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. 2002 Nov 13;30(2):189–200. doi: 10.1016/0165-5728(90)90103-T

Induction and regulation of class II major histocompatibility complex mRNA expression in astrocytes by interferon-γ and tumor necrosis factor-α

Maria Vidovic 1, Shaun M Sparacio 1, Michal Elovitz 1, Etty N Benveniste 1,2,∗
PMCID: PMC7119667  PMID: 2121799

Abstract

Astrocytes can function as antigen-presenting cells (APC) upon expression of class II major histocompatibility complex (MHC) antigens, which are induced by interferon-γ (IFN-γ). Previous data from this laboratory had shown that the cytokine tumor necrosis factor-α (TNF-α) enhances IFN-γ-mediated class II antigen expression on astrocytes. We have now investigated the effect of IFN-γ and TNF-α on class II MHC mRNA expression in astrocytes using Northern blot analysis. Astrocytes do not constitutively express mRNA for class II MHC. Kinetic analysis of class II MHC mRNA expression in IFN-γ-treated cells demonstrated an 8 h time lag, which was followed by an increase over the next 16 h. Optimal expression of class II mRNA was detected after a 24 h incubation with IFN-γ. This level of expression was further enhanced by the simultaneous addition of IFN-γ and TNF-α to the astrocytes, while TNF-α alone had no effect on class II mRNA expression. TNF-α does not act by increasing the stability of IFN-γ-induced class II mRNA, indicating its action is not at that specific level of post-transcriptional control. Furthermore, astrocyte class II mRNA expression was inhibited when cycloheximide (CHX) was added together with IFN-γ or IFN-γ/TNF-α, and when CHX was added up to 4 h after treatment with IFN-γ or IFN-γ/TNF-α. These results indicate that astrocyte class II mRNA expression is mediated by newly synthesized proteins induced by IFN-γ and/or IFN-γ/TNF-α. The expression of class II antigens on astrocytes, and cytokine modulation of their expression, may be important in the initiation and perpetuation of intracerebral immune responses.

Keywords: Astrocyte, Antigen-presenting cell, Class II major histocompatibility complex, Interferon-γ, Tumor necrosis factor-α

Abbreviations: APC, antigen-presenting cells; CNS, central nervous system; CHX, cycloheximide; EAE, experimental allergic encephalomyelitis; FACS, fluorescence-activated cell sorter; IFN-γ, interferon-γ; MHC, major histocompatibility complex; MS, multiple sclerosis; TNF-α, tumor necrosis factor-α

References

  1. Accolla R.S., Carra G., Guardiola J. Vol. 82. 1985. Reactivation by a trans-acting factor of human MHC-Ia gene expression in interspecies hybrids between an Ia-negative human B cell variant and an Ia-positive mouse B cell lymphoma; pp. 5145–5149. (Proc. Natl. Acad. Sci. U.S.A.). [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Amaldi I., Reith W., Berte C., Mach B. Induction of HLA class II genes by IFN-γ is transcriptional and requires a trans-acting protein. J. Immunol. 1989;142:999–1004. [PubMed] [Google Scholar]
  3. Basta P.V., Sherman P.A., Ting J.P.Y. Identification of an interferon-γ response region 5′ of the human histocompatibility leukocyte antigen DRα chain gene which is active in human glioblastoma multiform lines. J. Immunol. 1987;138:1275–1280. [PubMed] [Google Scholar]
  4. Basta P.V., Sherman P.A., Ting J.P. Vol. 85. 1988. Detailed delineation of an interferon-γ-responsive element important in human HLA-DRα gene expression in a glioblastoma multiform line; pp. 8618–8622. (Proc. Natl. Acad. Sci. U.S.A.). [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Benacerraf B. Role of MHC gene products in immune regulation. Science. 1981;212:1229–1238. doi: 10.1126/science.6165083. [DOI] [PubMed] [Google Scholar]
  6. Benveniste E.N., Merrill J.E. Stimulation of oligodendroglial proliferation and maturation by interleukin-2. Nature. 1986;321:610–613. doi: 10.1038/321610a0. [DOI] [PubMed] [Google Scholar]
  7. Benveniste E.N., Sparacio S.M., Bethea J.R. Tumor necrosis factor-α enhances interferon-γ mediated class II antigen expression on astrocytes. J. Neuroimmunol. 1989;25:209–219. doi: 10.1016/0165-5728(89)90139-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Benveniste E.N., Sparacio S.M., Norris J.G., Grenett H.E., Fuller G.M. Induction and regulation of interleukin-6 gene expression in rat astrocytes. J. Neuroimmunol. 1990;30:201–212. doi: 10.1016/0165-5728(90)90104-u. [DOI] [PubMed] [Google Scholar]
  9. Bignami A., Eng L.F., Dahl D., Uyeda C.T. Localization of the glial fibrillary acidic protein in astrocytes by immunofluorescence. Brain Res. 1972;43:429–435. doi: 10.1016/0006-8993(72)90398-8. [DOI] [PubMed] [Google Scholar]
  10. Blanar M.A., Boettger E.C., Flavell R.A. Vol. 85. 1988. Transcriptional activation of HLA-DRα by interferon γ requires a trans-acting protein; pp. 4672–4676. (Proc. Natl. Acad. Sci. U.S.A.). [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Boettger E.C., Blanar M.A., Flavell R.A. Cycloheximide, an inhibitor of protein synthesis, prevents γ-interferon-induced expression of class II mRNA in a macrophage cell line. Immunogenetics. 1988;28:215–220. doi: 10.1007/BF00345497. [DOI] [PubMed] [Google Scholar]
  12. Celada A., Klemsz M.J., Maki R.A. Interferon-γ activates multiple pathways to regulate the expression of the genes for major histocompatibility class II I-Aβ, tumor necrosis factor and complement component C3 in mouse macrophages. Eur. J. Immunol. 1989;19:1103–1109. doi: 10.1002/eji.1830190621. [DOI] [PubMed] [Google Scholar]
  13. Chomczynski P., Sacchi N. Single step method of RNA isolation by acid guanidinium thiocyanate-phenolchloroform extraction. Anal. Biochem. 1987;162:156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  14. Chung I.Y., Benveniste E.N. Tumor necrosis factor-alpha production by astrocytes: induction by lipopolysaccharide, interferon-gamma and interleukin-1. J. Immunol. 1990;144:2999–3007. [PubMed] [Google Scholar]
  15. Collins T., Lapierre L.A., Fiers W., Strominger J.L., Pober J.S. Vol. 83. 1986. Recombinant human tumor necrosis factor increases mRNA levels and surface expression of HLA-A,B antigens in vascular endothelial cells and dermal fibroblasts in vitro; pp. 446–451. (Proc. Natl. Acad. Sci. U.S.A.). [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Danielson P.E., Forss-Petter S., Brow M.A., Calavetta L., Douglass J., Milner R.J., Sutcliffe J.G. p1B15: a cDNA clone of the rat mRNA encoding cyclophilin. DNA. 1988;7:261–267. doi: 10.1089/dna.1988.7.261. [DOI] [PubMed] [Google Scholar]
  17. Fertsch D., Schoenberg D.R., Germain R.N., Tou J.Y.L., Vogel S.N. Induction of macrophage Ia antigen expression by rIFN-γ and down-regulation by IFN-α/β and dexamethasone are mediated by changes in steady-state levels of Ia mRNA. J. Immunol. 1987;139:244–249. [PubMed] [Google Scholar]
  18. Fertsch-Ruggio D., Schoenberg D.R., Vogel S.N. Induction of macrophage Ia antigen expression by rIFN-gamma and down regulation by IFN-alpha/beta and dexamethasone are regulated transcriptionally. J. Immunol. 1988;141:1582–1589. [PubMed] [Google Scholar]
  19. Fierz W., Endler B., Reske K., Wekerle H., Fontana A. Astrocytes as antigen presenting cells. I. Induction of Ia antigen expression on astrocytes by T cells via immune interferon and its effect on antigen presentation. J. Immunol. 1985;134:3785–3793. [PubMed] [Google Scholar]
  20. Fontana A., Kristensen F., Dubs R., Gemsa D., Weber E. Production of prostaglandin E and an interleukin-1-like factor by cultured astrocytes and C6 glioma cells. J. Immunol. 1982;129:2413–2419. [PubMed] [Google Scholar]
  21. Fontana A., Fierz W., Wekerle H. Astrocytes present myelin basic protein to encephalitogenic T-cell lines. Nature. 1984;307:273–276. doi: 10.1038/307273a0. [DOI] [PubMed] [Google Scholar]
  22. Frei K., Bodmer S., Schwerdel C., Fontana A. Astrocytes of the brain synthesize interleukin-3-like factors. J. Immunol. 1985;135:4044–4047. [PubMed] [Google Scholar]
  23. Frei K., Siepl C., Groscurth P., Bodmer S., Schwerdel C., Fontana A. Antigen presentation and tumor cytotoxicity by interferon-γ-treated microglial cells. Eur. J. Immunol. 1987;17:1271–1278. doi: 10.1002/eji.1830170909. [DOI] [PubMed] [Google Scholar]
  24. Frei K., Malipiero U.V., Leist T.P., Zinkernagel R.M., Schwab M.E., Fontana A. On the cellular source and function of interleukin-6 produced in the central nervous system in viral diseases. Eur. J. Immunol. 1989;19:689–694. doi: 10.1002/eji.1830190418. [DOI] [PubMed] [Google Scholar]
  25. Gaspari A.A., Jenkins M.K., Katz S. Class II MHC-bearing keratinocytes induce antigen-specific unresponsiveness in hapten-specific TH1 clones. J. Immunol. 1988;141:2216–2220. [PubMed] [Google Scholar]
  26. Giulian D., Baker T.J., Shih L., Lachman L.B. Interleukin-1 of the central nervous system is produced by ameboid microglia. J. Exp. Med. 1986;164:594–604. doi: 10.1084/jem.164.2.594. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Hammerling G.J., Mauve G., Goldberg E., McDevitt H.O. Tissue distribution of Ia antigens: Ia on spermatozoa, macrophages and epidermal cells. Immunogenetics. 1975;1:428–437. [Google Scholar]
  28. Hartung H.P., Heininger K., Toyka K.V. Primary rat astroglial cultures can generate leukotriene B4. J. Neuroimmunol. 1988;19:237–243. doi: 10.1016/0165-5728(88)90005-7. [DOI] [PubMed] [Google Scholar]
  29. Hertz L. Functional interactions between astrocytes and neurons. In: Fedoroff S., editor. Glial and Neuronal Cell Biology. Alan R. Liss; New York: 1981. pp. 45–58. [Google Scholar]
  30. Hickey W.F., Osborn J.P., Kirby W.M. Expression of Ia molecules by astrocytes during acute experimental allergic encephalomyelitis in the Lewis rat. Cell. Immunol. 1985;91:528–535. doi: 10.1016/0008-8749(85)90251-5. [DOI] [PubMed] [Google Scholar]
  31. Hofman F.M., VonHanwher R., Dinarello C., Mizel S., Hinton D., Merrill J.E. Immunoregulatory molecules and IL-2 receptors identified in multiple sclerosis brain. J. Immunol. 1986;136:3239–3245. [PubMed] [Google Scholar]
  32. Janzer R.C., Raff M.C. Astrocytes induce barrier blood-brain properties in endothelial cells. Nature. 1987;325:253–257. doi: 10.1038/325253a0. [DOI] [PubMed] [Google Scholar]
  33. Lieberman A.P., Pitha P.M., Shin H.S., Shin M.L. Vol. 86. 1989. Production of tumor necrosis factor and other cytokines by astrocytes stimulated with lipopolysaccharide or a neurotropic virus; pp. 6348–6352. (Proc. Natl. Acad. Sci. U.S.A.). [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Linthicum D.S., Frelinger J.A. Acute autoimmune encephalomyelitis in mice. II. Susceptibility is controlled by the combination of H-2 and histamine sensitization genes. J. Exp. Med. 1982;155:31–40. doi: 10.1084/jem.156.1.31. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Markmann J., Lo D., Naji A., Palmiter R.D., Brinster R.L., Heber-Katz E. Antigen presenting function of class II MHC expressing pancreatic beta cells. Nature. 1988;336:476–481. doi: 10.1038/336476a0. [DOI] [PubMed] [Google Scholar]
  36. Massa P.T., Dorries R., ter Meulen V. Viral particles induce Ia antigen expression on astrocytes. Nature. 1986;320:543–546. doi: 10.1038/320543a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Massa P.T., Brinkmann R., ter Meulen V. Inducibility of Ia antigen on astrocyte by murine coronavirus JHM is rat strain dependent. J. Exp. Med. 1987;166:259–264. doi: 10.1084/jem.166.1.259. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Massa P.T., ter Meulen V., Fontana A. Vol. 84. 1987. Hypersensitivity of Ia antigen on astrocytes correlates with strain-specific susceptibility to experimental autoimmune encephalomyelitis; pp. 4219–4223. (Proc. Natl. Acad. Sci. U.S.A.). [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Mathis D.J., Benoist C.O., Williams V.E., II, Kanter M.R., McDevitt H.O. The murine E-α immune response gene. Cell. 1983;32:745–754. doi: 10.1016/0092-8674(83)90060-0. [DOI] [PubMed] [Google Scholar]
  40. Matsumoto Y., Hara N., Tanaka R., Fujiwara M. Immunohistochemical analysis of the rat central nervous system during experimental allergic encephalomyelitis, with special reference to Ia-positive cells with dendritic morphology. J. Immunol. 1986;136:3668–3676. [PubMed] [Google Scholar]
  41. McCarron R.M., Kempsi O., Spatz M., McFarlin D.E. Presentation of myelin basic protein by murine cerebral vascular endothelial cells. J. Immunol. 1985;134:3100–3103. [PubMed] [Google Scholar]
  42. McCarthy K.D., de Vellis J. Preparation of separate astroglial and oligodendroglial cell cultures from rat cerebral tissues. J. Cell Biol. 1980;85:890–902. doi: 10.1083/jcb.85.3.890. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Rakic P. Neuron-glial relationship during granule cell migration in developing cerebellar cortex. A Golgi and electromicroscopic study in Maccacus rhesus. J. Comp. Neurol. 1971;141:238–312. doi: 10.1002/cne.901410303. [DOI] [PubMed] [Google Scholar]
  44. Robbins D.S., Shirazi Y., Drysdale B.E., Leiberman A., Shin H.S., Shin M.L. Production of cytotoxic factor for oligodendrocytes by stimulated astrocytes. J. Immunol. 1987;139:2593–2597. [PubMed] [Google Scholar]
  45. Rodriguez M., Pierce M.L., Howie E.A. Immune response gene products (Ia antigens) on glial and endothelial cells in virus-induced demyelination. J. Immunol. 1987;138:3438–3442. [PubMed] [Google Scholar]
  46. Rosa F.M., Fellous M. Regulation of HLA-DR gene by IFN-γ. Transcriptional and post-transcriptional control. J. Immunol. 1988;140:1660–1664. [PubMed] [Google Scholar]
  47. Sakai K., Tabira T., Endoh M., Steinman L. Ia expression in chronic relapsing experimental allergic encephalomyelitis induced by long-term cultured T cell lines in mice. Lab. Invest. 1986;54:345–352. [PubMed] [Google Scholar]
  48. Salter R.D., Alexander J., Levine F., Pious D., Cresswell P. Evidence for two trans-acting genes regulating HLA class II antigen expression. J. Immunol. 1985;135:4235–4238. [PubMed] [Google Scholar]
  49. Sawada M., Kondo N., Suzumura A., Marunouchi T. Production of tumor necrosis factor-alpha by microglia and astrocytes in culture. Brain Res. 1989;491:394–397. doi: 10.1016/0006-8993(89)90078-4. [DOI] [PubMed] [Google Scholar]
  50. Sherman P.A., Basta P.V., Ting J.P.Y. Vol. 84. 1987. Upstream DNA sequences required for tissue-specific expression of the HLA-DRα gene; pp. 4254–4258. (Proc. Natl. Acad. Sci. U.S.A.). [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Sherman P.A., Basta P.V., Moore T.L., Brown A.M., Ting J.P.Y. Class II box consensus sequences in the HLA-DRα gene: transcriptional function and interaction with nuclear proteins. Mol. Cell. Biol. 1989;9:50–56. doi: 10.1128/mcb.9.1.50. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Silver J., Sapiro J. Axonal guidance during development of the optic nerve: the role of pigmented epithelia and other intrinsic factors. J. Comp. Neurol. 1981;202:521–538. doi: 10.1002/cne.902020406. [DOI] [PubMed] [Google Scholar]
  53. Sun D., Wekerle H. Ia-restricted encephalitogenic T lymphocytes mediating EAE lyse autoantigen-presenting astrocytes. Nature. 1986;320:70–73. doi: 10.1038/320070a0. [DOI] [PubMed] [Google Scholar]
  54. Tedeschi B., Barrett J.N., Keane R.W. Astrocytes produce interferon that enhances the expression of H-2 antigens on a subpopulation of brain cells. J. Cell Biol. 1986;102:2244–2253. doi: 10.1083/jcb.102.6.2244. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Traugott U., Lebon P. Interferon-γ and Ia antigen are present on astrocytes in active chronic multiple sclerosis lesions. J. Neurol. Sci. 1988;84:257–264. doi: 10.1016/0022-510x(88)90130-x. [DOI] [PubMed] [Google Scholar]
  56. Traugott U., Scheinberg L.C., Raine C.S. On the presence of Ia-positive endothelial cells and astrocytes in multiple sclerosis lesions and its relevance to antigen presentation. J. Neuroimmunol. 1985;8:1–13. doi: 10.1016/s0165-5728(85)80043-6. [DOI] [PubMed] [Google Scholar]
  57. Vass K., Lassmann H., Wekerle H., Wisniewski H.M. The distribution of Ia antigen in the lesions of rat acute experimental allergic encephalomyelitis. Acta Neuropathol. 1986;70:149–160. doi: 10.1007/BF00691433. [DOI] [PubMed] [Google Scholar]
  58. Wong G.H.W., Bartlett P.F., Clark-Lewis I., Battye F., Schader J.W. Inducible expression of H-2 and Ia antigens on brain cells. Nature. 1984;310:688–691. doi: 10.1038/310688a0. [DOI] [PubMed] [Google Scholar]
  59. Woodward J.G., Omer K.W., Stuart P.M. MHC class II transcription in different mouse cell types: differential requirement for protein synthesis between B cells and macrophages. J. Immunol. 1989;142:4062–4069. [PubMed] [Google Scholar]

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