Type I interferon

Type I IFNs are two distinct groups of proteins, IFN-a (approx. 18kDa) and IFN-(3 (20kDa). IFN-a is subdivided into two subgroups, IFN-a 1 and IFN-a2/ IFN-io. Viral infection is the most potent natural signal for the synthesis of type I IFNs. 

The principal biological actions of type I IFNs include inhibition of viral replication, inhibition of cell proliferation, increase in the lytic potential of NK cells and the modulation of MHC molecule expression. They increase the expression of MHC class I molecules and decrease the expression of MHC class II molecules. 

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Honda K, Takaoka A, Taniguchi T (2006) Type I interferon gene induction by Hie interferon regulatory factor family of transcription factors. Immunity 25 349-360... 

TRIF can also activate IRF-3 leading to the production of type I interferons (EFNs). 

The key end result of TLR signalling is the induction of cytokines. Cytokines are proteins produced during an immune response that allow the maturation, activation and differentiation of effector cells in the immune system. The activation of NFkB and AP-1 by the MyD88 and the TREF dependent pathways leads to the production of proinflammatory cytokines such as IL-6, TNF-a and various chemokines. This pathway can also activate IRF-7 via TLR-7and TLR-9 allowing Type-I interferons to be produced. 

Chang, C.C., Konno, S., Wu, J.M. (1991). Enhanced expression of heat shock protein and mRNA synthesis by type I interferon in human HL-60 leukemic cells. Biochem Inti. 24, 369-377. 

Chang CC, Chen TT, Cox BW, Dawes GN, Stemmer WP, Punnonen J, Patten PA (1999) Evolution of a cytokine using DNA family shuffling. Nat Biotechnol 17 793-797 Chen J, Baig E, Eish EN (2004) Diversity and relatedness among the type I interferons. J Interferon Cytokine Res 24 687-698... 

Dumoutier L, Tounsi A, Michiels T, Sommereyns C, Kotenko SV, Renauld JC (2004) Role of the interleukin (lL)-28 receptor tyrosine residues for antiviral and antiproliferative activity of lL-29/interferon-lambda 1 similarities with type I interferon signaling. J Biol Chem 279 ... 

Honda K, Yanai H, Negishi H, Asagiri M, Sato M, Mizutani T, Shimada N, Ohba Y, Takaoka A, Yoshida N, Taniguchi T (2005) IRF-7 is the master reguiator of type-I interferon-dependent immune responses. Nature 434 772-777... 

Kozlowski A, Charles SA, Harris JM (2001) Development of pegylated interferons for the treatment of chronic hepatitis C. BioDrugs 15 419 29 Krown SE, AeppU D, Balfour HH Jr (1999) Phase II, randomized, open-label, community-based trial to compare the safety and activity of combination therapy with recombinant interferon-alpha2b and zidovudine versus zidovudine alone in patients with asymptomatic to mildly symptomatic HIV infection. J Acquir Immune Defic Syndr Hum Retrovirol 20 245-254 LaFleur DW, NardeUi B, Tsareva T, Mather D, Feng P, Semenuk M, Taylor K, Buergin M, Chinchilla D, Roshke V, Chen G, Ruben SM, Pitha PM, Coleman TA, Moore PA (2001) Interferon-kappa, a novel type I interferon expressed in human keratinocytes. J Biol Chem 276 39765-39771... 

Uematsu S, Akria S (2007) ToU-like receptors and type I interferons. J Biol Chem 282 15319-15323... 

Innate immune response to viral infections is predominately through interferon-alpha, -beta (IFN-a and -P) induction and activation of natural killer (NK) cells. Although viral replication can induce IFN-a and -P expression, macrophages are capable of producing and secreting cytokines which also induce the production of these type I interferons (Falk 2001). Bound IFNa and p to its receptors on NK cells increases its ability to lyse virally-infected cells. 

Type I interferons. These are acid-stable and comprise two major classes, leucocyte interferon (Le-IFN, IFN-a) released by stimulated leucocytes, and fibroblast interferon (F-IFN, FN-/3) released by shmulated fibroblasts. 

Type I interferons induce a vims-resistant state in human cells, whereas Type II are more active in inhibiting growth of tumour cells. 

Celia M, Jarrossay D, Facchetti F, et al. Plasmacytoid monocytes migrate to inflamed lymph nodes and produce large amounts of type I interferon. Nat Med 1999 5(8) 919—923. 

Besch R, Poeck H, Hohenauer T, Senft D, Hacker G, Berking C, Homung V, Endres S, Ruzicka T, Rothenfusser S, Hartmann G (2009) Proapoptotic signaling induced by RIG-I and MDA-5 results in type I interferon-independent apoptosis in human melanoma cells. J Clin Invest 119 2399-2411... 

No one interferon will display all of these biological activities. Effects are initiated by the binding of the interferon to its specific cell surface receptor present in the plasma membrane of sensitive cells. IFN-a and -P display significant amino acid sequence homology (30 per cent), bind to the same receptor, induce similar biological activities and are acid stable. For these reasons, IFN-a and IFN-P are sometimes collectively referred to as type I interferons, or acid-stable interferons. 

Studies have actually revealed two type I interferon receptor polypeptides. Sequence data from cloning studies place both in the class II cytokine receptor family. Both are transmembrane N-linked glycoproteins. Studies using isolated forms of each show that one polypeptide (called the a/p receptor) is capable of binding all type I interferons. The other one (the ap receptor) is specific for IFN-a-B (a specific member of the IFN-a family). Both receptors are present on most cell types. 

Not surprisingly different ligands activate different members of the STAT family (Table 8.6). Some, such as STATs 1 and 3, are activated by many ligands, whereas others respond to far fewer ligands, e.g. STAT2 appears to be activated only by type I interferons. 

Interferons induce a wide range of biological effects. Generally, type I interferons induce similar effects, which are distinct from the effects induced by IFN-y. The most pronounced effect of type I interferons relates to their antiviral activity, as well as their anti-proliferative effect on various cell types, including certain tumour cell types. Anti-tumour effects are likely due not only to a direct anti-proliferative effect on the tumour cells themselves, but also due to the ability of type I interferons to increase NK and T-cytotoxic cell activity. These cells can recognize and destroy cancer cells. 

Not all type I interferons induce exactly the same range of responses, and the antiviral to antiproliferative activity ratio differs from one type I interferon to another. As all bind the same receptor, the molecular basis by which variation in biological activities is achieved is poorly understood as yet. 

IFN-y exhibits, at best, weak antiviral and anti-proliferative activity. When co-administered with type I interferons, however, it potentates these IFN-a/p activities. IFN-y is directly involved in regulating most aspects of the immune and inflammatory responses. It promotes activation, growth and differentiation of a wide variety of cell types involved in these physiological processes (Table 8.7). 

IFN-a, -P and -y are all known to induce the enzyme in various animal cells. However, in human epithelial cells the kinase is induced only by type I interferons, whereas none of the interferons seem capable of inducing synthesis of the enzyme in human fibroblasts. The purified kinase is highly selective for initiation factor eIF-2, which it phosphorylates at a specific serine residue. 

Interferon, in particular type I interferon, is well adapted to its antiviral function. Upon entry into the body, viral particles are likely to encounter IFN-a/p-producing cells quickly, including macrophages and monocytes. This prompts interferon synthesis and release. These cells act like... 

The ability of interferons (especially type I interferons) to induce an antiviral state is unlikely to be solely dependent upon the enzymatic mechanisms discussed above. Furthermore the 2 -5 A synthetase and eIF-2a kinase systems may play important roles in mediating additional interferon actions. The ability of such systems to stall protein synthesis in cells may play a role in interferon-induced alterations of cellular differentiation or cell cycle progression. They may also be involved in mediating interferon-induced anti-proliferative effects on various transformed cells. 

Trophoblastin, therefore, has been named interferon-tau (IFN-x), and is classified as a type I interferon. There are at least three or four functional IFN-x genes in sheep and cattle. The molecule displays a molecular mass of 19 kDa and an isoelectric point of 5.5-5.7, in common with other type I interferons. Interestingly, the molecule can also promote inhibition of reverse transcriptase activity in cells infected with the HIV virus. 

IFN-x is currently generating considerable clinical interest. It induces effects similar to type I interferon, but it appears to exhibit significantly lower toxicity. Thus, it may prove possible to use this interferon safely at dosage levels far greater than the maximum dosage levels applied to currently used type I interferons. This, however, can only be elucidated by future clinical trials. 

Lau, F. and Horvath, C. 2002. Mechanisms of type I interferon cell signalling and STAT-mediated transcriptional responses. Mount Sinai Journal of Medicine 69(3), 156-168. 

Kadowaki, N. and Liu, Y.J., Natural type I interferon-producing cells as a link between innate and adaptive immunity, Hum. Immunol. 63, 12, 1126, 2002. 

Tough, D.F., Borrow, R, and Sprent, J., Induction of bystander T cell proliferation by viruses and type I interferon in vivo, Science, 272, 1947, 1996. 

Interferons There are two types of interferons Type I, which includes IFN-a and IFN-jS, and Type II consisting of IFN-y. IFN-a and IFN- 8 have about 30% homology in amino acid sequence. There are two more recently discovered Type I interferons they are called IFN-o and IFN-t. IFN-a and IFN- 8 each have 166 amino acids, and IFN-yhas 143. Both IFN-a and IFN-jS are of single chain structure and bind to the same type of cell surface receptors, whereas IFN-y is a dimer of two identical chains and interacts with another type of receptor. All our cells can produce Type I interferons when infected by viruses, bacteria, and fungi. However, only T cells and natural killer cells can produce... 

Type II interferon. Type I interferon binds to receptor, which in turn activates tyrosine kinase phosphorylation and the subsequent transcription pathway that induces viral resistance. Similarly, Type II interferon binds to another receptor and activates the immune response. 

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