The Role of Substance P in Cytokine Production by Glial Cells

  • Jean E. Merrill
  • Andrew C. Charles
  • Fredricka C. Martin
Part of the Altschul Symposia Series book series (ALSS, volume 2)


Substance P (SP), a neuropeptide released by peripheral sensory neurons, plays an important role in pain perception and acute inflammation (Sandberg and Iverson, 1982). It is also involved in peripheral autoimmune inflammatory diseases, most clearly with experimental adjuvant arthritis. Rats with adjuvant arthritis develop increased levels of SP in nerves innervating the arthritic joints, and depleting these animals of SP with capsaicin ameliorates the arthritis (Colpaert et al., 1983). Conversely, adding exogenous SP to the joint makes the arthritis more severe (Levine et al., 1984). Acute injury stimulates the release of SP (up to 2.8×10−15M into lymph) within 5–10 minutes (Jonsson et al., 1986). SP levels in blister fluid from infections, eczema, and bullous pemphigoid can be 3×10−11M (Wallengren et al., 1986), while SP in acute inflammatory exudates can be as much as 2×10−9M (Tissot et al., 1988), indicating high levels of SP secretion under these conditions. Inflammatory bowel disease tissue has a 1000-fold increase in SP receptors and is another instance where SP may be contributing to chronic inflammation (Mantyh et al., 1988).


Bullous Pemphigoid Calcium Ionophore A23187 Postcapillary Venule Tachykinin Receptor Rheumatoid Synoviocytes 


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  1. Adams, C.W.M., Abdulla, Y.H., Tomes, E.M., and Poston, R.N., 1987, Periventricular lesions in multiple sclerosis: their perivenous origin and relationship to granular ependymitis, Neuropath. Appl. Neurobiol. 13: 141.CrossRefGoogle Scholar
  2. Aggarwal, B.B., Kohr, W.J., Hass, P.E., Moffat, B., Spencer, S.A., Henzel, W.J., Bringman, T.S., Nedwin, G.E., Goeddel, D.V. and Harkins, R.N., 1985, Human tumor necrosis factor: production, purification, and characterization, J. Biol. Chem. 260: 2345.PubMedGoogle Scholar
  3. Bailey, S.J., Featherstone, R.L., Jordan, C.C. and Morton, I.K.M., 1986, An examination of the pharmacology of two substance P antagonists and the evidence for tachykinin receptor subtypes, Brit. J. Pharmacol. 87: 79.CrossRefGoogle Scholar
  4. Bar-Shavit, Z., Goldman. R., Stabinski, Y., Gottlieb, P., Fridkin, M., Teichberg, V.I., and Blumberg, S., 1980, Enhancement of phagocytosis - a newly found activity of substance P residing in its N-terminal tetrapeptide sequence, J. Immunol. 130: 89.Google Scholar
  5. Beaujouan, J.C., Torrens, Y., Saffroy, M., and Glowinski, J., 1986, Quantitative autoradiographic analysis of the distribution of binding sites for 125E Bolton Hunter derivatives of eledoisin and substance P in the rat brain, Neurosci. 18: 857.CrossRefGoogle Scholar
  6. Brandwein, S.R., 1986, Regulation of interleukin-1 production by mouse peritoneal macrophages. Effects of arachidonic acid metabolites, cyclic nucleotides, and interferon, J. Biol. Chem. 261: 8624.PubMedGoogle Scholar
  7. Broman, T., 1964, Blood-brain barrier damage in multiple sclerosis supravital test observations, Acta Neurol. Scand. 40 (Suppl. 10): 21.CrossRefGoogle Scholar
  8. Buck, S.H., Maurin, Y., Burks, T.F., and Yamamura, H.I., 1984, High-affinity 3H-substance P binding to longitudinal muscle membranes of the guinea pig small intestine, Life Sci. 34: 497.PubMedCrossRefGoogle Scholar
  9. Burcher, E., and Buck, S.H., 1986, Multiple tachykinin binding sites in hamster, rat, and guinea pig urinary bladder, Eur. J. Pharmacol. 128: 165.PubMedCrossRefGoogle Scholar
  10. Bynke, G., Hakanson, R., Horig, J., and Leander, S., 1983, Bradykinin contracts the pupillary sphincter and evokes ocular inflammation through release of neuronal substance P, Eur. J. Pharmacol. 91: 469.PubMedCrossRefGoogle Scholar
  11. Carpenter, M.B., 1969, “Human Neuroanatomy,” The Williams and Wilkins Company, Baltimore.Google Scholar
  12. Cavender, D., Haskard, D., Yu, C-L., Iguchi, T., Miossec, P., Oppenheimer-Marks, N., and Ziff, M., 1987, Pathways to chronic inflammation in rheumatoid synovitis, FASEB J. 46: 113.Google Scholar
  13. Charles, A.C., Merrill, J.E., Dirksen, E.R., and Sanderson, M.J., 1991, Intercellular signaling in glial cells: calcium waves and oscillations in response to mechanical stimulation and gluatamate, Neuron 6: 983.PubMedCrossRefGoogle Scholar
  14. Charles, A.C., Dirksen, E.R., Merrill, J.E., and Sanderson, M.J., Mechanisms of intercellular calcium signaling in glial cells studied with dantrolene and thapsigargin, Glia, in press.Google Scholar
  15. Colpaert, F.C., Donnerer,.J, and Lembeck, F., 1983, Effects of capsaicin on inflammation and on the substance P content of nervous tissue in rats with adjuvant arthritis, Life Sci. 32: 1827.Google Scholar
  16. Conlon, P.J., 1983, A rapid biologic assay for the detection of interleukin 1, J. Immunology 131: 1280.Google Scholar
  17. Conrad, G.W., and Rink, T.J., 1986, Platelet activating factor raises intracellular calcium ion concentration in macrophages, J. Cell Biol. 103: 439.PubMedCrossRefGoogle Scholar
  18. Dinarello, C.A. and Savage, N., 1989, Interleukin-1 and its receptor, Crit. Rev. Immunol. 9: 1.PubMedGoogle Scholar
  19. Edvinsson, L., McCulloch, J. and Uddman, R., 1982, Feline cerebral veins and arteries: comparison of autonomic innervation and vasomotor responses, J. Physiol. 325: 161.PubMedGoogle Scholar
  20. Edvinsson, L., Cervos-Navarro, J., Larsson, L-I., Owman, C.H., and Ronnberg A-L., 1977, Regional distribution of mast cells containing histamine, dopamine, or 5-hydroxytryptamine in the mammalian brain, Neurol. 27: 878.CrossRefGoogle Scholar
  21. Fog, T., 1965, The topography of plaques in multiple sclerosis, Acta Neurol. Scand. 41 (Suppl. 15): 3.Google Scholar
  22. Frank, E., Pulver, M., and de Tribolet, N., 1986, Expression of class II major histocompatibility antigens on reactive astrocytes and endothelial cells within the gliosis surrounding metastases and abscesses, J. Neuroimmunol. 12: 29.PubMedCrossRefGoogle Scholar
  23. Freemont AJ, and Ford WL: Functional and morphological changes in post capillary ventiles in relation to lymphocytic infiltration into BCG-induced granulomata in rat skin, J. Pathol. 147: 1.Google Scholar
  24. Graeber, M.B., Streit, W.J., Kiefer, R., Schoen, S.W., and Kreutzeberg, G.W., 1990, New expression of myelomonocytic antigens by microglia and perivascular cells following lethal motor neuron injury. J. Neuroimmunol. 27: 121.PubMedCrossRefGoogle Scholar
  25. Hartung, H.-P., Heininger, K., Schafer, B., and Toyka, K.V., 1988, Substance P and astrocytes: stimulation of the cyclooxygenase pathway of arachidonic acid metabolism, FASEB J. 2: 48.PubMedGoogle Scholar
  26. Hartung, H.-P., Wolters, K. and Toyka, K.V., 1986, Substance P: Binding properties and studies on cellular responses in guinea pig macrophages, J. Immunl. 136: 3856.Google Scholar
  27. Hashimoto, M., Ishikawa, Y., Yokota, S., Goto, F., Bando, T., Sakakibara, Y., and Iriki, M., 1991, Action site of circulating Interleukin-1 on the rabbit brain. Brain Res. 540: 217.PubMedCrossRefGoogle Scholar
  28. Hofman, F.M., von Hanwehr, R.I., Dinarello, C.A., Mizel, S.B., Hinton, D., and Merrill, J.E., 1986, Immunoregulatory molecules and IL2 receptors identified in multiple sclerosis brain, J. Immunol. 136: 3239.PubMedGoogle Scholar
  29. Itakura, T., Okuno, T., Nakakita, K., Kamei, I., Naka, Y., Nakai, K., Imai, H., Komai, N., Kimura, H., and Maeda, T., 1984, A light and electron microsopic immunohistochemical study of vasoactive intestinal polypeptide-and substance P-containing nerve fibers along the cerebral blood vessels: comparison with aminergic and cholinergic fibers, J. Cereb. Blood Flow Metabol. 4: 407.CrossRefGoogle Scholar
  30. Jonsson, C-E., Brodin, E., Dalsgaard, C-J., and Haegerstrand, A. 1986, Release of substance-P-like immunoreactivity in dog paw lymph after scalding injury, Acta Physiol. Scand., 126: 21.PubMedCrossRefGoogle Scholar
  31. Kimball, E.S., Persico, F.J. and Vaught, J.L., 1988, Substance P, neurokinin A, and neurokinin B induce generation of IL-1-like activity in P388D1 Cells, J. Immunol. 141: 3564.PubMedGoogle Scholar
  32. Kostyk, S.K., Kowall, N.W., and Hauser, S.L., 1989, Substance P immunoreactive astrocytes are present in multiple sclerosis plaques, Brain Res. 504: 284.PubMedCrossRefGoogle Scholar
  33. Larsen, P.J., Mikkelsen, J.D., and Saermak, T., 1989, Binding of an iodinated substance P analog to an NK1 receptor on isolated cell membranes from rat anterior pituitary. Endocrinol. 124: 2548CrossRefGoogle Scholar
  34. Laurenzi, M.A., Persson, M.A.A., Dalsgaard, C.-J. and Haegerstrand, A., 1990, The neuropeptide substance P stimulates production of interleukin 1 in human blood monocytes: activated cells are preferentially influenced by the neuropeptide, Scand. J. Immunol. 31: 529.PubMedCrossRefGoogle Scholar
  35. Lechleiter, J., Hellmiss, R., Duerson, K., Ennulat, D., David, N., Clapham, D., and Peralta, E., 1990, Distinct sequence elements control the specificity of G protein activation by muscarinic acetylcholine receptor subtypes, EMBO J. 9: 4381.PubMedGoogle Scholar
  36. Lemaire, I., 1988, Neurotensin enhances ILA production by activated alveolar macrophages, J. Immunol. 140: 2983.PubMedGoogle Scholar
  37. Levine, J.D., Clark, R., Devor, M., Helms, C., Moskowitz, M.A., and Basbaum, A., 1984, Intraneuronal substance P contributes to the severity of experimental arthritis, Science 226: 547.PubMedCrossRefGoogle Scholar
  38. Lieberman, A.P., Pitha, P.M., Shin, H.S., and Shin, M.L. 1989, Production of tumor necrosis factor and other cytokines by astrocytes stimulated with lipopolysaccharide or a neurotropic virus, Proc. Natl. Acad. Sci. USA 86: 6348.PubMedCrossRefGoogle Scholar
  39. Lotz, M., Carson, D. and Vaughan, J.H., 1987, Substance P activation of rheumatoid synoviocytes: neural pathway in pathogenesis of arthritis, Science 238: 893.CrossRefGoogle Scholar
  40. Lotz, M., Vaughan, J.H., and Carson, D.A., 1988, Effect of neuropeptides on production of inflammatory cytokines by human monocytes, Science 241: 1218.PubMedCrossRefGoogle Scholar
  41. Lundberg, J.M., Martling, C-R., Saria, A., Folkers, K., and Rosell, S, 1983, Cigarette smoke-induced airway edema due to activation of capsaicin-sensitive vagal afferents and substance P release, Neurosci. 10: 1361.CrossRefGoogle Scholar
  42. Mantyh, C.R., Gates, T.S., Zimmerman, R.P., Welton, M.L., Passaro, E.P., Vigna, S.R., Maggio, J.E., Kruger, L., and Mantyh, P.W., 1988, Receptor binding sites for substance P, but not substance K or neuromedin K, are expressed in high concentrations by arterioles, venules, and lymph nodes in surgical specimens obtained from patients with ulcerative colitis and Crohn disease, Proc. Natl. Acad. Sci. 85: 3235.PubMedCrossRefGoogle Scholar
  43. Mantyh, P.W., Hunt, S.P., and Maggio, J.E., 1984, Substance P receptors: Localization by light microscopic autoradiography in rat brain using [3H]SP as the radio-ligand, Brain Res. 307: 147.PubMedCrossRefGoogle Scholar
  44. Mantyh, P.W., Johnson, D.J., Boehmer, C.G., Calton, M.D., Vinters, H.V., Maggio, J.E., Too, H.-P. and Vigna, S.R., 1989, Substance P receptor binding sites are expressed by glia in vivo after neuronal injury, Proc. Natl. Acad. Sci. USA 86: 5193.PubMedCrossRefGoogle Scholar
  45. Marshall, K.W., Chiu, B. and Inman, R.D., 1990, Substance P and arthritis: Analysis of plasma and synovial fluid levels, Arth. Rheum. 33: 87.CrossRefGoogle Scholar
  46. Martin, F.C., Anton, P.A., Gombein, J.A., Shanahan, F., and Merrill, J.E., Production of IL1 by microglia in response to substance P: role for a nonclassical NK1 receptor, J. Neuroimmunol.,in press, a.Google Scholar
  47. Martin, F.C., Charles, A.C., Sanderson, M.J., and Merrill, M.J., Substance P stimulates IL1 production by astrocytes via intracellular calcium, Brain Res. in press, b.Google Scholar
  48. Matthijs, B., Himpens, B., Peeters, T.L., and Vantrappen, G., 1990, Effects of substance P on [Ca2+]t and force in intact guinea pig ileal smooth muscle, Am. J. Physiol. 159: C150.Google Scholar
  49. Merrill, J.E., 1991, Effects of interleukin-1 and tumor necrosis factor-a on astrocytes, microglia, oligodendrocytes, and glial precursors in vitro, Devel. Neurosci. 13: 130.CrossRefGoogle Scholar
  50. McLean, S., Ganong, A.H., Seeger,. J.F., Bryce, D.K., Pratt, K.G., Reynolds, L.S., Siok, C.J., Lowe, J.A. III, and Heym, J., 1991, Activity and distribution of binding sites in brain of a non peptide substance P (NK) receptor antagonist, Science 251: 437.Google Scholar
  51. Moore, R.N., Osmand, A.P., Dunn, J.A., Joshi, J.G. and Rouse, B.T., 1988, Substance P augmentation of CSF-1-stimulated in vitro myelopoiesis, J. Immunology 141: 2699.Google Scholar
  52. Payan, D.G., Brewster, D.R., Missirian-Bastian, A. and Goetzel, E.J., 1984, Substance P recognition by a subset of human T lymphocytes, J. Clin. Invest. 74: 1532.PubMedCrossRefGoogle Scholar
  53. Pearce, B., Murphy, S., Eds., 1983, “Neurotransmitter Receptors Coupled to Inositol Phospholipid Turnover and Ca2+ Flux: Consequences for Astrocyte Function,” Raven Press, Ltd., New York.Google Scholar
  54. Peck, R., 1987, Neuropeptides modulating macrophage function, Science 239: 264.Google Scholar
  55. Prpic, V., Weiel, J.E., Somers, S.D., DiGuiseppi, J., Gonias, S.L., Pizzo, S.V., Hamilton, T.A., Herman, B., and Adams, D.O., 1987, Effects of bacterial lipopolysaccharide on the hydrolysis of phosphatidylinositol-4,5-bisphosphate in murine peritoneal macrophages, J. Immunol. 139: 526.PubMedGoogle Scholar
  56. Regoli, D., Drapeau, G., Dion, S. and D’Orleans-Juste, P., 1989, Receptors for substance P and related neurokinins, Pharmacology 38: 1.PubMedCrossRefGoogle Scholar
  57. Ruff, M.R., Wahl, S.M., and Pert, C.B., 1985, Substance P receptor-mediated chemotaxis of human monocytes, Peptides 6 (Suppl 2): 107.PubMedCrossRefGoogle Scholar
  58. Saito, K., Liu-Chen, L-Y., and Moskowitz, M.A., 1987, Substance P-like immunoreactivity in rat forebrain leptomeninges and cerebral vessels originates from the trigeminal but not sympathetic ganglia, Brain Res. 403: 55.CrossRefGoogle Scholar
  59. Sandberg, B.E.B., and Iversen, L.L., 1982, Substance P, J. Med. Chem. 25: 1009.PubMedCrossRefGoogle Scholar
  60. Saria, A., 1984, Substance P in sensory nerve fibres contributes to the development of oedema in the rat hind paw after thermal injury, Brit. J. Pharmacol. 82: 217.CrossRefGoogle Scholar
  61. Schade, U.F., Burmeister, I., Elekes, E., Engel, R. and Wolter, D.T., 1989, Mononuclear phagocytes and eicosanoids: aspects of their synthesis and biological activities, Blut 59: 475.PubMedCrossRefGoogle Scholar
  62. Shanahan, F., Denburg, J.A., Fox, J., Bienenstock, J., and Befus, D., 1985, Mast cell heterogeneity: effects of neuroenteric peptides on histamine release, J. Immunol. 135: 1331.PubMedGoogle Scholar
  63. Shinomiya, H., and Nakano, M., 1987, Calcium ionophore A23187 does not stimulate lipopolysaccharide nonresponsive C3H/HeJ peritoneal macrophages to produce interleukin 1, J. Immunology 139: 2730.Google Scholar
  64. Snider, R.M., Constantine, J.W., III, J.A.L., Longo, K.P., Lebel, W.S., Woody, H.A., Drozda, S.E., Desai, M.C., Vinick, F.J., Spencer, R.W. and Hess, H.-J., 1991, A potent nonpeptide antagonist of the substance P (NK1) receptor, Science 251: 435.Google Scholar
  65. Stanisz, A.M., Bufus, D., and Bienenstock, J., 1986, Differential effects of vasoactive intestinal peptide, substance P, and somatostatin on immunoglobulin synthesis and proliferations by lymphocytes from Peyer’s patches, mesenteric lymph nodes, and spleen, J. Immunol. 136: 152.PubMedGoogle Scholar
  66. Terada, Y., Shinomiya, H., and Nakano, M., 1989, Defect of calmodium-binding protein in expression of interleukin-113 gene by LPS-nonresponder C3H/HeJ mouse macrophages, Biochem. Biophys. Res. Com. 158: 723.PubMedCrossRefGoogle Scholar
  67. Thomas, K.L., Andrews, P.V., Khalil, Z., and Helme, R.D. 1989, Substance P induced hydrolysis of inositol phopolipids in rat skin in an in vivo model of inflammation, Neuropeptides 13: 191.PubMedCrossRefGoogle Scholar
  68. Thureson-Klein, A., Hedqvist, P., Ohlen, A., Raud, J., and Lindbom, L., 1987, Leukotriene B4, platelet-activating factor and substance P as mediators of acute inflammation, Pathol. Immunopathol. Res. 6: 190.PubMedCrossRefGoogle Scholar
  69. Tissot, M., Pradelles, P., and Giroud, J.P., 1988, Substance-P-like levels in inflammatory exudates. Inflammation 12: 25.PubMedCrossRefGoogle Scholar
  70. Torrens, Y., Beaujouan, J.C., and Glowinski, J., 1985, Pharmacological characterization of two tachykinin binding sites in the rat cerebral cortex, Neuropeptides 6: 59.PubMedCrossRefGoogle Scholar
  71. Torrens, Y., Beaujouan, J.C., Saffray, M., Daguet de MonTety, M.C., Bergstrom, L., and Glowinski, J., 1986, Substance P receptors in primary cultures of cortical astrocytes from the mouse, Proc. Natl. Acad. Sci. USA 83: 9216.PubMedCrossRefGoogle Scholar
  72. Torrens, Y., Daguet De Montety, M.C., El Etr, M., Beaujouan, J.C., and Glowinski, J., 1989, Tachykinin receptors of the NK1 type (substance P) coupled positively to phospholipase Con cortical astrocytes from the newborn mouse in primary culture, J. Neurochem. 52: 1913.PubMedCrossRefGoogle Scholar
  73. Wallengren, J., Ekman, R. and Moller, H., 1986, Substance P and vasoactive intestinal peptide in bullous and inflammatory skin disease, Acta Derm. Venereol. 66: 23.PubMedGoogle Scholar
  74. Wienrich, M., and Kettenmanm, H., 1989, Activation of substance P receptors leads to membrane potential responses in cultured astrocytes, Glia 2: 155.PubMedCrossRefGoogle Scholar
  75. Woodroofe, M.N., Sama, G.W., Wadhwa, M., Hayes, G.M., Loughlin, A.J., Tinker, A., and Cuzner, M.L., 1991, Detection of interleukin 1 and interleukin 6 in adult rat brain following mechanical injury by in vivo microdialysis: evidence of a role for microglia in cytokine production, J. Neuroimmunol. 33: 227.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1993

Authors and Affiliations

  • Jean E. Merrill
    • 1
  • Andrew C. Charles
    • 1
  • Fredricka C. Martin
    • 1
  1. 1.Department of Neurology Reed Neurological Research CenterUCLA School of MedicineLos AngelesUSA

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