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Anti-inflammatory action of type I interferons deduced from mice expressing interferon β

Gene Therapy volume 7, pages 817–825 (2000)Cite this article

Abstract

Type I interferons (IFN) are widely used for the therapeutic treatment of viral infections, tumor growth and various chronic diseases such as multiple sclerosis. Antagonism between type I IFNs and IFN-γ has been described in cells of the immune system, in particular in the activation of macrophages. To study the systemic effects of type I IFNs we used transgenic mice carrying a human IFN-β (hIFN-β) gene under the control of the rat insulin I promoter. These animals expressed high levels of hIFN-β in β-pancreatic cells, and the ability of the macrophages to respond to pro-inflammatory stimuli was analyzed. Transgenic mice exhibited an increased extravasation of cells to the peritoneal cavity after eliciting with thioglycollate broth. The expression of the inducible form of nitric oxide synthase and cyclooxygenase-2, two enzymes involved in inflammation, was impaired in transgenic animals challenged with lipopolysaccharide and IFN-γ. Analysis of the mechanisms leading to this attenuated inflammatory response showed a decrease in the serum levels of TNF-α and an inhibition of the activation of the transcription factor NF-κB in various tissues. These results indicate that systemic administration of IFN-β might influence the response to pro-inflammatory stimuli, in particular through the antagonism of IFN-γ signaling.

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References

  1. Sen GC, Lengyel P . The interferon system. A bird's eye view of its biochemistry J Biol Chem 1992 267: 5017–5020

    CAS  PubMed  Google Scholar 

  2. Erlandsson L et al. Interferon-β is required for interferon-α production in mouse fibroblasts Curr Biol 1998 8: 223–226

    Article  CAS  PubMed  Google Scholar 

  3. Croze E et al. The human type I interferon receptor. Identification of the interferon β-specific receptor-associated phosphoprotein J Biol Chem 1996 271: 33165–33168

    Article  CAS  PubMed  Google Scholar 

  4. Domanski P et al. Differential use of the βL subunit of the type I interferon (IFN) receptor determines signaling specificity for IFNα2 and IFNβ J Biol Chem 1998 273: 3144–3147

    Article  CAS  PubMed  Google Scholar 

  5. Lopez-Callazo E, Hortelano S, Rojas A, Bosca L . Triggering of peritoneal macrophages with IFN-α/β attenuates the expression of inducible nitric oxide synthasse through a decrease in NF-κB activation J Immunol 1998 160: 2889–2895

    Google Scholar 

  6. Diefenbach A et al. Type 1 interferon (IFNα/β) and type 2 nitric oxide synthase regulate the innate immune response to a protozoan parasite Immunity 1998 8: 77–87

    Article  CAS  PubMed  Google Scholar 

  7. Hamilton JA, Whitty GA, Kola I, Hertzog PJ . Endogenous IFN-αβ ssuppresses colony-stimulating factor (CSF)-1-stimulated macrophage DNA synthesis and mediates inhibitory effects of lipopolysaccharide and TNF-α J Immunol 1996 156: 2553–1557

    CAS  PubMed  Google Scholar 

  8. Zhou A et al. Exogenous interferon-γ induces endogenous synthesis of interferon-α and -β by murine macrophages for induction of nitric oxide synthase J Interfer Cytokin Res 1995 15: 897–904

    Article  CAS  Google Scholar 

  9. MacMicking J, Xie QW, Natahn C . Nitric oxide and macrophage function Annu Rev Immunol 1997 15: 323–350

    Article  CAS  PubMed  Google Scholar 

  10. Xie Q, Nathan C . The high-output nitric oxide pathway: role and regulation J Leuk Biol 1994 56: 576–582

    Article  CAS  Google Scholar 

  11. Xie K et al. Transfection with the inducible nitric oxide synthase gene suppressses tumorigenity and abrogates metastasis by K-1735 murine melanoma cells J Exp Med 1995 181: 1333–1343

    Article  CAS  PubMed  Google Scholar 

  12. Xie QW et al. Cloning and characterization of inducible nitric oxide synthase from mouse macrophages Science 1992 256: 225–228

    Article  CAS  PubMed  Google Scholar 

  13. Xie QW, Whisnant R, Nathan C . Promoter of the mouse gene encoding calcium-independent nitric oxide synthase confers inducibility by interferon γ and bacterial lipopolysaccharide J Exp Med 1993 177: 1779–1784

    Article  CAS  PubMed  Google Scholar 

  14. Lowenstein CJ et al. Macrophage nitric oxide synthase gene: two upstream regions mediate induction by interferon γ and lipopolysaccharide Proc Natl Acad Sci USA 1993 90: 9730–9734

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Martin E, Nathan C, Xie QW . Role of interferon regulatory factor 1 in induction of nitric oxide synthase J Exp Med 1994 180: 977–984

    Article  CAS  PubMed  Google Scholar 

  16. Kamijo R et al. Requirement for transcription factor IRF-1 in NO synthase induction in macrophages Science 1994 263: 1612–1615

    Article  CAS  PubMed  Google Scholar 

  17. Dalton DK et al. Multiple defects of immune cell function in mice with disrupted interferon-γ genes Science 1993 259: 1739–1742

    Article  CAS  PubMed  Google Scholar 

  18. Koka P et al. Human immunodeficiency virus 1 envelope proteins induce interleukin 1, tumor necrosis factor α, and nitric oxide in glial cultures derived from fetal, neonatal, and adult human brain J Exp Med 1995 182: 941–951

    Article  CAS  PubMed  Google Scholar 

  19. Karupiah G et al. Rapid interferon gamma-dependent clearance of influenza A virus and protection from consolidating pneumonitis in nitric oxide synthase 2-deficient mice J Exp Med 1998 188: 1541–1546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ricote M et al. The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation Nature 1998 391: 79–82

    Article  CAS  PubMed  Google Scholar 

  21. Deguchi M et al. Exogenous and endogenous type I interferons inhibit interferon-γ-induced nitric oxide production and nitric oxide synthase expression in murine peritoneal macrophages J Interfer Cytokin Res 1995 15: 977–984

    Article  CAS  Google Scholar 

  22. Faure V, Courtois Y, Goureau O . Inhibition of inducible nitric oxide synthase expression by interferons α and β in bovine retinal pigmented epithelial cells J Biol Chem 1997 272: 32169–32175

    Article  CAS  PubMed  Google Scholar 

  23. Van Weyenbergh J et al. Antagonistic action of IFN-β and IFN-γ on high affinity Fc γ receptor expression in healthy controls and multiple sclerosis patiens J Immunol 1998 161: 1568–1574

    CAS  PubMed  Google Scholar 

  24. Lu HT et al. Interferon (IFN) β acts downstream of IFN-γ-induced class II transactivator messenger RNA accumulation to block major histocompatibility complex class II gene expression and requires the 48-kD DNA-binding protein, ISGF3-gamma J Exp Med 1995 182: 1517–1525

    Article  CAS  PubMed  Google Scholar 

  25. Pelegrin M et al. Evidence from transgenic mice that interferon-β may be involved in the onset of diabetes mellitus J Biol Chem 1998 273: 12332–12340

    Article  CAS  PubMed  Google Scholar 

  26. Binder D, Fehr J, Hengartner H, Zinkernagal RM . Virus-induced transient bone marrow aplasia: major role of interferon-α/β during acute infection with the noncytopathic lymphocyticchoriomeningitis virus J Exp Med 1997 185: 517–530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Bramanti P et al. Enhanced spasticity in primary progressive MS patients treated with interferon β-1b Neurology 1998 51: 1720–1723

    Article  CAS  PubMed  Google Scholar 

  28. Lopez-Collazo E, Hortelano S, Bosca L . Interferon-α/β inhibits the apoptosis induced by lipopolysaccharide and interferon-γ in murine peritoneal macrophages J Interf Cytok Res 1998 18: 461–467

    Article  CAS  Google Scholar 

  29. Herschman H, Gilbert R, Reddy S, Xie WL . Coordinate regulation of the inducible forms of prostaglandin synthase and nitric oxide synthase in fibroblasts and macrophages Adv Exp Med Biol 1997 400A: 177–182

    Article  CAS  PubMed  Google Scholar 

  30. Baeuerle PA, Baichwal VR . NF-κB as a frequent target for immunosuppressive and anti-inflammatory molecules Adv Immunol 1997 65: 111–137

    Article  CAS  PubMed  Google Scholar 

  31. Ghosh S, May MJ, Kopp EB . NF-βK and Rel proteins: evolutionarily conserved mediators of immune responses Annu Rev Immunol 1998 16: 225–260

    Article  CAS  PubMed  Google Scholar 

  32. Darnell JEJ, Kerr IM, Stark GR . Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins Science 1994 264: 1415–1421

    Article  CAS  PubMed  Google Scholar 

  33. Gao J et al. An interferon-γ-activated site (GAS) is necessary for full expression of the mouse iNOS gene in response to interferon-γ and lipopolysaccharide J Biol Chem 1997 272: 1226–1230

    Article  CAS  PubMed  Google Scholar 

  34. Lu W, Fidler IJ, Dong Z . Eradication of primary murine fibrosarcomas and induction of systemic immunity by adenovirus-mediated interferon β gene therapy Cancer Res 1999 59: 5202–5208

    CAS  PubMed  Google Scholar 

  35. Kuniyasu H et al. Growth inhibitory effect of interferon-β is associated with the induction of cyclin-dependent kinase inhibitor p27Kip1 in a human gastric carcinoma cell line Cell Growth Diff 1997 8: 47–52

    CAS  PubMed  Google Scholar 

  36. Qin XQ et al. Interferon-β gene therapy inhibits tumor formation and causes regression of established tumors in immune-deficient mice Proc Natl Acad Sci USA 1998 95: 14411–14416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Xu L, Xie K, Fidler IJ . Therapy of human ovarian cancer by transfection with the murine interferon β gene: role of macrophage-inducible nitric oxide synthase Hum Gene Ther 1998 9: 2699–2708

    Article  CAS  PubMed  Google Scholar 

  38. Jiang H, Lin JJ, Tao J, Fisher PB . Suppression of human ribosomal protein L23A expression during cell growth inhibition by interferon-β Oncogene 1997 14: 473–480

    Article  CAS  PubMed  Google Scholar 

  39. Ossege LM, Sindern E, Patzold T, Malin JP . Immunomodulatory effects of interferon-β-1b in vivo: induction of the expression of transforming growth factor-β1 and its receptor type II J Neuroimmunol 1998 91: 73–81

    Article  CAS  PubMed  Google Scholar 

  40. Tomoda K et al. Cationic multilamellar liposome-mediated human innterferon-beta gene transfer into cervical cancer cell Anticancer Res 1998 18: 1367–1371

    CAS  PubMed  Google Scholar 

  41. Bluyssen AR, Durbin JE, Levy DE . ISGF3 gamma p48, a specificity switch for interferon activated transcription factors Cytok Growth Factor Rev 1996 7: 11–17

    Article  CAS  Google Scholar 

  42. Min W, Pober JS, Johnson DR . Interferon induction of TAP1: the phosphatase SHP-1 regulates crossover between the IFN-α/β and the IFN-γ signal-transduction pathways Circ Res 1998 83: 815–823

    Article  CAS  PubMed  Google Scholar 

  43. Schafer SL et al. Regulation of type I interferon gene expression by interferon regulatory factor-2 J Biol Chem 1998 273: 2714–2720

    Article  CAS  PubMed  Google Scholar 

  44. Zhang X, Alley EW, Russell SW, Morrison DC . Necessity and sufficiency of beta interferon for nitric oxide production in mouse peritoneal macrophages Infect Immunol 1994 62: 33–40

    CAS  Google Scholar 

  45. McRae BL, Semnani RT, Hayes MP, van Seventer GA . Type I IFNS inhibit human dendritic cell IL-12 production and Th1 cell development J Immunol 1998 160: 4298–4304

    CAS  PubMed  Google Scholar 

  46. Kreil TR, Eibl MM . Nitric oxide and viral infection: NO antiviral activity against a flavivirus in vitro, and evidence for contribution to pathogenesis in experimental infection in vivo Virology 1996 219: 304–306

    Article  CAS  PubMed  Google Scholar 

  47. Kreil TR, Eibl MM . Viral infection of macrophages profoundly alters requirements for induction of nitric oxide synthesis Virology 1995 212: 174–178

    Article  CAS  PubMed  Google Scholar 

  48. Deifenbach A et al. Type 1 interferon (IFNα/β) and type 2 nitric oxide synthase regulate the innate immune response to a protozoan parasite Immunity 1998 8: 77–87

    Article  Google Scholar 

  49. Jiang H et al. IFN-α/β reconstitutes the deficiency in lipid A-activated AKR macrophages for nitric oxide synthase J Immunol 1996 157: 305–312

    CAS  PubMed  Google Scholar 

  50. Croxford JL et al. Cytokine gene therapy in experimental allergic encephalomyelitis by injection of plasmid DNA-cationic liposome complex into the central nervous system J Immunol 1998 160: 5181–5187

    CAS  PubMed  Google Scholar 

  51. Chabot S, Williams G, Yong VW . Microglial production of TNF-α is induced by activated T lymphocytes. Involvement of VLA-4 and inhibition by interferonβ-1b J Clin Invest 1997 100: 604–612

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Baeuerle PA . IβB-NG-κB structures: at the interface of inflammation control Cell 1998 95: 729–731

    Article  CAS  PubMed  Google Scholar 

  53. Lucas M, Sanchez-Solino O, Solano F, Lizquierdo G . Interferon β-1b inhibits reactive oxygen species sproduction in peripheral blood monocytes of patients with relapsing-remitting multiple sclerosis Neurochem Int 1998 33: 101–102

    Article  CAS  PubMed  Google Scholar 

  54. Giri DK, Mehta RT, Kansal RG, Aggarwall BB . Mycobacterium avium–intracellulare complex activates nuclear transcription factor-κB in different cell types through reactive oxygen intermediates J Immunol 1998 161: 4834–4841

    CAS  PubMed  Google Scholar 

  55. Mirochnitchenko O, Inouye M . Effect of overexpression of human Cu, Zn superoxide dismutase in transgenic mice on macrophage functions J Immunol 1996 156: 1578–1586

    CAS  PubMed  Google Scholar 

  56. Weber KS, Klickstein LB, Weber PC, Weber C . Chemokine-induced monocyte transmigration requires cdc42-mediated cytoskeletal changes Eur J Immunol 1998 28: 2245–2251

    Article  CAS  PubMed  Google Scholar 

  57. Hadida F et al. Acquired constitutive expression of interferon beta after gene transduction enhances human immunodeficiency virus type 1-specific cytotoxic T lymphocyte activity by a RANTES-dependent mechanism Hum Gene Ther 1999 10: 1803–1810

    Article  CAS  PubMed  Google Scholar 

  58. Yagi K et al. Basic study on gene therapy of human malignant glioma by use of the cationic multilamellar liposome-entrapped human interferon β gene Hum Gene Ther 1999 10: 1975–1982

    Article  CAS  PubMed  Google Scholar 

  59. Velasco M et al. Macrophage triggering with cecropin A and melittin-derived peptides induces type II nitric oxide synthase expression J Immunol 1997 158: 4437–4443

    CAS  PubMed  Google Scholar 

  60. De Kimpe SJ, Kengatharan M, Thiemermann C, Vane JR . The cell wall components peptidoglycan and lipoteichoic acid from Staphylococcus aureus act in synergy to cause shock and multiple organ failure Proc Natl Acad Sci USA 1995 92: 10359–10363

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Velasco M et al. Rapid up-regulation of IκBβ and abrogation of NF-βB activity in peritoneal macrophages stimulated with lipopolysaccharide J Biol Chem 1997 272: 23025–23030

    Article  CAS  PubMed  Google Scholar 

  62. Chromczynski P, Sacchi N . Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction Anal Biochem 1987 162: 156–159

    Google Scholar 

  63. Fletcher BS, Kujubu DA, Perrin DM, Herschman HR . Structure of the mitogen-inducible TIS10 gene and demonstration that the TIS10-encoded protein is a functional prostaglandin G/Hsynthase J Biol Chem 1992 267: 4338–4344

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Dr Q-w Xie and C Nathan for the generous gift of the iNOS cDNA, and E Lundin for help in the preparation of the manuscript. This work was supported by grant PM98–120 from Dirección General de Enseñanza Superior, and FIS98/1063 from Fondo de Investigación Sanitaria, Spain.

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  1. Instituto de Bioquímica (Centro Mixto CSIC-UCM), Facultad de Farmacia, Universidad Complutense, Madrid, Spain

    L Boscá, O G Bodelón & S Hortelano

  2. Departament de Bioquímica i Biologia Molecular, Facultat de Veterinària, Universitat Autònoma de Barcelona, Bellaterra, Spain

    A Casellas & F Bosch

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Boscá, L., Bodelón, O., Hortelano, S. et al. Anti-inflammatory action of type I interferons deduced from mice expressing interferon β. Gene Ther 7, 817–825 (2000). https://doi.org/10.1038/sj.gt.3301179

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