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. 1997 Feb;150(2):617–630.

Synchronous synthesis of alpha- and beta-chemokines by cells of diverse lineage in the central nervous system of mice with relapses of chronic experimental autoimmune encephalomyelitis.

A R Glabinski 1, M Tani 1, R M Strieter 1, V K Tuohy 1, R M Ransohoff 1
PMCID: PMC1858292  PMID: 9033275

Abstract

Chemokines are secreted peptides that exhibit selective chemoattractant properties for target leukocytes. Two subfamilies, alpha- and beta-chemokines, have been described, based on structural, genetic, and functional considerations. In acute experimental autoimmune encephalomyelitis (EAE), chemokines are up-regulated systemically and in central nervous system (CNS) tissues at disease onset. Functional significance of this expression was supported by other studies; intervention with an antichemokine antibody abrogated passive transfer of EAE, and chemokines expressed in brains of transgenic mice recruited appropriate leukocyte populations into the CNS compartment. Chemokine expression in the more relevant circumstance of chronic EAE has not been addressed. We monitored the time course and cellular sources of chemokines (monocyte chemoattractant protein-1, macrophage inflammatory protein-1 alpha, interferon-gamma-inducible protein of 10 kd, KC, and regulated on activation, normal T-cell expressed and secreted cytokine) in CNS and peripheral tissues during spontaneous relapses of chronic EAE. We found coordinate chemokine up-regulation in brain and spinal cord during clinical relapse, with expression confined to CNS tissues. Monocyte chemoattractant protein-1, interferon-gamma-inducible protein of 10 kd, and KC were synthesized by astrocytic cells, whereas macrophage inflammatory protein-1 alpha and regulated on activation, normal T-cell expressed and secreted cytokine were elaborated by infiltrating leukocytes. The results demonstrate stringent regulation of multiple chemokines in vivo during a complex organ-specific autoimmune disease. We propose that chemokine expression links T-cell antigen recognition and activation to subsequent CNS inflammatory pathology in chronic relapsing EAE.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bacon K. B., Premack B. A., Gardner P., Schall T. J. Activation of dual T cell signaling pathways by the chemokine RANTES. Science. 1995 Sep 22;269(5231):1727–1730. doi: 10.1126/science.7569902. [DOI] [PubMed] [Google Scholar]
  2. Baggiolini M., Dewald B., Moser B. Interleukin-8 and related chemotactic cytokines--CXC and CC chemokines. Adv Immunol. 1994;55:97–179. [PubMed] [Google Scholar]
  3. Baggiolini M., Walz A., Kunkel S. L. Neutrophil-activating peptide-1/interleukin 8, a novel cytokine that activates neutrophils. J Clin Invest. 1989 Oct;84(4):1045–1049. doi: 10.1172/JCI114265. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Baron J. L., Madri J. A., Ruddle N. H., Hashim G., Janeway C. A., Jr Surface expression of alpha 4 integrin by CD4 T cells is required for their entry into brain parenchyma. J Exp Med. 1993 Jan 1;177(1):57–68. doi: 10.1084/jem.177.1.57. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Ben-Baruch A., Michiel D. F., Oppenheim J. J. Signals and receptors involved in recruitment of inflammatory cells. J Biol Chem. 1995 May 19;270(20):11703–11706. doi: 10.1074/jbc.270.20.11703. [DOI] [PubMed] [Google Scholar]
  6. Berman J. W., Guida M. P., Warren J., Amat J., Brosnan C. F. Localization of monocyte chemoattractant peptide-1 expression in the central nervous system in experimental autoimmune encephalomyelitis and trauma in the rat. J Immunol. 1996 Apr 15;156(8):3017–3023. [PubMed] [Google Scholar]
  7. Brocke S., Gijbels K., Allegretta M., Ferber I., Piercy C., Blankenstein T., Martin R., Utz U., Karin N., Mitchell D. Treatment of experimental encephalomyelitis with a peptide analogue of myelin basic protein. Nature. 1996 Jan 25;379(6563):343–346. doi: 10.1038/379343a0. [DOI] [PubMed] [Google Scholar]
  8. Butcher E. C., Picker L. J. Lymphocyte homing and homeostasis. Science. 1996 Apr 5;272(5258):60–66. doi: 10.1126/science.272.5258.60. [DOI] [PubMed] [Google Scholar]
  9. Cochran B. H., Reffel A. C., Stiles C. D. Molecular cloning of gene sequences regulated by platelet-derived growth factor. Cell. 1983 Jul;33(3):939–947. doi: 10.1016/0092-8674(83)90037-5. [DOI] [PubMed] [Google Scholar]
  10. Cook D. N., Beck M. A., Coffman T. M., Kirby S. L., Sheridan J. F., Pragnell I. B., Smithies O. Requirement of MIP-1 alpha for an inflammatory response to viral infection. Science. 1995 Sep 15;269(5230):1583–1585. doi: 10.1126/science.7667639. [DOI] [PubMed] [Google Scholar]
  11. Davatelis G., Tekamp-Olson P., Wolpe S. D., Hermsen K., Luedke C., Gallegos C., Coit D., Merryweather J., Cerami A. Cloning and characterization of a cDNA for murine macrophage inflammatory protein (MIP), a novel monokine with inflammatory and chemokinetic properties. J Exp Med. 1988 Jun 1;167(6):1939–1944. doi: 10.1084/jem.167.6.1939. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Driscoll K. E. Macrophage inflammatory proteins: biology and role in pulmonary inflammation. Exp Lung Res. 1994 Nov-Dec;20(6):473–490. doi: 10.3109/01902149409031733. [DOI] [PubMed] [Google Scholar]
  13. Farber J. M. HuMig: a new human member of the chemokine family of cytokines. Biochem Biophys Res Commun. 1993 Apr 15;192(1):223–230. doi: 10.1006/bbrc.1993.1403. [DOI] [PubMed] [Google Scholar]
  14. Fuentes M. E., Durham S. K., Swerdel M. R., Lewin A. C., Barton D. S., Megill J. R., Bravo R., Lira S. A. Controlled recruitment of monocytes and macrophages to specific organs through transgenic expression of monocyte chemoattractant protein-1. J Immunol. 1995 Dec 15;155(12):5769–5776. [PubMed] [Google Scholar]
  15. Furie M. B., Randolph G. J. Chemokines and tissue injury. Am J Pathol. 1995 Jun;146(6):1287–1301. [PMC free article] [PubMed] [Google Scholar]
  16. Gautam S., Battisto J., Major J. A., Armstrong D., Stoler M., Hamilton T. A. Chemokine expression in trinitrochlorobenzene-mediated contact hypersensitivity. J Leukoc Biol. 1994 Apr;55(4):452–460. doi: 10.1002/jlb.55.4.452. [DOI] [PubMed] [Google Scholar]
  17. Glabinski A. R., Balasingam V., Tani M., Kunkel S. L., Strieter R. M., Yong V. W., Ransohoff R. M. Chemokine monocyte chemoattractant protein-1 is expressed by astrocytes after mechanical injury to the brain. J Immunol. 1996 Jun 1;156(11):4363–4368. [PubMed] [Google Scholar]
  18. Glabinski A. R., Tani M., Aras S., Stoler M. H., Tuohy V. K., Ransohoff R. M. Regulation and function of central nervous system chemokines. Int J Dev Neurosci. 1995 Jun-Jul;13(3-4):153–165. doi: 10.1016/0736-5748(95)00017-b. [DOI] [PubMed] [Google Scholar]
  19. Glabinski A. R., Tani M., Tuohy V. K., Tuthill R. J., Ransohoff R. M. Central nervous system chemokine mRNA accumulation follows initial leukocyte entry at the onset of acute murine experimental autoimmune encephalomyelitis. Brain Behav Immun. 1995 Dec;9(4):315–330. doi: 10.1006/brbi.1995.1030. [DOI] [PubMed] [Google Scholar]
  20. Godiska R., Chantry D., Dietsch G. N., Gray P. W. Chemokine expression in murine experimental allergic encephalomyelitis. J Neuroimmunol. 1995 May;58(2):167–176. doi: 10.1016/0165-5728(95)00008-p. [DOI] [PubMed] [Google Scholar]
  21. Gómez-Chiarri M., Ortíz A., Serón D., Gonzalez E., Egido J. The intercrine superfamily and renal disease. Kidney Int Suppl. 1993 Jan;39:S81–S85. [PubMed] [Google Scholar]
  22. Hayashi M., Luo Y., Laning J., Strieter R. M., Dorf M. E. Production and function of monocyte chemoattractant protein-1 and other beta-chemokines in murine glial cells. J Neuroimmunol. 1995 Jul;60(1-2):143–150. doi: 10.1016/0165-5728(95)00064-9. [DOI] [PubMed] [Google Scholar]
  23. Heeger P., Wolf G., Meyers C., Sun M. J., O'Farrell S. C., Krensky A. M., Neilson E. G. Isolation and characterization of cDNA from renal tubular epithelium encoding murine Rantes. Kidney Int. 1992 Jan;41(1):220–225. doi: 10.1038/ki.1992.31. [DOI] [PubMed] [Google Scholar]
  24. Hulkower K., Brosnan C. F., Aquino D. A., Cammer W., Kulshrestha S., Guida M. P., Rapoport D. A., Berman J. W. Expression of CSF-1, c-fms, and MCP-1 in the central nervous system of rats with experimental allergic encephalomyelitis. J Immunol. 1993 Mar 15;150(6):2525–2533. [PubMed] [Google Scholar]
  25. Kaplan A. P., Kuna P., Reddigari S. R. Chemokines and the allergic response. Exp Dermatol. 1995 Aug;4(4 Pt 2):260–265. doi: 10.1111/j.1600-0625.1995.tb00255.x. [DOI] [PubMed] [Google Scholar]
  26. Karpus W. J., Lukacs N. W., McRae B. L., Strieter R. M., Kunkel S. L., Miller S. D. An important role for the chemokine macrophage inflammatory protein-1 alpha in the pathogenesis of the T cell-mediated autoimmune disease, experimental autoimmune encephalomyelitis. J Immunol. 1995 Nov 15;155(10):5003–5010. [PubMed] [Google Scholar]
  27. Karpus W. J., Lukacs N. W. The role of chemokines in oral tolerance. Abrogation of nonresponsiveness by treatment with antimonocyte chemotactic protein-1. Ann N Y Acad Sci. 1996 Feb 13;778:133–144. doi: 10.1111/j.1749-6632.1996.tb21122.x. [DOI] [PubMed] [Google Scholar]
  28. Kelner G. S., Kennedy J., Bacon K. B., Kleyensteuber S., Largaespada D. A., Jenkins N. A., Copeland N. G., Bazan J. F., Moore K. W., Schall T. J. Lymphotactin: a cytokine that represents a new class of chemokine. Science. 1994 Nov 25;266(5189):1395–1399. doi: 10.1126/science.7973732. [DOI] [PubMed] [Google Scholar]
  29. Kim J. S., Gautam S. C., Chopp M., Zaloga C., Jones M. L., Ward P. A., Welch K. M. Expression of monocyte chemoattractant protein-1 and macrophage inflammatory protein-1 after focal cerebral ischemia in the rat. J Neuroimmunol. 1995 Feb;56(2):127–134. doi: 10.1016/0165-5728(94)00138-e. [DOI] [PubMed] [Google Scholar]
  30. Kuchroo V. K., Martin C. A., Greer J. M., Ju S. T., Sobel R. A., Dorf M. E. Cytokines and adhesion molecules contribute to the ability of myelin proteolipid protein-specific T cell clones to mediate experimental allergic encephalomyelitis. J Immunol. 1993 Oct 15;151(8):4371–4382. [PubMed] [Google Scholar]
  31. Kunkel S. L., Strieter R. M., Lindley I. J., Westwick J. Chemokines: new ligands, receptors and activities. Immunol Today. 1995 Dec;16(12):559–561. doi: 10.1016/0167-5699(95)80076-X. [DOI] [PubMed] [Google Scholar]
  32. Liles W. C., Van Voorhis W. C. Review: nomenclature and biologic significance of cytokines involved in inflammation and the host immune response. J Infect Dis. 1995 Dec;172(6):1573–1580. doi: 10.1093/infdis/172.6.1573. [DOI] [PubMed] [Google Scholar]
  33. Lira S. A., Zalamea P., Heinrich J. N., Fuentes M. E., Carrasco D., Lewin A. C., Barton D. S., Durham S., Bravo R. Expression of the chemokine N51/KC in the thymus and epidermis of transgenic mice results in marked infiltration of a single class of inflammatory cells. J Exp Med. 1994 Dec 1;180(6):2039–2048. doi: 10.1084/jem.180.6.2039. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Luster A. D., Unkeless J. C., Ravetch J. V. Gamma-interferon transcriptionally regulates an early-response gene containing homology to platelet proteins. Nature. 1985 Jun 20;315(6021):672–676. doi: 10.1038/315672a0. [DOI] [PubMed] [Google Scholar]
  35. Narumi S., Wyner L. M., Stoler M. H., Tannenbaum C. S., Hamilton T. A. Tissue-specific expression of murine IP-10 mRNA following systemic treatment with interferon gamma. J Leukoc Biol. 1992 Jul;52(1):27–33. doi: 10.1002/jlb.52.1.27. [DOI] [PubMed] [Google Scholar]
  36. Ohmori Y., Wyner L., Narumi S., Armstrong D., Stoler M., Hamilton T. A. Tumor necrosis factor-alpha induces cell type and tissue-specific expression of chemoattractant cytokines in vivo. Am J Pathol. 1993 Mar;142(3):861–870. [PMC free article] [PubMed] [Google Scholar]
  37. Oppenheim J. J., Zachariae C. O., Mukaida N., Matsushima K. Properties of the novel proinflammatory supergene "intercrine" cytokine family. Annu Rev Immunol. 1991;9:617–648. doi: 10.1146/annurev.iy.09.040191.003153. [DOI] [PubMed] [Google Scholar]
  38. Oquendo P., Alberta J., Wen D. Z., Graycar J. L., Derynck R., Stiles C. D. The platelet-derived growth factor-inducible KC gene encodes a secretory protein related to platelet alpha-granule proteins. J Biol Chem. 1989 Mar 5;264(7):4133–4137. [PubMed] [Google Scholar]
  40. Prieschl E. E., Kulmburg P. A., Baumruker T. The nomenclature of chemokines. Int Arch Allergy Immunol. 1995 Aug;107(4):475–483. doi: 10.1159/000237089. [DOI] [PubMed] [Google Scholar]
  41. Ransohoff R. M., Glabinski A., Tani M. Chemokines in immune-mediated inflammation of the central nervous system. Cytokine Growth Factor Rev. 1996 Jun;7(1):35–46. doi: 10.1016/1359-6101(96)00003-2. [DOI] [PubMed] [Google Scholar]
  42. Ransohoff R. M., Hamilton T. A., Tani M., Stoler M. H., Shick H. E., Major J. A., Estes M. L., Thomas D. M., Tuohy V. K. Astrocyte expression of mRNA encoding cytokines IP-10 and JE/MCP-1 in experimental autoimmune encephalomyelitis. FASEB J. 1993 Apr 1;7(6):592–600. doi: 10.1096/fasebj.7.6.8472896. [DOI] [PubMed] [Google Scholar]
  43. Rollins B. J. JE/MCP-1: an early-response gene encodes a monocyte-specific cytokine. Cancer Cells. 1991 Dec;3(12):517–524. [PubMed] [Google Scholar]
  44. Rutledge B. J., Rayburn H., Rosenberg R., North R. J., Gladue R. P., Corless C. L., Rollins B. J. High level monocyte chemoattractant protein-1 expression in transgenic mice increases their susceptibility to intracellular pathogens. J Immunol. 1995 Nov 15;155(10):4838–4843. [PubMed] [Google Scholar]
  45. Schall T. J., Bacon K. B. Chemokines, leukocyte trafficking, and inflammation. Curr Opin Immunol. 1994 Dec;6(6):865–873. doi: 10.1016/0952-7915(94)90006-x. [DOI] [PubMed] [Google Scholar]
  46. Schall T. J., Jongstra J., Dyer B. J., Jorgensen J., Clayberger C., Davis M. M., Krensky A. M. A human T cell-specific molecule is a member of a new gene family. J Immunol. 1988 Aug 1;141(3):1018–1025. [PubMed] [Google Scholar]
  47. Seebach J., Bartholdi D., Frei K., Spanaus K. S., Ferrero E., Widmer U., Isenmann S., Strieter R. M., Schwab M., Pfister H. Experimental Listeria meningoencephalitis. Macrophage inflammatory protein-1 alpha and -2 are produced intrathecally and mediate chemotactic activity in cerebrospinal fluid of infected mice. J Immunol. 1995 Nov 1;155(9):4367–4375. [PubMed] [Google Scholar]
  48. Smith R. E., Strieter R. M., Zhang K., Phan S. H., Standiford T. J., Lukacs N. W., Kunkel S. L. A role for C-C chemokines in fibrotic lung disease. J Leukoc Biol. 1995 May;57(5):782–787. doi: 10.1002/jlb.57.5.782. [DOI] [PubMed] [Google Scholar]
  49. Strieter R. M., Koch A. E., Antony V. B., Fick R. B., Jr, Standiford T. J., Kunkel S. L. The immunopathology of chemotactic cytokines: the role of interleukin-8 and monocyte chemoattractant protein-1. J Lab Clin Med. 1994 Feb;123(2):183–197. [PubMed] [Google Scholar]
  50. Strieter R. M., Kunkel S. L. Acute lung injury: the role of cytokines in the elicitation of neutrophils. J Investig Med. 1994 Dec;42(4):640–651. [PubMed] [Google Scholar]
  51. Strieter R. M., Kunkel S. L., Arenberg D. A., Burdick M. D., Polverini P. J. Interferon gamma-inducible protein 10 (IP-10), a member of the C-X-C chemokine family, is an inhibitor of angiogenesis. Biochem Biophys Res Commun. 1995 May 5;210(1):51–57. doi: 10.1006/bbrc.1995.1626. [DOI] [PubMed] [Google Scholar]
  52. Strieter R. M., Kunkel S. L., Burdick M. D., Lincoln P. M., Walz A. The detection of a novel neutrophil-activating peptide (ENA-78) using a sensitive ELISA. Immunol Invest. 1992 Oct;21(6):589–596. doi: 10.3109/08820139209069393. [DOI] [PubMed] [Google Scholar]
  53. Swanborg R. H. Experimental autoimmune encephalomyelitis in rodents as a model for human demyelinating disease. Clin Immunol Immunopathol. 1995 Oct;77(1):4–13. doi: 10.1016/0090-1229(95)90130-2. [DOI] [PubMed] [Google Scholar]
  54. Tani M., Fuentes M. E., Peterson J. W., Trapp B. D., Durham S. K., Loy J. K., Bravo R., Ransohoff R. M., Lira S. A. Neutrophil infiltration, glial reaction, and neurological disease in transgenic mice expressing the chemokine N51/KC in oligodendrocytes. J Clin Invest. 1996 Jul 15;98(2):529–539. doi: 10.1172/JCI118821. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Tani M., Glabinski A. R., Tuohy V. K., Stoler M. H., Estes M. L., Ransohoff R. M. In situ hybridization analysis of glial fibrillary acidic protein mRNA reveals evidence of biphasic astrocyte activation during acute experimental autoimmune encephalomyelitis. Am J Pathol. 1996 Mar;148(3):889–896. [PMC free article] [PubMed] [Google Scholar]
  56. Tani M., Ransohoff R. M. Do chemokines mediate inflammatory cell invasion of the central nervous system parenchyma? Brain Pathol. 1994 Apr;4(2):135–143. doi: 10.1111/j.1750-3639.1994.tb00824.x. [DOI] [PubMed] [Google Scholar]
  57. Taub D. D., Conlon K., Lloyd A. R., Oppenheim J. J., Kelvin D. J. Preferential migration of activated CD4+ and CD8+ T cells in response to MIP-1 alpha and MIP-1 beta. Science. 1993 Apr 16;260(5106):355–358. doi: 10.1126/science.7682337. [DOI] [PubMed] [Google Scholar]
  58. Taub D. D., Oppenheim J. J. Chemokines, inflammation and the immune system. Ther Immunol. 1994 Aug;1(4):229–246. [PubMed] [Google Scholar]
  59. Vanguri P. Interferon-gamma-inducible genes in primary glial cells of the central nervous system: comparisons of astrocytes with microglia and Lewis with brown Norway rats. J Neuroimmunol. 1995 Jan;56(1):35–43. doi: 10.1016/0165-5728(94)00131-7. [DOI] [PubMed] [Google Scholar]
  60. Wilson S. D., Kuchroo V. K., Israel D. I., Dorf M. E. Expression and characterization of TCA3: a murine inflammatory protein. J Immunol. 1990 Oct 15;145(8):2745–2750. [PubMed] [Google Scholar]
  61. Wu X., Dolecki G. J., Lefkowith J. B. GRO chemokines: a transduction, integration, and amplification mechanism in acute renal inflammation. Am J Physiol. 1995 Aug;269(2 Pt 2):F248–F256. doi: 10.1152/ajprenal.1995.269.2.F248. [DOI] [PubMed] [Google Scholar]
  62. Yednock T. A., Cannon C., Fritz L. C., Sanchez-Madrid F., Steinman L., Karin N. Prevention of experimental autoimmune encephalomyelitis by antibodies against alpha 4 beta 1 integrin. Nature. 1992 Mar 5;356(6364):63–66. doi: 10.1038/356063a0. [DOI] [PubMed] [Google Scholar]
  63. Yoshida T., Imai T., Kakizaki M., Nishimura M., Yoshie O. Molecular cloning of a novel C or gamma type chemokine, SCM-1. FEBS Lett. 1995 Feb 27;360(2):155–159. doi: 10.1016/0014-5793(95)00093-o. [DOI] [PubMed] [Google Scholar]
  64. Yoshimura T., Robinson E. A., Tanaka S., Appella E., Kuratsu J., Leonard E. J. Purification and amino acid analysis of two human glioma-derived monocyte chemoattractants. J Exp Med. 1989 Apr 1;169(4):1449–1459. doi: 10.1084/jem.169.4.1449. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Yoshimura T., Robinson E. A., Tanaka S., Appella E., Leonard E. J. Purification and amino acid analysis of two human monocyte chemoattractants produced by phytohemagglutinin-stimulated human blood mononuclear leukocytes. J Immunol. 1989 Mar 15;142(6):1956–1962. [PubMed] [Google Scholar]
  66. Yu M., Johnson J. M., Tuohy V. K. A predictable sequential determinant spreading cascade invariably accompanies progression of experimental autoimmune encephalomyelitis: a basis for peptide-specific therapy after onset of clinical disease. J Exp Med. 1996 Apr 1;183(4):1777–1788. doi: 10.1084/jem.183.4.1777. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Yu M., Nishiyama A., Trapp B. D., Tuohy V. K. Interferon-beta inhibits progression of relapsing-remitting experimental autoimmune encephalomyelitis. J Neuroimmunol. 1996 Jan;64(1):91–100. doi: 10.1016/0165-5728(95)00160-3. [DOI] [PubMed] [Google Scholar]

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