Interferon tau
Identifiers
OrganismBos taurus
SymbolIFNT2
Alt. symbolsIFNT; IFNT1; TP-1
Entrez317698
RefSeq (mRNA)NM_001015511.4
RefSeq (Prot)NP_001015511.3
UniProtP15696
Other data
Chromosome8: 22.61 - 22.61 Mb
Search for
StructuresSwiss-model
DomainsInterPro

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.[1][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.[2]

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.[7] 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]

References

  1. 1 2 Bazer FW, Ying W, Wang X, Dunlap KA, Zhou B, Johnson GA, Wu G (March 2015). "The many faces of interferon tau". Amino Acids. 47 (3): 449–60. doi:10.1007/s00726-014-1905-x. PMID 25557050. S2CID 14940718.
  2. 1 2 Imakawa K, Bai R, Nakamura K, Kusama K (July 2017). "Thirty years of interferon-tau research; Past, present and future perspective". Animal Science Journal. 88 (7): 927–936. doi:10.1111/asj.12807. PMID 28504476.
  3. ↑ Li SF, Gong MJ, Zhao FR, Shao JJ, Xie YL, Zhang YG, Chang HY (2018). "Type I Interferons: Distinct Biological Activities and Current Applications for Viral Infection". Cellular Physiology and Biochemistry. 51 (5): 2377–2396. doi:10.1159/000495897. PMID 30537741.
  4. ↑ Graber JJ, Dhib-Jalbut S (2014). "Interferons". Encyclopedia of the Neurological Sciences. Elsevier. pp. 718–723. doi:10.1016/b978-0-12-385157-4.00182-2. ISBN 978-0-12-385158-1.
  5. ↑ Choi Y, Johnson GA, Burghardt RC, Berghman LR, Joyce MM, Taylor KM, et al. (October 2001). "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. doi:10.1095/biolreprod65.4.1038. PMID 11566724.
  6. ↑ Bazer FW, Spencer TE, Ott TL (June 1997). "Interferon tau: a novel pregnancy recognition signal". American Journal of Reproductive Immunology. 37 (6): 412–20. doi:10.1111/j.1600-0897.1997.tb00253.x. PMID 9228295. S2CID 2928770.
  7. 1 2 Pontzer CH, Ott TL, Bazer FW, Johnson HM (June 1994). "Structure/function studies with interferon tau: evidence for multiple active sites". Journal of Interferon Research. 14 (3): 133–41. doi:10.1089/jir.1994.14.133. PMID 7930760.
  8. ↑ Leaman DW, Roberts RM (February 1992). "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. doi:10.1089/jir.1992.12.1. PMID 1374107.
  9. ↑ DeCarlo CA, Severini A, Edler L, Escott NG, Lambert PF, Ulanova M, Zehbe I (October 2010). "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. doi:10.1038/labinvest.2010.95. PMID 20479716.
  10. ↑ Roberts RM (October 2007). "Interferon-tau, a Type 1 interferon involved in maternal recognition of pregnancy". Cytokine & Growth Factor Reviews. 18 (5–6): 403–8. doi:10.1016/j.cytogfr.2007.06.010. PMC 2000448. PMID 17662642.
  11. ↑ Manjari P, Hyder I, Kapoor S, Senthilnathan M, Dang AK (December 2018). "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. doi:10.1002/jcb.27345. PMID 30171720. S2CID 206028552.
  12. ↑ Shirasuna K, Matsumoto H, Matsuyama S, Kimura K, Bollwein H, Miyamoto A (September 2015). "Possible role of interferon tau on the bovine corpus luteum and neutrophils during the early pregnancy". Reproduction. 150 (3): 217–25. doi:10.1530/REP-15-0085. PMID 26078085.
  13. ↑ Brooks K, Spencer TE (February 2015). "Biological roles of interferon tau (IFNT) and type I IFN receptors in elongation of the ovine conceptus". Biology of Reproduction. 92 (2): 47. doi:10.1095/biolreprod.114.124156. PMID 25505203.
  14. ↑ Spencer TE, Ott TL, Bazer FW (May 1998). "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. doi:10.1095/biolreprod58.5.1154. PMID 9603248.
  15. ↑ Stewart MD, Stewart DM, Johnson GA, Vyhlidal CA, Burghardt RC, Safe SH, et al. (January 2001). "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. doi:10.1210/endo.142.1.7891. PMID 11145571.
  16. ↑ Platanias LC (May 2005). "Mechanisms of type-I- and type-II-interferon-mediated signalling". Nature Reviews. Immunology. 5 (5): 375–86. doi:10.1038/nri1604. PMID 15864272.
  17. ↑ Tanikawa N, Seno K, Kawahara-Miki R, Kimura K, Matsuyama S, Iwata H, et al. (October 2017). "Interferon Tau Regulates Cytokine Production and Cellular Function in Human Trophoblast Cell Line". Journal of Interferon & Cytokine Research. 37 (10): 456–466. doi:10.1089/jir.2017.0057. PMID 29028431.
  18. ↑ Hansen TR, Sinedino LD, Spencer TE (November 2017). "Paracrine and endocrine actions of interferon tau (IFNT)". Reproduction. 154 (5): F45–F59. doi:10.1530/REP-17-0315. PMID 28982937.
  19. ↑ Bazer FW, Thatcher WW (November 2017). "Chronicling the discovery of interferon tau". Reproduction. 154 (5): F11–F20. doi:10.1530/REP-17-0257. PMC 5630494. PMID 28747540.
  20. ↑ Ying W, Kanameni S, Chang CA, Nair V, Safe S, Bazer FW, Zhou B (2014-06-06). Zissel G (ed.). "Interferon tau alleviates obesity-induced adipose tissue inflammation and insulin resistance by regulating macrophage polarization". PLOS ONE. 9 (6): e98835. Bibcode:2014PLoSO...998835Y. doi:10.1371/journal.pone.0098835. PMC 4048269. PMID 24905566.
  21. ↑ Tekwe CD, Lei J, Yao K, Rezaei R, Li X, Dahanayaka S, et al. (2013). "Oral administration of interferon tau enhances oxidation of energy substrates and reduces adiposity in Zucker diabetic fatty rats". BioFactors. 39 (5): 552–63. doi:10.1002/biof.1113. PMC 3786024. PMID 23804503.
  22. ↑ Sobel DO, Ahvazi B, Amjad F, Mitnaul L, Pontzer C (November 2008). "Interferon-tau inhibits the development of diabetes in NOD mice". Autoimmunity. 41 (7): 543–53. doi:10.1080/08916930802194195. PMID 18608174. S2CID 20611672.
  23. ↑ Maneglier B, Rogez-Kreuz C, Dereuddre-Bosquet N, Martal J, Devillier P, Dormont D, Clayette P (November 2008). "[Anti-HIV effects of IFN-tau in human macrophages: role of cellular antiviral factors and interleukin-6]". Pathologie-Biologie (in French). 56 (7–8): 492–503. doi:10.1016/j.patbio.2008.06.002. PMID 18842358.
  24. ↑ Martín V, Pascual E, Avia M, Rangel G, de Molina A, Alejo A, Sevilla N (January 2016). Schultz-Cherry S (ed.). "A Recombinant Adenovirus Expressing Ovine Interferon Tau Prevents Influenza Virus-Induced Lethality in Mice". Journal of Virology. 90 (7): 3783–8. doi:10.1128/JVI.03258-15. PMC 4794696. PMID 26739058.
  25. ↑ Ealy AD, Larson SF, Liu L, Alexenko AP, Winkelman GL, Kubisch HM, et al. (July 2001). "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. doi:10.1210/endo.142.7.8249. PMID 11416010.
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