Substance P, Immunity and Inflammation of the Intestinal Mucosa

  • Andrzej M. Stanisz
Part of the Hans Selye Symposia on Neuroendocrinology and Stress book series (HSSN, volume 3)


The concept of “neurogenic inflammation” is now receiving more attention in the literature. It has been discussed extensively in the context of polyarthritis and inflammation of the eye, skin and respiratory tract; however, the putative role(s) of neuropeptides in inflammatory reactions in the gastrointestinal tract has received comparatively little attention. Neurogenic inflammation usually describes reactions that include vasodilatation, plasma extravasation, and smooth muscle contraction due to neuronal activation and release of mediators from unmyelinated afferent (sensory) nerve endings. In addition, activation of axon collaterals associated with these afferent nerve endings results in further release of inflammatory mediators. There is a considerable body of evidence suggesting that neuropeptides play an important role in mediating this response. Enteric nerve plexuses ramify extensively in the lamina propria, with some fibres projecting into the sub-mucosa.1,2 Several neuropeptides [e.g. Substance P (SP), Vasoactive Intestinal Peptide (VIP), Somatostatin (SOM) and Calcitonin Gene-Related Peptide (CGRP)] have been localized within the gastrointestinal tract.3,4 Accompanying these events there is cellular infiltration and activation of mast cells, monocytes, neutrophils, eosinophils and lymphocytes; all of which have been implicated as playing an important role in inflammatory processes. Direct membrane/membrane contact between mast cells, eosinophils or plasma cells and nerves often occurs, suggesting that a supply of neurotransmitters to inflammatory cells is likely to be readily available.5


Mast Cell Vasoactive Intestinal Peptide Neurogenic Inflammation Plasma Extravasation Unmyelinated Afferent 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    J. Christensen and D. Wingate, eds., “Guide to Gastrointestinal Motility,” Wright, Bristol UK (1983).Google Scholar
  2. 2.
    J.B. Furness and M. Costa, Types of nerves in the enteric nervous system, Neuroscience 5:1 (1980).PubMedCrossRefGoogle Scholar
  3. 3.
    E. Ekblad, C. Winther, R. Ekman, R. Hakanson and F. Sundler, Projections of peptide-containing neurons in rat small intestine, Neuroscience 20:169 (1987).PubMedCrossRefGoogle Scholar
  4. 4.
    J.M. Polak and S.R. Bloom, Distribution and tissue localization of VIP in the central nervous system and seven peripheral organs, in: “Vasoactive Intestinal Peptide,” S.I. Said, ed., Raven Press, New York (1982).Google Scholar
  5. 5.
    R.H. Stead, M.F. Dixon, N.H. Bramwell, R.H. Riddell and J. Bienenstock, Mast cells are closely apposed to nerves in the human gastrointestinal mucosa, Gastroenterology 97:575 (1989).PubMedGoogle Scholar
  6. 6.
    R.H. Stead, M. Tomioka, G. Quinonez, G.T. Simon, S.Y. Feiten and J. Bienenstock, Intestinal mucosal mast cells in normal and nematode-infected rat intestines are in intimate contact with peptidergic nerves. Proc. Natl. Acad. Sci. USA 84:2975 (1987).PubMedCrossRefGoogle Scholar
  7. 7.
    R.H. Stead, J. Bienenstock and A.M. Stanisz, Neuropeptide regulation of mucosal immunity, Immunol. Rev. 100:333 (1987).PubMedCrossRefGoogle Scholar
  8. 8.
    A.M. Stanisz, J. Bienenstock and A. Agro, Neuromodulation of mucosal immunity. Regional Immunol. 2:414 (1989).Google Scholar
  9. 9.
    F. Lembeck and P. Holzer, Substance P as a neurogenic mediator of antidromic vasodilatation and neurogenic plasma extravasation. Naunyn-Schmiedeberg’s Arch. Pharmacol. 310:175 (1979).CrossRefGoogle Scholar
  10. 10.
    J.P. Barnes, F.K. Chung and C.P. Page, Inflammatory mediators in asthma, Pharmacol. Rev. 40:49 (1988).PubMedGoogle Scholar
  11. 11.
    P.W. Mantyh, M.D. Cotton, C.G. Boehme, M.L. Welton, E.P. Passaro, J.E. Maggio and S.R. Vigna, Receptors for sensory neuropeptides in human inflammatory disease: implications for the effector role of sensory neurons, Peptides 10:627 (1989).PubMedCrossRefGoogle Scholar
  12. 12.
    C.R. Mantyh, T.S. Gates, R.P. Zimmerman, M.L. Welton, E.P. Passard, S.R. Vigna, J.E. Maggio, L. Kruger and P.W. Mantyh, Receptor binding sites for substance P, but not substance K or neuromedin K, are expressed in high concentrations by arterioles, venules, and lymph nodules in surgical speciments obtained from patients with ulcerative colitis and Crohn’s disease, Proc. Natl. Acad. Sci. USA 85:3235 (1988).PubMedCrossRefGoogle Scholar
  13. 13.
    B. Pernow, Substance P, Pharmacol. Rev. 35:85 (1983).PubMedGoogle Scholar
  14. 14.
    J.V. Weinstock, A. Blum, J. Walder and R. Walder, Eosinophils from granulomas in murine Schistosomiasis Mansoni produce substance P, J. Immunol. l41:961 (1988).Google Scholar
  15. 15.
    G.A. Neil, A. Blum and J.V. Weinstock, Substance P but not vasoactive intestinal peptide modulates immunoglobulin secretion in murine schistosomiasis, Cell Immunol. 135:394 (1991).PubMedCrossRefGoogle Scholar
  16. 16.
    D.W. Pascual and K.L. Bost, Substance P production by macrophage cell lines: A possible autocrine function for this neuropeptide, Immunology 71:52 (1990).PubMedGoogle Scholar
  17. 17.
    D.G. Payan, D.R. Brewster and E.J. Goetzl, Stereo-specific receptors for substance P on cultured IM-9 lymphoblasts, J. Immunol. 133:3260 (1984).PubMedGoogle Scholar
  18. 18.
    A. Eglezos, P.V. Andrews, R.L. Boyd and R.D. Helme, Tachykinin-mediated modulation of the primary antibody response in rats: evidence for mediation by an NK-2 receptor, J. Neuroimmunol. 32:11 (1991).PubMedCrossRefGoogle Scholar
  19. 19.
    P. Parnet, M. Mitsuhashi, C.W. Turck, B. Kerdelhue and D.G. Payan, Tachykinin receptor crosstalk. Immunological cross-reactivity between the external domains of the substance K and substance P receptors, B.B.I. 5:73 (1991).Google Scholar
  20. 20.
    R.M. Snider, J.W. Constantine, JA. Lowe III, K.P. Longo, W.S. Lebel, HA. Woody, S.E. Drozda, M.C. Desai, F.J. Vinick, R.W. Spencer and HJ. Hess, A potent nonpeptide antagonist of substance P (NK-1) receptor, Science 251:435 (1991).PubMedCrossRefGoogle Scholar
  21. 21.
    C.A. Maggi, S. Giuliani, L. Ballati, A. Lecci, S. Manzini, R. Patacchini, A.R. Renzetti, P. Rovero, L. Quartara and A. Giachetti, In vivo evidence for tachykininergic transmission using a new NK-2 receptor-selective antagonist MEN10,376, J. Pharmacol. Exp. Ther. 257:1172 (1991).PubMedGoogle Scholar
  22. 22.
    M. Mousli, J.L. Bueb, C. Bronner, B. Rouot and Y. Landry, G protein activation: a receptor independent mode of action for cationic amphiphilic neuropeptides and venom peptides, TiPS. 11:358 (1990).PubMedGoogle Scholar
  23. 23.
    H. Duplaa, O. Convert, A.M. Sautereau, J.F. Tocanne and G. Chassaing, Binding of substance P to monolayers and vesicle made of phosphatidylcholine and/or phosphatidylserine, Biochim. Biophys. Acta. 1107:12 (1992).PubMedCrossRefGoogle Scholar
  24. 24.
    A. Wozniak, R. Scicchitano, W.H. Betts, G. McLennan, The effect of substance P on neutrophil function in normal and asthmatic subjects, Ann. NY Acad. Sci. 650:154 (1992).PubMedCrossRefGoogle Scholar
  25. 25.
    A. Kavelaars, F. Jeurissen, J. von Frijtag, D. Kunzel, J.H. van Roijen, G.T. Rijkers and C.J. Heijnen, Substance P induces a rise in intracellular calcium concentration in human T lymphocytes in vitro: evidence of a receptor-independent mechanism, J. Neuroimmunol. 42:61 (1993).PubMedCrossRefGoogle Scholar
  26. 26.
    Z. Bar-Shavit, R. Goldman, Y. Stabinsky, P. Gottlieb, M. Fridkin, V.I. Teichborg and S. Blumberg, Evidence of phagocytosis — a newly found activity of substance P residing in its N-terminal tetrapeptide sequence, Biochem. Biophys. Res. Com. 94:1445 (1980).PubMedCrossRefGoogle Scholar
  27. 27.
    H.P. Hartung, K. Wolters and K.V. Toyka, Substance P: Binding properties and studies on cellular responses in guinea-pig macrophages, J. Immunol. 136:3856 (1986).PubMedGoogle Scholar
  28. 28.
    W. Piotrowski and J.C. Foreman, On the action of substance P, somatostatin and vasoactive intestinal polypeptide on rat peritoneal mast cells and human skin, Arch. Pharmacol. 331:364 (1985).CrossRefGoogle Scholar
  29. 29.
    I. Hafstrom, H. Gyllenhammar, J. Palmblad and B. Ringertz, Substance P activates and modulates neutrophil oxidative metabolism and aggregation, J. Rheumatol. 16:1033 (1989).PubMedGoogle Scholar
  30. 30.
    J. Gauldie, A. Xaubet, T. Otoshi, M. Jordana and A. Stanisz, Neuropeptide mediated relese of Il-6 and other cytokines from human fibroblasts. 7th Int. Cong. Immunol. West Berlin. (1989).Google Scholar
  31. 31.
    P. Rameshwar, D. Ganea and P. Gascon, In vitro stimulatory effects of substance P on hematopoiesis, Blood. 81:391 (1993).PubMedGoogle Scholar
  32. 32.
    P. Rameshwar, P. Gascon and D. Ganea, Immunoregulatory effects of neuropeptides. Stimulation of interleukin-2 production by substance P, J. Neuroimmunol. 37:65 (1992).PubMedCrossRefGoogle Scholar
  33. 33.
    T.C. Moore, Modification of lymphocyte traffic by vasoactive neurotransmitter substances, Immunology 52:511 (1984).PubMedGoogle Scholar
  34. 34.
    R.D. Helme, A. Eglezos, G.W. Dandie, P.V. Andrews and R.L. Boyd, The effect of substance P on the regional lymph node antibody response to antigenic stimulation in capsaicin-pretreated rats, J. Immunol. 139:3470 (1987).PubMedGoogle Scholar
  35. 35.
    K.L. Bost, D.W. Pascual, Substance P: a late-acting B lymphocyte differentiation cofactor, Am. J. Physiol. 262:C537 (1992).Google Scholar
  36. 36.
    A.M. Stanisz, R. Scicchitano, P. Dazin, J. Bienenstock and D.G. Payan, Distribution of substance P receptors on murine spleen and Peyer’s patch T and B cells, J. Immunol. 139:749 (1987).PubMedGoogle Scholar
  37. 37.
    K.W. Marshall, B. Chiu and R.D. Inman, Substance P and arthritis: analysis of plasma and synovial fluid levels, Arthritis Rheumat. 33:87 (1990).PubMedCrossRefGoogle Scholar
  38. 38.
    M. Gronblad, Y.T. Konttinen, O. Korkala, P. Liesi, M. Hukkanen and J.M. Polak. Neuropeptides in synovium of patients with rheumatoid arthritis and osteoarthritis, J. Rheumatol. 15:1807 (1988).PubMedGoogle Scholar
  39. 39.
    J.D. Levine, D.H. Collier, A.I. Basbaum, M. A. Moskowitz and C.A. Helms, Hypothesis: the nervous system may contribute to the pathophysiology of rheumatoid arthritis, J. Rheumatol. 12:406 (1985).PubMedGoogle Scholar
  40. 40.
    V.E. Eysselein, M. Reinshagen, F. Cominelli, C. Sternini, W. Davis, A. Patel, C. C. Nast, D. Bernstein, K. Anderson, H. Khan and W.J. Snape Jr., Calcitonin-related gene peptide and substance P decrease in rabbit colon during colitis, Gastroenterology 101:1211 (1991).PubMedGoogle Scholar
  41. 41.
    M. Reinshagen, A. Patel, M. Sottili, W. Davis and V.E. Eysselein, Regulation of substance P gene expression in experimental colitis, Gastroenterology 102: A505 (1992).Google Scholar
  42. 42.
    A.M. Stanisz, A.D. Befus and J. Bienenstock, Differential effect of vasoactive intestinal peptide, substance P and somatostatin on immunoglobulin synthesis and cell proliferation by lymphocytes from spleen, Peyer’s patches and mesenteric lymph nodes, J. Immunol. 136:152 (1986).PubMedGoogle Scholar
  43. 43.
    R. Scicchitano, A.M. Stanisz and J. Bienenstock, In vivo immunomodulation by the neuropeptide substance P, Immunology 63:733 (1988).PubMedGoogle Scholar
  44. 44.
    I. Padol, A. Agro and A.M. Stanisz, Stimulatory effect of the neuropeptide substance P on antigen-specific immune response in mice, P.N.E.I. 3:277 (1990).Google Scholar
  45. 45.
    K. Croitoru, P.B. Ernst, J. Bienenstock, I. Padol and A.M. Stanisz, Selective modulation of the natural killer activity of murine intestinal intraepithelial leukocytes by the neuropeptide substance P, Immunology 71:196 (1990).PubMedGoogle Scholar
  46. 46.
    M.G. Swain, A. Agro, P. Blennerhassett, A.M. Stanisz and S.M. Collins, Increased levels of substance P in the myenteric plexus of Trichinella-infected rats, Gastroenterology 102:1913 (1992).PubMedGoogle Scholar
  47. 47.
    A. Agro and A.M. Stanisz, Depletion of substance P levels reduces intestinal inflammation and restores lymphocyte reactivity to substance P in Trichinella spiralis infected mice, Reg. Immunol. 5:120 (1993).PubMedGoogle Scholar
  48. 48.
    A.M. Stanisz, Neuroimmunomodulation in the gastrointestinal tract, Ann. N.Y. Acad. Sci. USA (in press).Google Scholar

Copyright information

© Springer Science+Business Media New York 1994

Authors and Affiliations

  • Andrzej M. Stanisz
    • 1
  1. 1.Department of Pathology and Intestinal Diseases Research ProgrammeMcMaster UniversityHamiltonCanada

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