiquimod · Podophyllotoxin Vaccinia assembly: Rifampicin Poxviridae Methisazone Hepatitis B (VII) Nucleoside analogues/NARTIs: Entecavir · Lamivudine · Telbivudine · Clevudine Nucleotide analogues/NtRTIs: Adefovir · Tenofovir Multiple/general Nucleic acid inhibitors Cidofovir Interferon Interferon alfa-2b · Peginterferon alfa-2a Multiple/unknown Ribavirin#/Taribavirin† ErbB2/PI3K Pathway NOV-205§ · NOV-002† #WHO-EM. ‡Withdrawn from market. CLINICAL TRIALS: †Phase III. §Never to phase III

v • d • e Cell signaling: cytokines By family Interleukin IL-1 superfamily 1 (1Ra) · 18 · 33 IL-6 like/gp130 using 6  · 11 · 27 · 30 · 31 (+non IL Oncostatin M, Leukemia inhibitory factor, Ciliary neurotrophic factor, Cardiotrophin 1) IL-10 family 10 · 19 · 20 · 22 · 24 · 26 Interferon type III 28 · 29 Common γ-chain family 2/15 · 3 · 4 · 7 · 9 · 13 · 21 IL-12 family 12 · 23 · 27 · 35 Other 5 · 8 · 14 · 16 · 17/25 (A) · 32 Chemokine CCL 1 · 2 · 3 · 4 · 5 · 6 · 7 · 8 · 9 · 10 · 11 · 12 · 13 · 14 · 15 · 16 · 17 · 18 · 19 · 20 · 21 · 22 · 23 · 24 · 25 · 26 · 27 · 28 CXCL 1 · 2 · 3 · 4 · 5 · 6 · 7 · 8 · 9 · 10 · 11 · 12 · 13 · 14 · 15 · 16 · 17 CX3CL 1 XCL 1 · 2 TNF Main TNF-alpha TNF (ligand) superfamily 4-1BB ligand · B-cell activating factor · FAS ligand · Lymphotoxin · OX40L · RANKL · TRAIL Cluster of differentiation CD70 · CD153 · CD154 Interferon I alpha (Pegylated 2a, Pegylated 2b), beta (1a, 1b) II Gamma III 28 · 29 Other Monokine · Lymphokine (Lymphotoxin, Transfer factor) · Growth factor · Hematopoietic (Stem cell factor, Colony-stimulating factor) · Autocrine motility factor · Osteopontin By function proinflammatory cytokine (IL-1, TNF-alpha) · Th1 (interferon-gamma and tumor necrosis factor-beta) Th2 (interleukin 4, interleukin 5, interleukin 6, interleukin 10, interleukin 13)