Interferon tau explained

Interferon tau
Organism:Bos taurus
Taxid:1758
Symbol:IFNT2
Altsymbols:IFNT; IFNT1; TP-1
Entrezgene:317698
Refseqmrna:NM_001015511.4
Refseqprotein:NP_001015511.3
Uniprot:P15696
Chromosome:8
Entrezchromosome:NC_037335.1
Genloc Start:22608236
Genloc End:22609942

Interferon tau (IFNτ, IFNT) is a Type I interferon made of a single chain of amino acids. IFN-τ was first discovered in ruminants as the signal for the maternal recognition of pregnancy and originally named ovine trophoblast protein-1 (oTP-1). It has many physiological functions in the mammalian uterus, and also has anti-inflammatory effect that aids in the protection of the semi-allogeneic conceptus trophectoderm from the maternal immune system.[1] [2]

IFN-τ genes have only been found in ruminants that belong to the Artidactyla order, and multiple polymorphisms and several variants of IFN-τ have been identified.[3] Although IFN-τ has been shown not to be produced in humans, both human and mouse cells respond to its effects. IFN-τ binds to the same IFN receptors as IFN-α and induces intracellular signalling through STAT1, STAT2, and Tyk2. This leads to the production of antiviral and immunomodulatory cytokines, including IL-4, IL-6, and IL-10.[4]

Structure

IFN-τ consists of 172 amino acids with two disulfide bridges (1–99, 29–139) and amino terminal proline. Similar to other Type I interferons, IFN-τ binds to the Interferon-alpha/beta receptor (IFNAR).[5]

Its molecular weight is between 19 and 24 kDa, depending on glycosylation state. Not all variants of IFN-τ are glycosylated. Bovine IFN-τ is N-glycosylated at ASN78, caprine IFN-τ is a combination between nonglycosylated and glycosylated forms and ovine IFN-τ is not glycosylated.[6] Receptor binding site can be found at the C-terminus, biologically active site is located at the N-terminus.[7]

Compared to other interferons, IFN-τ shares about 75% of its identity to IFN-ω, which can be found quite commonly in mammals. However, Southern blot analysis and genome sequencing data proved that genes encoding IFN-τ can be found only in ruminant species.[8] Studies also show 85% sequence identity between human trophoblast IFN in placental trophoblast cells and IFN-τ.[9]

Function and biological activity

IFN-τ is constitutively secreted by trophoblast and endometrial cells during ovine pregnancy. Its secretion begins around tenth day and increases between days 13 and 16, when it reaches its peak, and then stopping after day 24 of pregnancy. IFN-τ is essential to maintain the levels of progesterone production by the corpus luteum for the maternal recognition of pregnancy, and together with progesterone increases expression of genes for transport of nutrients into the uterine lumen, growth factors for hematopoiesis and angiogenesis and other molecules that are crucial for implantation and placentation.[10] It has both endocrine and paracrine effects, immunomodulatory influence on several types of cells including neutrophils, and antiproliferative, antiluteolytic and immunosuppressive effects on the endometrium.[11] [12]

IFN-τ binds to IFNAR cell membrane receptor and induces dimerization of its subunits, IFNAR1 and IFNAR2, which leads to activation of canonical and noncanonical signaling pathways. The canonical pathway involves Janus kinase-signal transducer and activator of transcription-interferon regulatory factor (JAK-STAT-IRF) signaling.[13] [14] This leads to induction of classical interferon stimulated genes (ISGs).[15] The noncanonical signaling pathway includes mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase thymoma viral proto-onco- gene 1 (PI3K-AKT1) cascades.[16]

IFN-τ can also stimulate expression of interleukins IL-6 and IL-8. However, the mechanism is not STAT1, but STAT3 dependent.[17]

Synthetic gene for ovine IFN-τ was produced using Pichia pastoris yeast system. The recombinant IFN-τ had the same antiviral, antiluteolytic and immunosuppressive properties as native IFN-τ.

Clinical use

Understanding the role of IFN-τ in pregnancy recognition in ruminants and its mechanism of action led to its use in pregnancy diagnosis, as it can be measured directly from blood, and knowledge of its actions can be used to improve the reproductive efficiency in ruminants.[18] [19]

Since the effects of IFN-τ are not limited to ruminants and pregnancy, it has been studied for its anti-inflammatory properties as a treatment for diabetes.[20] [21] NOD mice that were treated with IFN-τ, which was administered either orally, intraperitoneally, or subcutaneously, have shown delayed or even inhibited development of diabetes.[22]

IFN-τ is able to inhibit human immunodeficiency virus replication in vitro more effectively than human IFN-α. It was observed that IFN-τ decreased intracellular HIV RNA in human macrophages and inhibited reverse transcription of viral RNA into proviral DNA.[23] Because of difference in both selectivity of individual N-termini towards receptors and different degree of receptor avidity, IFN-τ displays much less cytotoxicity than IFNT-α. This can be useful in treatment of viral diseases. IFN-τ has also demonstrated biological effects against influenza virus.[24] However, IFN-τ has high species specificity which can cause a significant decrease in biological activity when administered to another species.[25]

Notes and References

  1. Bazer FW, Ying W, Wang X, Dunlap KA, Zhou B, Johnson GA, Wu G . The many faces of interferon tau . Amino Acids . 47 . 3 . 449–60 . March 2015 . 25557050 . 10.1007/s00726-014-1905-x . 14940718 .
  2. Imakawa K, Bai R, Nakamura K, Kusama K . Thirty years of interferon-tau research; Past, present and future perspective . Animal Science Journal . 88 . 7 . 927–936 . July 2017 . 28504476 . 10.1111/asj.12807 . free .
  3. Li SF, Gong MJ, Zhao FR, Shao JJ, Xie YL, Zhang YG, Chang HY . Type I Interferons: Distinct Biological Activities and Current Applications for Viral Infection . Cellular Physiology and Biochemistry . 51 . 5 . 2377–2396 . 2018 . 30537741 . 10.1159/000495897 . free .
  4. Book: Graber JJ, Dhib-Jalbut S . Interferons. 2014 . Encyclopedia of the Neurological Sciences. 718–723. Elsevier. en. 10.1016/b978-0-12-385157-4.00182-2. 978-0-12-385158-1 .
  5. Choi Y, Johnson GA, Burghardt RC, Berghman LR, Joyce MM, Taylor KM, Stewart MD, Bazer FW, Spencer TE . 6 . Interferon regulatory factor-two restricts expression of interferon-stimulated genes to the endometrial stroma and glandular epithelium of the ovine uterus . Biology of Reproduction . 65 . 4 . 1038–49 . October 2001 . 11566724 . 10.1095/biolreprod65.4.1038 . free .
  6. Bazer FW, Spencer TE, Ott TL . Interferon tau: a novel pregnancy recognition signal . American Journal of Reproductive Immunology . 37 . 6 . 412–20 . June 1997 . 9228295 . 10.1111/j.1600-0897.1997.tb00253.x . 2928770 .
  7. Pontzer CH, Ott TL, Bazer FW, Johnson HM . Structure/function studies with interferon tau: evidence for multiple active sites . Journal of Interferon Research . 14 . 3 . 133–41 . June 1994 . 7930760 . 10.1089/jir.1994.14.133 .
  8. Leaman DW, Roberts RM . Genes for the trophoblast interferons in sheep, goat, and musk ox and distribution of related genes among mammals . Journal of Interferon Research . 12 . 1 . 1–11 . February 1992 . 1374107 . 10.1089/jir.1992.12.1 .
  9. DeCarlo CA, Severini A, Edler L, Escott NG, Lambert PF, Ulanova M, Zehbe I . IFN-κ, a novel type I IFN, is undetectable in HPV-positive human cervical keratinocytes . Laboratory Investigation; A Journal of Technical Methods and Pathology . 90 . 10 . 1482–91 . October 2010 . 20479716 . 10.1038/labinvest.2010.95 . free .
  10. Roberts RM . Interferon-tau, a Type 1 interferon involved in maternal recognition of pregnancy . Cytokine & Growth Factor Reviews . 18 . 5–6 . 403–8 . October 2007 . 17662642 . 2000448 . 10.1016/j.cytogfr.2007.06.010 .
  11. Manjari P, Hyder I, Kapoor S, Senthilnathan M, Dang AK . Exploring the concentration-dependent actions of interferon-τ on bovine neutrophils to understand the process of implantation . Journal of Cellular Biochemistry . 119 . 12 . 10087–10094 . December 2018 . 30171720 . 10.1002/jcb.27345 . 206028552 .
  12. Shirasuna K, Matsumoto H, Matsuyama S, Kimura K, Bollwein H, Miyamoto A . Possible role of interferon tau on the bovine corpus luteum and neutrophils during the early pregnancy . Reproduction . 150 . 3 . 217–25 . September 2015 . 26078085 . 10.1530/REP-15-0085 . free .
  13. Brooks K, Spencer TE . Biological roles of interferon tau (IFNT) and type I IFN receptors in elongation of the ovine conceptus . Biology of Reproduction . 92 . 2 . 47 . February 2015 . 25505203 . 10.1095/biolreprod.114.124156 . free .
  14. Spencer TE, Ott TL, Bazer FW . Expression of interferon regulatory factors one and two in the ovine endometrium: effects of pregnancy and ovine interferon tau . Biology of Reproduction . 58 . 5 . 1154–62 . May 1998 . 9603248 . 10.1095/biolreprod58.5.1154 . free .
  15. Stewart MD, Stewart DM, Johnson GA, Vyhlidal CA, Burghardt RC, Safe SH, Yu-Lee LY, Bazer FW, Spencer TE . 6 . Interferon-tau activates multiple signal transducer and activator of transcription proteins and has complex effects on interferon-responsive gene transcription in ovine endometrial epithelial cells . Endocrinology . 142 . 1 . 98–107 . January 2001 . 11145571 . 10.1210/endo.142.1.7891 . free .
  16. Platanias LC . Mechanisms of type-I- and type-II-interferon-mediated signalling . Nature Reviews. Immunology . 5 . 5 . 375–86 . May 2005 . 15864272 . 10.1038/nri1604 . free .
  17. Tanikawa N, Seno K, Kawahara-Miki R, Kimura K, Matsuyama S, Iwata H, Kuwayama T, Shirasuna K . 6 . Interferon Tau Regulates Cytokine Production and Cellular Function in Human Trophoblast Cell Line . Journal of Interferon & Cytokine Research . 37 . 10 . 456–466 . October 2017 . 29028431 . 10.1089/jir.2017.0057 .
  18. Hansen TR, Sinedino LD, Spencer TE . Paracrine and endocrine actions of interferon tau (IFNT) . Reproduction . 154 . 5 . F45–F59 . November 2017 . 28982937 . 10.1530/REP-17-0315 . free .
  19. Bazer FW, Thatcher WW . Chronicling the discovery of interferon tau . Reproduction . 154 . 5 . F11–F20 . November 2017 . 28747540 . 5630494 . 10.1530/REP-17-0257 .
  20. Ying W, Kanameni S, Chang CA, Nair V, Safe S, Bazer FW, Zhou B . Interferon tau alleviates obesity-induced adipose tissue inflammation and insulin resistance by regulating macrophage polarization . PLOS ONE . 9 . 6 . e98835 . 2014-06-06 . 24905566 . 4048269 . 10.1371/journal.pone.0098835 . 2014PLoSO...998835Y . Zissel G . free .
  21. Tekwe CD, Lei J, Yao K, Rezaei R, Li X, Dahanayaka S, Carroll RJ, Meininger CJ, Bazer FW, Wu G . 6 . Oral administration of interferon tau enhances oxidation of energy substrates and reduces adiposity in Zucker diabetic fatty rats . BioFactors . 39 . 5 . 552–63 . 2013 . 23804503 . 3786024 . 10.1002/biof.1113 .
  22. Sobel DO, Ahvazi B, Amjad F, Mitnaul L, Pontzer C . Interferon-tau inhibits the development of diabetes in NOD mice . Autoimmunity . 41 . 7 . 543–53 . November 2008 . 18608174 . 10.1080/08916930802194195 . 20611672 .
  23. Maneglier B, Rogez-Kreuz C, Dereuddre-Bosquet N, Martal J, Devillier P, Dormont D, Clayette P . [Anti-HIV effects of IFN-tau in human macrophages: role of cellular antiviral factors and interleukin-6] . fr . Pathologie-Biologie . 56 . 7–8 . 492–503 . November 2008 . 18842358 . 10.1016/j.patbio.2008.06.002 .
  24. Martín V, Pascual E, Avia M, Rangel G, de Molina A, Alejo A, Sevilla N . A Recombinant Adenovirus Expressing Ovine Interferon Tau Prevents Influenza Virus-Induced Lethality in Mice . Journal of Virology . 90 . 7 . 3783–8 . January 2016 . 26739058 . 4794696 . 10.1128/JVI.03258-15 . Schultz-Cherry S .
  25. Ealy AD, Larson SF, Liu L, Alexenko AP, Winkelman GL, Kubisch HM, Bixby JA, Roberts RM . 6 . Polymorphic forms of expressed bovine interferon-tau genes: relative transcript abundance during early placental development, promoter sequences of genes and biological activity of protein products . Endocrinology . 142 . 7 . 2906–15 . July 2001 . 11416010 . 10.1210/endo.142.7.8249 . free .

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