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. 2005 Aug 19;94(5):405–411. doi: 10.1111/j.1349-7006.2003.tb01455.x

New aspects of IFN‐α/β signalling in immunity, oncogenesis and bone metabolism

Akinori Takaoka 1,, Tadatsugu Taniguchi 1
PMCID: PMC11160234  PMID: 12824884

Abstract

Although interferons (IFNs) were originally identified as humoral factors that confer an antiviral state upon cells, they have been demonstrated to be multifunctional in a variety of biological systems. The IFN‐α/β system modulates not only the cellular immune response to viral and bacterial infections, but also the oncogenic process and bone metabolism. Further studies have revealed additional unique facets of the IFN‐α/β system. A weak signal by constitutively produced IFN‐α/β is critical not only for the regulation of cellular amplification of IFN‐α/β production upon viral infection or the enhancement of signalling by other cytokines, but also for the regulation of adaptive immune responses, such as the enhancement of CD8+ T cell activation. Furthermore, IFN‐β signalling is critical for the regulation of the bone‐resorbing osteo‐clasts. In this review, we focus on the newly discovered roles of the IFN‐α/β system in host defense and bone remodeling, particularly on the functions of the weak IFN‐α/β signalling in the context of what we refer to as the “rewing‐up” model. (Cancer Sci 2003; 94: 405–411)

References

  • 1. De Maeyer E, De Maeyer‐Guignard J. In: Interferons and other regulatory cytokines. New York : John Wiley and Sons; 1988. [Google Scholar]
  • 2. Vilcek J, Sen GS. Interferons and other cytokines. In: Fields DM, Knipe PM, Howley PM, editors . Fields virology. 3rd ed. Philadelphia : Lippincott‐Raven; 1996. p. 375–99. [Google Scholar]
  • 3. Pestka S, Langer JA, Zoon KC, Samuel CE. Interferons and their actions. Anna Rev Biochem 1987; 56: 727–77. [DOI] [PubMed] [Google Scholar]
  • 4. Biron CA, Nguyen KB, Pien GC, Cousens LP, Salazar‐Mather TP. Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annu Rev Immunol 1999; 17: 189–220. [DOI] [PubMed] [Google Scholar]
  • 5. Bocci V. The physiological interferon response. Immunol Today 1985; 6: 7–9. [DOI] [PubMed] [Google Scholar]
  • 6. Tovey MG, Streuli M, Gresser I, Gugenheim J, Blanchard B, Guymarho J, Vignaux F, Gigou M. Interferon messenger RNA is produced constitutively in the organs of normal individuals. Proc Natl Acad Sci USA 1987; 84: 5038–42. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7. Sato M, Suemori H, Hata N, Asagiri M, Ogasawara K, Nakao K, Nakaya T, Katsuki M, Noguchi S, Tanaka N, Taniguchi T. Distinct and essential roles of transcription factors IRF‐3 and IRF‐7 in response to viruses for IFN‐α/β gene induction. Immunity 2000; 13: 539–48. [DOI] [PubMed] [Google Scholar]
  • 8. Takaoka A, Mitani Y, Suemori H, Sato M, Yokochi T, Noguchi S, Tanaka N, Taniguchi T. Cross talk between interferon‐γ and ‐α/β signaling components in caveolar membrane domains. Science 2000; 288: 2357–60. [DOI] [PubMed] [Google Scholar]
  • 9. Hida S, Ogasawara K, Sato K, Abe M, Takayanagi H, Yokochi T, Sato T, Hirose S, Shirai T, Taki S, Taniguchi T. CD8(+) T cell‐mediated skin disease in mice lacking IRF‐2, the transcriptional attenuator of interferon‐α/β signaling. Immunity 2000; 13: 643–55. [DOI] [PubMed] [Google Scholar]
  • 10. Takayanagi H, Kim S, Matsuo K, Suzuki H, Suzuki T, Sato K, Yokochi T, Oda H, Nakamura K, Ida N, Wagner EF, Taniguchi T. RANKL maintains bone homeostasis through c‐Fos‐dependent induction of interferon‐β. Nature 2002; 416: 744–9. [DOI] [PubMed] [Google Scholar]
  • 11. Darnell JE Jr, Kerr IM, Stark GR. Jak‐STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 1994; 264: 1415–21. [DOI] [PubMed] [Google Scholar]
  • 12. Ihle JN, Kerr IM. Jaks and Stats in signaling by the cytokine receptor super‐family. Trends Genet 1995; 11: 69–74. [DOI] [PubMed] [Google Scholar]
  • 13. Schindler C, Darnell JE Jr. Transcriptional responses to polypeptide ligands: the JAK‐STAT pathway. Annu Rev Biochem 1995; 64: 621–51. [DOI] [PubMed] [Google Scholar]
  • 14. Stark GR, Kerr IM, Williams BR, Silverman RH, Schreiber RD. How cells respond to interferons. Annu Rev Biochem. 1998; 67: 227–64. [DOI] [PubMed] [Google Scholar]
  • 15. Maniatis T, Whittermore LA, Du W, Fan CM, Keller A, Palmobella V, Thanos D. In: McKnight SL, Yamamoto KR, editors. Transcriptional regulation. Part 2. Positive and negative control of human interferon‐β gene expression, New York, Cold Spring Harbor : Cold Spring Harbor Laboratory Press; 1992, p. 1193–220. [Google Scholar]
  • 16. Taniguchi T, Ogasawara K, Takaoka A, Tanaka N. IRF family of transcription factors as regulators of host defense. Annu Rev Immunol 2001; 19: 623–55. [DOI] [PubMed] [Google Scholar]
  • 17. Du W, Thanos D, Maniatis T. Mechanisms of transcriptional synergism between distinct virus‐inducible enhancer elements. Cell 1993; 74: 887–98. [DOI] [PubMed] [Google Scholar]
  • 18. Fujita T, Sakakibara J, Sudo Y, Miyamoto M, Kimura Y, Taniguchi T. Evidence for a nuclear factor(s), IRF‐1, mediating induction and silencing properties to human IFN‐β gene regulatory elements. EMBO J 1988; 7: 3397–405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. Miyamoto M, Fujita T, Kimura Y, Maruyama M, Harada H, Sudo Y, Miyata T, Taniguchi T. Regulated expression of a gene encoding a nuclear factor, IRF‐1, that specifically binds to IFN‐βgene regulatory elements. Cell 1988; 54: 903–13. [DOI] [PubMed] [Google Scholar]
  • 20. Fujita T, Kimura Y, Miyamoto M, Barsoumian EL, Taniguchi T. Induction of endogenous IFN‐α and IFN‐β genes by a regulatory transcription factor, IRF‐1. Nature 1989; 337: 270–2. [DOI] [PubMed] [Google Scholar]
  • 21. Harada H, Fujita T, Miyamoto M, Kimura Y, Maruyama M, Furia A, Miyata T, Taniguchi T. Structurally similar but functionally distinct factors, IRF‐1 and IRF‐2, bind to the same regulatory elements of IFN and IFN‐inducible genes. Cell 1989; 58: 729–39. [DOI] [PubMed] [Google Scholar]
  • 22. Ryals J, Dierks P, Ragg H, Weissmann C. A 46‐nucleotide promoter segment from an IFN‐α gene renders an unrelated promoter inducible by virus. Cell 1985; 41: 497–507. [DOI] [PubMed] [Google Scholar]
  • 23. Nguyen H, Hiscott J, Pitha PM. The growing family of interferon regulatory factors. Cytokine Growth Factor Rev 1997; 8: 293–312. [DOI] [PubMed] [Google Scholar]
  • 24. Mamane Y, Heylbroeck C, Genin P, Algarte M, Servant MJ, LePage C, DeLuca C, Kwon H, Lin R, Hiscott J. Interferon regulatory factors: the next generation. Gene 1999; 237: 1–14. [DOI] [PubMed] [Google Scholar]
  • 25. Harada H, Matsumoto M, Sato M, Kashiwazaki Y, Kimura T, Kitagawa M, Yokochi T, Tan RS, Takasugi T, Kadokawa Y, Schindler C, Schreiber RD, Noguchi S, Taniguchi T. Regulation of IFN‐α/β genes: evidence for a dual function of the transcription factor complex ISGF3 in the production and action of IFN‐α/β. Genes Cells 1996; 1: 995–1005. [DOI] [PubMed] [Google Scholar]
  • 26. Juang Y, Lowther W, Kellum M, Au WC, Lin R, Hiscott J, Pitha PM. Primary activation of interferon α and interferon β gene transcription by interferon regulatory factor 3. Proc Natl Acad Sci USA 1998; 95: 9837–42. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27. Yoneyama M, Suhara W, Fukuhara Y, Fukuda M, Nishida E, Fujita T. Direct triggering of the type I interferon system by virus infection: activation of a transcription factor complex containing IRF‐3 and CBP/p300. EMBO J 1998; 17: 1087–95. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28. Lin R, Heylbroeck C, Pitha PM, Hiscott J. Virus‐dependent phosphorylation of the IRF‐3 transcription factor regulates nuclear translocation, transactivation potential, and proteasome‐mediated degradation. Mol Cell Biol 1998; 18: 2986–96. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29. Marie I, Durbin JE, Levy DE. Differential viral induction of distinct interferon‐α genes by positive feedback through interferon regulatory factor‐7. EMBO J 1998; 17: 6660–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30. Sato M, Hata N, Asagiri M, Nakaya T, Taniguchi T, Tanaka N. Positive feedback regulation of type I IFN genes by the IFN‐inducible transcription factor IRF‐7. FEBS Lett 1998; 441: 106–10. [DOI] [PubMed] [Google Scholar]
  • 31. Hata N, Sato M, Takaoka A, Asagiri M, Tanaka N, Taniguchi T. Constitutive IFN‐α/β signal for efficient IFN‐α/β gene induction by virus. Biochem Biophys Res Commun 2001; 285: 518–25. [DOI] [PubMed] [Google Scholar]
  • 32. Gresser I, Maury C, Kaido T, Bandu MT, Tovey MG, Maunoury MT, Fantuzzi L, Gessani S, Greco G, Belardelli F. The essential role of endogenous IFN α/SbT in the anti‐metastatic action of sensitized T lymphocytes in mice injected with Friend erythroleukemia cells. Int J Cancer 1995; 63: 726–31. [DOI] [PubMed] [Google Scholar]
  • 33. Mitani Y, Takaoka A, Kim SH, Kato Y, Yokochi T, Tanaka N, Taniguchi T. Cross talk of the interferon‐α/β signalling complex with gp130 for effective interleukin‐6 signalling. Genes Cells 2001; 6: 631–40. [DOI] [PubMed] [Google Scholar]
  • 34. Taniguchi T, Takaoka A. A weak signal for strong responses: interferon‐α/β revisited. Nat Rev Mol Cell Biol 2001; 2: 378–86. [DOI] [PubMed] [Google Scholar]
  • 35. Alexopoulou L, Holt AC, Medzhitov R, Flavell RA. Recognition of double‐stranded RNA and activation of NF‐kappaB by Toll‐like receptor 3. Nature 2001; 413: 732–8. [DOI] [PubMed] [Google Scholar]
  • 36. Stewart WE 2nd, Gosser LB, Lockart RZ Jr. Priming: a nonantiviral function of interferon. J Virol 1971; 7: 792–801. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37. Ogasawara K, Hida S, Weng Y, Saiura A, Sato K, Takayanagi H, Sakaguchi S, Yokochi T, Kodama T, Naitoh M, De Martino JA, Taniguchi T. Requirement of the IFN‐α/β‐induced CXCR3 chemokine signalling for CD8+ T cell activation. Genes Cells 2002; 7: 309–20. [DOI] [PubMed] [Google Scholar]
  • 38. Buller RM, Holmes KL, Hugin A, Frederickson TN, Morse HC 3rd. Induction of cytotoxic T‐cell responses in vivo in the absence of CD4 helper cells. Nature 1987; 328: 77–9. [DOI] [PubMed] [Google Scholar]
  • 39. Hou S, Mo XY, Hyland L, Doherty PC. Host response to Sendai virus in mice lacking class II majorhistocompatibility complex glycoproteins. J Virol 1995; 69: 1429–34. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40. Ridge JP, Di Rosa F, Matzinger P. A conditioned dendritic cell can be a temporal bridge between a CD4+ T‐helper and a T‐killer cell. Nature 1998; 393: 474–8. [DOI] [PubMed] [Google Scholar]
  • 41. Strander H, Einhorn S. Interferons and the tumor cell. Biotherapy 1996; 8: 213–8. [DOI] [PubMed] [Google Scholar]
  • 42. Belardelli F, Ferrantini M, Proietti E, Kirkwood JM. Interferon‐α in tumor immunity and immunotherapy. Cytokine Growth Factor Rev 2002; 13: 119–34. [DOI] [PubMed] [Google Scholar]
  • 43. Der SD, Zhou A, Williams BR, Silverman RH. Identification of genes differentially regulated by interferon α, β, or γ using oligonucleotide arrays. Proc Natl Acad Sci USA 1998; 95: 15623–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44. Kimchi A, Shure H, Lapidot Y, Rapoport S, Panel A, Revel M. Antimitogenic effects of interferon and (2′‐5′)‐oligoadenylate in synchronized 3T3 fibroblasts. FEBS Lett 1981; 134: 212–6. [DOI] [PubMed] [Google Scholar]
  • 45. Koromilas AE, Roy S, Barber GN, Katze MG, Sonenberg N. Malignant transformation by a mutant of the IFN‐inducible dsRNA‐dependent protein kinase. Science 1992; 257: 1685–9. [DOI] [PubMed] [Google Scholar]
  • 46. Harada H, Kitagawa M, Tanaka N, Yamamoto H, Harada K, Ishihara M, Taniguchi T. Anti‐oncogenic and oncogenic potentials of interferon regulatory factors‐1 and ‐2. Science 1993; 259: 971–4. [DOI] [PubMed] [Google Scholar]
  • 47. Meurs EF, Galabru J, Barber GN, Katze MG, Hovanessian AG. Tumor suppressor function of the interferon‐induced double‐stranded RNA‐activated protein kinase. Proc Natl Acad Sci USA 1993; 90: 232–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48. Harada H, Kondo T, Ogawa S, Tamura T, Kitagawa M, Tanaka N, Lamphier MS, Hirai H, Taniguchi T. Accelerated exon skipping of IRF‐1 mRNA in human myelodysplasia/leukemia; a possible mechanism of tumor suppressor inactivation. Oncogene 1994; 9: 3313–20. [PubMed] [Google Scholar]
  • 49. Tanaka N, Ishihara M, Lamphier MS, Nozawa H, Matsuyama T, Mak TW, Aizawa S, Tokino T, Oren M, Taniguchi T. Cooperation of the tumor suppressors IRF‐1 and p53 in response to DNA damage. Nature 1996; 382: 816–8. [DOI] [PubMed] [Google Scholar]
  • 50. Nozawa H, Oda E, Ueda S, Tamura G, Maesawa C, Muto T, Taniguchi T, Tanaka N. Functionally inactivating point mutation in the tumor‐suppressor IRF‐1 gene identified in human gastric cancer. Int J Cancer 1998; 77: 522–7. [DOI] [PubMed] [Google Scholar]
  • 51. Nozawa H, Oda E, Nakao K, Ishihara M, Ueda S, Yokochi T, Ogasawara K, Nakatsuru Y, Shimizu S, Ohira Y, Hioki K, Aizawa S, Ishikawa T, Katsuki M, Muto T, Taniguchi T, Tanaka N. Loss of transcription factor IRF‐1 affectstumor susceptibility in mice carrying the Ha‐ras transgene or nullizygosity forp p53 . Genes Dev 1999; 13: 1240–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52. Belardelli F, Ferrantini M. Cytokines as a link between innate and adaptive antitumor immunity. Trends Immunol 2002; 23: 201–8. [DOI] [PubMed] [Google Scholar]
  • 53. Gutterman JU. Cytokine therapeutics: lessons from interferon α. Proc Natl Acad Sci USA 1994; 91: 1198–205. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54. Pfeffer LM, Dinarello CA, Herberman RB, Williams BR, Borden EC, Bordens R, Walter MR, Nagabhushan TL, Trotta PP, Pestka S. Biological properties of recombinant ointerferons: 40th anniversary of the discovery of interferons. Cancer Res 1998; 58: 2489–99. [PubMed] [Google Scholar]
  • 55. Takayanagi H, Ogasawara K, Hida S, Chiba T, Murata S, Sato K, Takaoka A, Yokochi T, Oda H, Tanaka K, Nakamura K, Taniguchi T. T‐cell‐mediated regulation of osteoclastogenesis by signalling cross‐talk between RANKL and IFN‐y. Nature 2000; 408: 600–5. [DOI] [PubMed] [Google Scholar]
  • 56. Arron JR, Choi Y. Bone versus immune system. Nature 2000; 408: 535–6. [DOI] [PubMed] [Google Scholar]
  • 57. Takayanagi H, Kim S, Taniguchi T. Signaling crosstalk between RANKL and interferons in osteoclast differentiation. Arthritis Res 2002; 4 Suppl 3: S227–32. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58. Manolagas SC. Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev 2000; 21: 115–37. [DOI] [PubMed] [Google Scholar]
  • 59. Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR, Burgess T, Elliott R, Colombero A, Elliott G, Scully S, Hsu H, Sullivan J, Hawkins N, Davy E, Capparelli C, Eli A, Qian YX, Kaufman S, Sarosi I, Shalhoub V, Senaldi G, Guo J, Delaney J, Boyle WJ. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 1998; 93: 165–76. [DOI] [PubMed] [Google Scholar]
  • 60. Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M, Mochizuki S, Tomoyasu A, Yano K, Goto M, Murakami A, Tsuda E, Morinaga T, Higashio K, Udagawa N, Takahashi N, Suda T. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis‐inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci USA 1998; 95: 3597–602. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61. Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, Morony S, Oliveira‐dos‐Santos AJ, Van G, Itie A, Khoo W, Wakeham A, Dunstan CR, Lacey DL, Mak TW, Boyle WJ, Penninger JM. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph‐node organogenesis. Nature 1999; 397: 315–23. [DOI] [PubMed] [Google Scholar]
  • 62. Medzhitov R, Janeway CA Jr. Innate immunity: the virtues of a nonclonal system of recognition. Cell 1997; 91: 295–8. [DOI] [PubMed] [Google Scholar]
  • 63. Medzhitov R, Janeway C Jr. Innate immune recognition: mechanisms and pathways. Immunol Rev 2000; 173: 89–97. [DOI] [PubMed] [Google Scholar]
  • 64. Aderem A, Ulevitch RJ. Toll‐like receptors in the induction of the innate immune response. Nature 2000; 406: 782–7. [DOI] [PubMed] [Google Scholar]
  • 65. Akira S, Takeda K, Kaisho T. Toll‐like receptors: critical proteins linking innate and acquired immunity. Nat Immunol 2001; 2: 675–80. [DOI] [PubMed] [Google Scholar]
  • 66. Doyle S, Vaidya S, O'Connell R, Dadgostar H, Dempsey P, Wu T, Rao G, Sun R, Haberland M, Modlin R, Cheng G. IRF3 mediates a TLR3/TLR4‐specific antiviral gene program. Immunity 2002; 17: 251–63. [DOI] [PubMed] [Google Scholar]
  • 67. Ito T, Amakawa R, Kaisho T, Hemmi H, Tajima K, Uehira K, Ozaki Y, Tomizawa H, Akira S, Fukuhara S. Interferon‐a and interleukin‐12 are induced differentially by Toll‐like receptor 7 ligands in human blood dendritic cell subsets. J Exp Med 2002; 195: 1507–12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68. Krieg AM. CpG motifs in bacterial DNA and their immune effects. Annu Rev Immunol 2002; 20: 709–60. [DOI] [PubMed] [Google Scholar]
  • 69. Shinobu N, Iwamura T, Yoneyama M, Yamaguchi K, Suhara W, Fukuhara Y, Amano F, Fujita T. Involvement of TIRAP/MAL in signaling for the activation of interferon regulatory factor 3 by lipopolysaccharide. FEBS Lett 2002; 517: 251–6. [DOI] [PubMed] [Google Scholar]
  • 70. Yamamoto M, Sato S, Mori K, Hoshino K, Takeuchi O, Takeda K, Akira S. Cutting edge: a novel Toll/IL‐1 receptor domain‐containing adapter that preferentially activates the IFN‐β promoter in the Toll‐like receptor signaling. J Immunol 2002; 169: 6668–72. [DOI] [PubMed] [Google Scholar]

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