Recent clinical trials have shown that interferon beta (IFN-β) is effective in reducing exacerbations in relapsing-remitting MS, while interferon gamma (IFN-γ) precipitates the relapses. To investigatge mechanisms underlying the beneficial effects of IFN-β and the detrimental effects of IFN-γ in MS, cell growth-regulatory effects of IFNs were examined in astrocyte-enriched cultures isolated from fetal brains of 12–20 weeks' gestation. Treatment with IFN-γ (50 or 500 IU ml-1) stimulated significantly the proliferation of astrocytes in 6 out of 9 culture series examined, while IFN-β (50 or 500 IU ml-1) inhibited the astrocytic proliferation in 3 out of 9 cultures, and IFN-α (50 or 500 IU ml-1) did not affect the proliferation. IFN-β and to a lesser degree IFN-α reduced the astrocytic proliferation induced by IFN-γ-treatment in 8 out of 9 culture series. The counteracting effect of IFN-α/IFN-β against IFN-γ-induced astrocytic proliferation was verified by the DNA content distribution analysis of propidium iodide-labeled cells. The antagonistic effect of IFN-α/IFN-β on the growth-promoting activity of IFN-γ in cultured human astrocytes suggests that interferons serve as growth regulators of astrocytes at sites of reactive gliosis lesions of MS.
1 deMaeyer E, de Maeyer-Guignard J. (1994) Interferons. In: Thomson AW, ed. The cytokine handbook.2nd ed.Academic Press, San Diego, pp 265–288.
2.
2 Waksmann BH, Reynolds WE. (1984) Multiple sclerosis as a disease of immune regulation. Proc Soc Exp Biol Med175: 282–294.
3.
3 Hafler DA, Weiner HL. (1989) MS: a CNS and systemic autoimmune disease. Immunol Today10: 104–107.
4.
4 Whitaker JN. (1994) Rationale for immunotherapy in multiple sclerosis. Ann Neurol36: S103–S107.
5.
5 The IFNB Multiple Sclerosis Study Group. (1993) Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial.Neurology43: 655–661.
6.
6 Paty DW, Li DKB. The UBC MS/MRI Study Group. (1993) Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. II. MRI analysis results of a multi-center, randomized, double-blind, placebo-controlled trial.Neurology43: 662–667.
7.
7 Panitch HS, Hirsch RL, Schindler J, Johnson KP. (1987) Treatment of multiple sclerosis with gamma interferon: exacerbations associated with activation of the immune system. Neurology37: 1097–1102.
8.
8 Panitch HS. (1992) Interferons and multiple sclerosis. A review of the evidence. Drugs44: 946–962.
11 Weinstock-Guttman B, Ransohoff RM, Kinkel RP, Rudicka RA. (1995) The interferons: Biological effects, mechanisms of action, and use in multiple sclerosis. Ann Neurol37: 7–15.
12.
12 Eng LF, Yu ACH, Lee YL. (1992) Astrocytic response to injury. Prog Brain Res94: 353–365.
13.
13 McMillian MK, Thai L, Hong J-S, O'Callaghan JP, Pennypacker KR. (1994) Brain injury in a dish: a model for reactive gliosis. Trends Neurosci17: 138–142.
14.
14 Wu E, Raine CS. (1992) Multiple sclerosis. Interactions between oligodendrocytes and hypertrophic astrocytes and their occurrence in other, nondemyelinating conditions. Lab Invest67: 88–99.
15.
15 Norton WT, Aquino DA, Hozumi I, Chiu F-C, Brosnan CF. (1992) Quantitative aspects of reactive gliosis: a review. Neurochem Res17: 877–885.
16.
16 Benveniste EN. (1992) Inflammatory cytokines within the central nervous system: sources, function, and mechanism of action. Am J Physiol263: C1–C16.
17.
17 Cannella B, Raine CS. (1995) The adhesion molecule and cytokine prof ile of multiple sclerosis lesions. Ann Neurol37: 424–435.
18.
18 Raine CS, Bornstein MB. (1970) Experimental allergic encephalomyelitis: a light and electron microscope study of remyelination and ‘sclerosis’ in vitro. J Neuropathol Exp Neurol29: 552–574.
19.
19 Yong VW, Moumdjian R, Yong FP et al. (1991) γ-Interferon promotes proliferation of adult human astrocytes in vitro and reactive gliosis in the adult mouse brain in vivo. Proc Natl Acad Sci USA88: 7016–7020.
20.
20 Yong VW, Tejada-Berges T, Goodyer CG, et al. (1992) Differential proliferative response of human and mouse astrocytes to gamma-interferon. Glia6: 269–280.
21.
21 Traugott U, Lebon P. (1988) Multiple sclerosis: involvement of interferons in lesion pathogenesis. Ann Neurol24: 243–251.
22.
22 Traugott U, Scheinberg LC, Raine CS. (1985) On the presence of Ia-positive endothelial cells and astrocytes in multiple sclerosis lesions and its relevance to antigen presentation. J Neuroimmunol8: 1–14.
23.
23 Satoh J-I, Paty DW, Kim SU. (1995) Differential effects of beta and gamma interferons on expression of major histocompatibility complex antigens and intercellular adhesion molecule-1 in cultured fetal human astrocytes. Neurology45: 367–373.
24.
24 Satoh J-I, Muramatsu H, Moretto G, et al. (1993) Midkine that promotes survival offetal human neurons is produced by fetal human astrocytes in culture. Dev Brain Res75: 201–205.
25.
25 Satoh J-I, Kim SU. (1994) HSP72 induction by heat stress in human neurons and glial cells in culture.Brain Res, 653: 243–250.
26.
26 Kim SU, Stern J, Kim M, Pleasure D. (1983) Culture of purified rat astrocytes in serum-free medium supplemented with mitogen. Brain Res274: 79–86.
27.
27 Darzynkiewicz Z. (1994) Cell cycle analysis by flow cytometry. In: Celis JE, ed. Cell biology. A laboratory handbookAcademic Press, San Diego. 262–271.
28.
28 Waseem NH, Lane DP. (1990) Monoclonal antibody analysis of the proliferating cell nuclear antigen (PCNA). Structural conservation and the detection of a nucleolar form. J Cell Sci96: 121–129.
29.
29 Pestka S, Langer JA, Zoon C, Samuel CE. (1987) Interferons and their actions. Ann Rev Biochem56: 727–777.
30.
30 Czarniecki CW, Fennie CW, Powers DB, Estell DA. (1984) Synergistic antiviral and antiproliferative activities of Escherichia coli-derived human alpha, beta, and gamma interferons. J Virol49: 490–496.
31.
31 Schiller JH, Groveman DS, Schmid SM, Willson JKV, et al. (1986) Synergistic antiproliferative effects of human recombinant α54-or βser-interferon with γ-interferon on human cell lines of various histogenesis. Cancer Res46: 483–488.
32.
32 Hannigan GE, Fish EN, Williams BRG. (1984) Modulation of human interferon-α receptor expression by human interferon-γ.J Biol Chem259: 8084–8086.
33.
33 Garotta G, Talmadge KW, Pink JRL, et al. (1986) Functional antagonism between type I and type II interferons on human macrophages. Biochem Biophys Res Commun140: 948–954.
34.
34 Yoshida R, Murray HW, Nathan CF. (1988) Agonist and antagonist effects of interferon α and β on activation of human macrophages. Two classes of interferon γ receptors and blockade of the high-affinity sites by interferon α or β. J Exp Med167: 1171–1185.
35.
35 Ling PD, Warren MK, Vogel SN. (1985) Antagonistic effect of interferon-β on the interferon-γ-induced expression of Ia antigen in murine macrophages. J Immunol135: 1857–1863.
36.
36 Inaba K, Kitamura M, Kato T, et al. (1986) Contrasting effects of α/β and γ-interferons on expression of Ia antigen in murine macrophages. J Exp Med163: 1030–1035.
37.
37 Fertsch-Ruggio D, Schoenberg D, Vogel SN. (1988) Induction of macrophage Ia antigen expression by rIFN-γ and down-regulation by IFN-α/β and dexamethasone are regulated transcriptionally. J Immunol141: 1582–1589.
38.
38 Lapierre LA, Fiers W, Pober JS. (1988) Three distinct classes of regulatory cytokines control endothelial cell MHC antigen expression. Interaction with immune γ interferon differentiates the effects of tumor necrosis factor and lymphotoxin from those of leukocyte α and fibroblast β interferons. J Exp Med167: 794–804.
39.
39 Barna BP, Chou SM, Jacobs B, et al. (1989) Interferon-β impairs induction of HLA-DR antigen expression in cultured adult human astrocytes. J Neuroimmunol23: 45–53.
40.
40 Joseph J, Knobler RL, D'Imperio C, Lublin FD. (1988) Down-regulation of interferon-γ-induced class II expression on human glioma cells by recombinant interferon-β: effects of dosage treatment schedule. J Neuroimmunol20: 39–44.
41.
41 Ransohoff RM, Devajyothi C, Estes ML, et al. (1991) Interferon-β specifically inhibits interferon-γ-induced class II major histocompatibility complex gene transcription in a human astrocytoma cell line. J Neuroimmunol33: 103–112.
42.
42 Weil J, Epstein CJ, Epstein LB, et al. (1983) A unique set of polypeptides is induced by γ interferon in addition to those induced in common with α and β interferons. Nature301: 437–439.
43.
43 Pellegrini S, Schindler C. (1993) Early events in signalling by interferons. Trends Biochem Sci18: 338–342.
44.
44 Clemens MI, McNurlan MA. (1985) Regulation of cell proliferation and differentiation by interferons. Biochem J226: 345–360.
45.
45 Shearer M, Taylor-Papadimitriou J. (1987) Regulation of cell growth by interferon. Cancer Metastasis Rev6: 199–221.
46.
46 Creasey AA, Bartholomew JC, Merigan TC. (1980) Role of G0-G1 arrest in the inhibition of tumor cell growth by interferon. Proc Natl Acad Sci USA77: 1471–1475.
47.
47 Einat M, Resnitzky D, Kimchi A. (1985) A close link between reduction of c-myc expression by interferon and G0/G1 arrest. Nature313: 597–600.
48.
48 Balkwill F, Waatling D, Taylor-Papadimitriou J. (1978) Inhibition by lymphoblastoid interferon of growth of cells derived from the human breast. Int J Cancer22: 258–265.
49.
49 Balkwill FR, Bokhon'Ko AI. (1984) Differential effects of pure human alpha and gamma interferons on fibroblast cell growth and the cell cycle. Exp Cell Res155: 190–197.
50.
50 Hillman MC Jr, Knight E jr, Blomstrom DC. (1987) A membrane protein from IFN-β-treated Daudi cells causes a cessation in cell growth. Biochem Biophys Res Commun148: 140–147.
51.
51 Zoon KC, Karasaki Y, zur Nedden DL, Hu R, Arnheitter H. (1986) Modulation of epidermal growth factor receptors by human α interferon. Proc Natl Acad Sci USA83: 8226–8230.
52.
52 Awatsuji H, Furukawa Y, Hirota M, et al. (1995) Interferons suppress nerve growth factor synthesis as a result of interference with cell growth in astrocytes cultured from neonatal mouse brain. J Neurochem64: 1476–1482.
53.
53 Bradley EC, Ruscetti FW. (1981) Effects offibroblast, lymphoid, and myeloid interferons on human tumor colony formation in vitro. Cancer Res41: 244–249.
54.
54 Ludwig CU, Durie BGM, Salmon SE, Moon TE. (1983) Tumor growth stimulation in vitro by interferons. Eur J Cancer Clin Oncol19: 1625–1632.
55.
55 Tan C-K, Sullivan K, Li X, Tan EM, et al. (1987) Autoantibody to the proliferating cell nuclear antigen neutralizes the activity of the auxiliary protein for DNA polymerase delta. Nucl Acid Res15: 9299–9308.
56.
56 McCormick D, Hall PA. (1992) The complexities of proliferating cell nuclear antigen.Histopathol21591–594.
