Immunomodulatory properties of substance P: The gastrointestinal system as a model

Annals of the New York Academy of Sciences

Volumn 1088, Issue , 2006, Pages 23-40

  Hon, Wai Koon ^a   Pothoulakis, Charalabos ^a,b  

^a HARVARD MEDICAL SCHOOL   (United States)

^b Division of Gastroenterology   (United States)

Author keywords

Colon; Epithelial; Inflammation; Neuropeptide

Indexed keywords

2 BENZHYDRYL 3 (2 METHOXYBENZYLAMINO) 1 AZABICYCLO[2.2.2]OCTANE; CAPSAZEPINE; CHEMOKINE; G PROTEIN COUPLED RECEPTOR; NEUROKININ 1 RECEPTOR; NEUROPEPTIDE; NONSTEROID ANTIINFLAMMATORY AGENT; SUBSTANCE P; TOXIN; TRINITROBENZENESULFONIC ACID;

CELL INTERACTION; CLOSTRIDIUM DIFFICILE; COLITIS; CONFERENCE PAPER; CYTOKINE RELEASE; DIARRHEA; DISEASE COURSE; ENTERITIS; EPITHELIUM CELL; HUMAN; IMMUNOCOMPETENT CELL; INFLAMMATORY CELL; INTESTINE INNERVATION; LAMINA PROPRIA; MACROPHAGE; MAST CELL; MONOCYTE; NONHUMAN; PARASITOSIS; PROTEIN BINDING; SALMONELLOSIS; SENSORY NERVE CELL; T LYMPHOCYTE; TRICHINELLA SPIRALIS; ANIMAL; GASTROENTERITIS; GASTROINTESTINAL TRACT; IMMUNOLOGY; IMMUNOMODULATION; INNERVATION; PHYSIOLOGY; REVIEW;

MUS;

ANIMALS; GASTROENTERITIS; GASTROINTESTINAL TRACT; HUMANS; INFLAMMATORY BOWEL DISEASES; NEUROIMMUNOMODULATION; SUBSTANCE P;

EID: 34250022689     PISSN: 00778923     EISSN: 17496632     Source Type: Book Series    
DOI: 10.1196/annals.1366.024     Document Type: Conference Paper

References (116)

1. CHANG, M.M. & S.E. LEEMAN. 1970. Isolation of a sialogogic peptide from bovine hypothalamic tissue and its characterization as substance P. J. Biol. Chem. 245: 4784-4790.
2. KIMURA, S. et al. 1984. Pharmacological characterization of novel mammalian tachykinins, neurokinin alpha and neurokinin beta. Neurosci. Res. 2: 97-104.
3. HARRISON, S. & P. GEPPETTI. 2001. Substance P. Int. J. Biochem. Cell Biol. 33: 555-576.
4. SEVERINI, C. et al. 2002. The tachykinin peptide family. Pharmacol. Rev. 54: 285-322.
5. HOLZER, P. & U. HOLZER-PETSCHE. 1997. Tachykinins in the gut. Part I. Expression, release and motor function. Pharmacol. Ther. 73: 173-217.
6. HOLZER, P. & U. HOLZER-PETSCHE. 1997. Tachykinins in the gut. Part II. Roles in neural excitation, secretion and inflammation. Pharmacol. Ther. 73: 219-263.
7. ZHANG, Y. et al. 2000. Hemokinin is a hematopoietic-specific tachykinin that regulates B lymphopoiesis. Nat. Immunol. 1: 392-397.
8. BELLUCCI, F. et al. 2002. Pharmacological profile of the novel mammalian tachykinin, hemokinin 1. Br. J. Pharmacol. 135: 266-274.
9. MORTEAU, O. et al. 2001. Hemokinin 1 is a full agonist at the substance P receptor. Nat. Immunol. 2: 1088.
10. MANTYH, C.R. et al. 1988. 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 specimens obtained from patients with ulcerative colitis and Crohn's disease. Proc. Natl. Acad. Sci. USA 85: 3235-3239.
11. POTHOULAKIS, C. et al. 1998. Substance P receptor expression in intestinal epithelium in Clostridium difficile toxin A enteritis in rats. Am. J. Physiol. 275: G68-G75.
12. GOODE, T. et al. 2000. Neurokinin-1 receptor expression in inflammatory bowel disease: molecular quantitation and localisation. Gut 47: 387-396.
13. RIEGLER, M. et al. 1999. Effects of substance P on human colonic mucosa in vitro. Am. J. Physiol. 276: G1473-G1483.
14. RENZI, D. et al. 2000. Substance P (neurokinin-1) and neurokinin A (neurokinin-2) receptor gene and protein expression in the healthy and inflamed human intestine. Am. J. Pathol. 157: 1511-1522.
15. ZHAO, D. et al. 2002. Substance P-stimulated interleukin-8 expression in human colonic epithelial cells involves Rho family small GTPases. Biochem. J. 368: 665-672.
16. LIU, L. et al. 2002. Roles of substance P receptors in human colon circular muscle: alterations in diverticular disease. J. Pharmacol. Exp. Ther. 302: 627-635.
17. CAO, W. et al. 2000. Gq-linked NK(2) receptors mediate neurally induced contraction of human sigmoid circular smooth muscle. Gastroenterology 119: 51-61.
18. WARNER, F.J. et al. 2000. Circular muscle contraction, messenger signalling and localization of binding sites for neurokinin A in human sigmoid colon. Clin. Exp. Pharmacol. Physiol. 27: 928-933.
19. MAGGI, C.A. et al. 1997. Tachykinin receptors and intestinal motility. Can. J. Physiol. Pharmacol. 75: 696-703.
20. MANN, P.T. et al. 1997. Localisation of neurokinin 3 (NK3) receptor immunoreactivity in the rat gastrointestinal tract. Cell Tissue Res. 289: 1-9.
21. WANG, H. et al. 2002. Localization of neurokinin B receptor in mouse gastrointestinal tract. World J. Gastroenterol. 8: 172-175.
22. MANNING, B.P. & G.M. MAWE. 2001. Tachykinins mediate slow excitatory postsynaptic transmission in guinea pig sphincter of Oddi ganglia. Am. J. Physiol. Gastrointest. Liver Physiol. 281: G357-G364.
23. LAMBRECHT, B.N. et al. 1999. Endogenously produced substance P contributes to lymphocyte proliferation induced by dendritic cells and direct TCR ligation. Eur. J. Immunol. 29: 3815-3825.
24. MARRIOTT, I. & K.L. BOST. 2001. Substance P receptor mediated macrophage responses. Adv. Exp. Med. Biol. 493: 247-254.
25. LAI, J.P. et al. 2000. Detection of substance P and its receptor in human fetal microglia. Neuroscience 101: 1137-1144.
26. HO, W.Z. et al. 1997. Human monocytes and macrophages express substance P and neurokinin-1 receptor. J. Immunol. 159: 5654-5660.
27. LAI, J.P. et al. 1998. Identification of a delta isoform of preprotachykinin mRNA in human mononuclear phagocytes and lymphocytes. J. Neuroimmunol. 91: 121-128.
28. LAI, J.P., S.D. DOUGLAS & W.Z. HO. 1998. Human lymphocytes express substance P and its receptor. J. Neuroimmunol. 86: 80-86.
29. PAYAN, D.G., D.R. BREWSTER & E.J. GOETZL. 1983. Specific stimulation of human T lymphocytes by substance P. J. Immunol. 131: 1613-1615.
30. STANISZ, A.M. et al. 1987. Distribution of substance P receptors on murine spleen and Peyer's patch T and B cells. J. Immunol. 139: 749-754.
31. WOZNIAK, A. et al. 1989. Activation of human neutrophils by substance P: effect on FMLP-stimulated oxidative and arachidonic acid metabolism and on antibody-dependent cell-mediated cytotoxicity. Immunology 68: 359-364.
32. SHANAHAN, F. et al. 1985. Mast cell heterogeneity: effects of neuroenteric peptides on histamine release. J. Immunol. 135: 1331-1337.
33. FEISTRITZER, C. et al. 2003. Natural killer cell functions mediated by the neuropeptide substance P. Regul. Pept. 116: 119-126.
34. CASTAGLIUOLO, I. et al. 1997. Increased substance P responses in dorsal root ganglia and intestinal macrophages during Clostridium difficile toxin A enteritis in rats. Proc. Natl. Acad. Sci. USA 94: 4788-4793.
35. WEINSTOCK, J.V. et al. 2003. Substance P regulates Th1-type colitis in IL-10 knockout mice. J. Immunol. 171: 3762-3767.
36. KELLY, C.P., C. POTHOULAKIS & J.T. LAMONT. 1994. Clostridium difficile colitis. N. Engl. J. Med. 330: 257-262.
37. POTHOULAKIS, C. & J.T. LAMONT. 2001. Microbes and microbial toxins: paradigms for microbial-mucosal interactions II. The integrated response of the intestine to Clostridium difficile toxins. Am. J. Physiol. Gastrointest. Liver Physiol. 280: G178-G183.
38. CASTAGLIUOLO, I. et al. 1994. Neuronal involvement in the intestinal effects of Clostridium difficile toxin A and Vibrio cholerae enterotoxin in rat ileum. Gastroenterology 107: 657-665.
39. MANTYH, C.R. et al. 1996. Substance P activation of enteric neurons in response to intraluminal Clostridium difficile toxin A in the rat ileum. Gastroenterology 111: 1272-1280.
40. MANTYH, C.R., D.C. MCVEY & S.R. VIGNA. 2000. Extrinsic surgical denervation inhibits Clostridium difficile toxin A-induced enteritis in rats. Neurosci. Lett. 292: 95-98.
41. MCVEY, D.C. & S.R. VIGNA. 2001. The capsaicin VR1 receptor mediates substance P release in toxin A-induced enteritis in rats. Peptides 22: 1439-1446.
42. POTHOULAKIS, C. et al. 1994. CP-96,345, a substance P antagonist, inhibits rat intestinal responses to Clostridium difficile toxin A but not cholera toxin. Proc. Natl. Acad. Sci. USA 91: 947-951.
43. MANTYH, C.R. et al. 1996. Increased substance P receptor expression by blood vessels and lymphoid aggregates in Clostridium difficile-induced pseudomembranous colitis. Dig. Dis. Sci. 41: 614-620.
44. CASTAGLIUOLO, I. et al. 1998. Neurokinin-1 (NK-1) receptor is required in Clostridium difficile-induced enteritis. J. Clin. Invest. 101: 1547-1550.
45. CASTAGLIUOLO, I. et al. 1999. Neurotensin is a proinflammatory neuropeptide in colonic inflammation. J. Clin. Invest. 103: 843-849.
46. ANTON, P.M. et al. 2004. Corticotropin-releasing hormone (CRH) requirement in Clostridium difficile toxin A-mediated intestinal inflammation. Proc. Natl. Acad. Sci. USA 101: 8503-8508.
47. OKAMOTO, A. et al. 1994. Interactions between neutral endopeptidase (EC 3.4.24.11) and the substance P (NK1) receptor expressed in mammalian cells. Biochem. J. 299(Pt 3): 683-693.
48. KIRKWOOD, K.S. et al. 2001. Deletion of neutral endopeptidase exacerbates intestinal inflammation induced by Clostridium difficile toxin A. Am. J. Physiol. Gastrointest. Liver Physiol. 281: G544-G551.
49. BIENENSTOCK, J. et al. 1987. The role of mast cells in inflammatory processes: evidence for nerve/mast cell interactions. Int. Arch. Allergy Appl. Immunol. 82: 238-243.
50. MORIARTY, D. et al. 2001. Potent NK1 antagonism by SR-140333 reduces rat colonic secretory response to immunocyte activation. Am. J. Physiol. Cell Physiol. 280: C852-C858.
51. POTHOULAKIS, C. et al. 1993. Ketotifen inhibits Clostridium difficile toxin A-induced enteritis in rat ileum. Gastroenterology 105: 701-707.
52. WERSHIL, B.K., I. CASTAGLIUOLO & C. POTHOULAKIS. 1998. Direct evidence of mast cell involvement in Clostridium difficile toxin A-induced enteritis in mice. Gastroenterology 114: 956-964.
53. BISCHOFF, S.C. et al. 2004. Substance P and other neuropeptides do not induce mediator release in isolated human intestinal mast cells. Neurogastroenterol. Motil. 16: 185-193.
54. LIGUMSKY, M. et al. 1990. Role of interleukin 1 in inflammatory bowel disease - enhanced production during active disease. Gut 31: 686-689.
55. LAURENZI, M.A. et al. 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: 529-533.
56. LOTZ, M., J.H. VAUGHAN & D.A. CARSON. 1988. Effect of neuropeptides on production of inflammatory cytokines by human monocytes. Science 241: 1218-1221.
57. BOST, K.L., S.A. BREEDING & D.W. PASCUAL. 1992. Modulation of the mRNAs encoding substance P and its receptor in rat macrophages by LPS. Reg. Immunol. 4: 105-112.
58. MARRIOTT, I. & K.L. BOST. 2000. IL-4 and IFN-γ up-regulate substance P receptor expression in murine peritoneal macrophages. J. Immunol. 165: 182-191.
59. DE SIMONE, C. et al. 1989. Effects of substance P on the spontaneous binding of Salmonella minnesota R345 (Rb) to human peripheral blood lymphocytes. J. Clin. Lab. Anal. 3: 345-349.
60. KINCY-CAIN, T. & K.L. BOST. 1996. Increased susceptibility of mice to Salmonella infection following in vivo treatment with the substance P antagonist, spantide II. J. Immunol. 157: 255-264.
61. KINCY-CAIN, T., J.D. CLEMENTS & K.L. BOST. 1996. Endogenous and exogenous interleukin-12 augment the protective immune response in mice orally challenged with Salmonella dublin. Infect. Immun. 64: 1437-1440.
62. KINCY-CAIN, T. & K.L. BOST. 1997. Substance P-induced IL-12 production by murine macrophages. J. Immunol. 158: 2334-2339.
63. WALTERS, N. et al. 2005. Enhanced immunoglobulin A response and protection against Salmonella enterica serovar typhimurium in the absence of the substance P receptor. Infect. Immun. 73: 317-324.
64. WOODBURY, R.G. et al. 1984. Mucosal mast cells are functionally active during spontaneous expulsion of intestinal nematode infections in rat. Nature 312: 450-452.
65. KHAN, W.I. & S.M. COLLINS. 2004. Immune-mediated alteration in gut physiology and its role in host defence in nematode infection. Parasite Immunol. 26: 319-326.
66. SWAIN, M.G. et al. 1992. Increased levels of substance P in the myenteric plexus of Trichinella-infected rats. Gastroenterology 102: 1913-1919.
67. GREENWOOD, B. & J.M. PALMER. 1996. Neural integration of jejunal motility and ion transport in nematode-infected ferrets. Am. J. Physiol. 271: G48-G55.
68. AGRO, A. & A.M. STANISZ. 1993. Inhibition of murine intestinal inflammation by anti-substance P antibody. Reg. Immunol. 5: 120-126.
69. KATAEVA, G., A. AGRO & A.M. STANISZ. 1994. Substance-P-mediated intestinal inflammation: inhibitory effects of CP 96345 and SMS 201-995. Neuroimmunomodulation 1: 350-356.
70. HWANG, L. et al. 1993. Downregulation of neutral endopeptidase (EC 3.4.24.11) in the inflamed rat intestine. Am. J. Physiol. 264: G735-G743.
71. STEAD, R.H. et al. 1987. Intestinal mucosal mast cells in normal and nematode-infected rat intestines are in intimate contact with peptidergic nerves. Proc. Natl. Acad. Sci. USA 84: 2975-2979.
72. GAY, J. et al. 2000. Development and sequels of intestinal inflammation in nematode-infected rats: role of mast cells and capsaicin-sensitive afferents. Neuroimmunomodulation 8: 171-178.
73. MASSON, S.D. et al. 1996. Nippostrongylus brasiliensis infection evokes neuronal abnormalities and alterations in neurally regulated electrolyte transport in rat jejunum. Parasitology 113(Pt 2): 173-182.
74. WEINSTOCK, J.V. 2004. The role of substance P, hemokinin and their receptor in governing mucosal inflammation and granulomatous responses. Front. Biosci. 9: 1936-1943.
75. WEINSTOCK, J.V. et al. 1988. Eosinophils from granulomas in murine schistosomiasis mansoni produce substance P. J. Immunol. 141: 961-966.
76. COOK, G.A. et al. 1994. Molecular evidence that granuloma T lymphocytes in murine schistosomiasis mansoni express an authentic substance P (NK-1) receptor. J. Immunol. 152: 1830-1835.
77. NEIL, G.A., A. BLUM & J.V. WEINSTOCK. 1991. Substance P but not vasoactive intestinal peptide modulates immunoglobulin secretion in murine schistosomiasis. Cell Immunol. 135: 394-401.
78. BLUM, A.M. et al. 1993. Substance P modulates antigen-induced, IFN-γ production in murine Schistosomiasis mansoni. J. Immunol. 151: 225-233.
79. ARSENESCU, R. et al. 2005. IL-12 induction of mRNA encoding substance P in murine macrophages from the spleen and sites of inflammation. J. Immunol. 174: 3906-3911.
80. BLUM, A.M. et al. 1999. The substance P receptor is necessary for a normal granulomatous response in murine schistosomiasis mansoni. J. Immunol. 162: 6080-6085.
81. METWALI, A. et al. 2004. Cutting edge: hemokinin has substance P-like function and expression in inflammation. J. Immunol. 172: 6528-6532.
82. WEINSTOCK, J.V. & D. ELLIOTT. 2000. The somatostatin immunoregulatory circuit present at sites of chronic inflammation. Eur. J. Endocrinol. 143(Suppl 1): S15-S19.
83. MANTYH, C.R. et al. 1995. Differential expression of substance P receptors in patients with Crohn's disease and ulcerative colitis. Gastroenterology 109: 850-860.
84. MANTYH, C.R. et al. 1994. Substance P binding sites on intestinal lymphoid aggregates and blood vessels in inflammatory bowel disease correspond to authentic NK-1 receptors. Neurosci. Lett. 178: 255-259.
85. RAITHEL, M., H.T. SCHNEIDER & E.G. HAHN. 1999. Effect of substance P on histamine secretion from gut mucosa in inflammatory bowel disease. Scand. J. Gastroenterol. 34: 496-503.
86. GOLDIN, E. et al. 1989. Colonic substance P levels are increased in ulcerative colitis and decreased in chronic severe constipation. Dig. Dis. Sci. 34: 754-757.
87. MAZUMDAR, S. & K.M. DAS. 1992. Immunocytochemical localization of vasoactive intestinal peptide and substance P in the colon from normal subjects and patients with inflammatory bowel disease. Am. J. Gastroenterol. 87: 176-181.
88. BERNSTEIN, C.N., M.E. ROBERT & V.E. EYSSELEIN. 1993. Rectal substance P concentrations are increased in ulcerative colitis but not in Crohn's disease. Am. J. Gastroenterol. 88: 908-913.
89. YAMAMOTO, H. et al. 1996. Abnormal neuropeptide concentration in rectal mucosa of patients with inflammatory bowel disease. J. Gastroenterol. 31: 525-532.
90. RENZI, D. et al. 1998. Substance P and vasoactive intestinal polypeptide but not calcitonin gene-related peptide concentrations are reduced in patients with moderate and severe ulcerative colitis. Ital. J. Gastroenterol. Hepatol. 30: 62-70.
91. BROWN, D.R., A.M. PARSONS & S.M. O'GRADY. 1992. Substance P produces sodium and bicarbonate secretion in porcine jejunal mucosa through an action on enteric neurons. J. Pharmacol. Exp. Ther. 261: 1206-1212.
92. PARSONS, A.M. et al. 1992. Neurokinin receptors and mucosal ion transport in porcine jejunum. J. Pharmacol. Exp. Ther. 261: 1213-1221.
93. WANG, L. et al. 1995. Substance P induces ion secretion in mouse small intestine through effects on enteric nerves and mast cells. Am. J. Physiol. 269: G85-G92.
94. KUWAHARA, A. & H.J. COOKE. 1990. Tachykinin-induced anion secretion in guinea pig distal colon: role of neural and inflammatory mediators. J. Pharmacol. Exp. Ther. 252: 1-7.
95. RIEGLER, M. et al. 1999. Substance P causes a chloride-dependent short-circuit current response in rabbit colonic mucosa in vitro. Scand. J. Gastroenterol. 34: 1203-1211.
96. TURVILL, J.L., P. CONNOR & M.J. FARTHING. 2000. Neurokinin 1 and 2 receptors mediate cholera toxin secretion in rat jejunum. Gastroenterology 119: 1037-1044.
97. DI SEBASTIANO, P. et al. 1999. SR140333, a substance P receptor antagonist, influences morphological and motor changes in rat experimental colitis. Dig. Dis. Sci. 44: 439-444.
98. CASTAGLIUOLO, I. et al. 2002. Protective effects of neurokinin-1 receptor during colitis in mice: role of the epidermal growth factor receptor. Br. J. Pharmacol. 136: 271-279.
99. STUCCHI, A.F. et al. 2000. NK-1 antagonist reduces colonic inflammation and oxidative stress in dextran sulfate-induced colitis in rats. Am. J. Physiol. Gastrointest. Liver Physiol. 279: G1298-G1306.
100. STUCCHI, A.F. et al. 2003. A neurokinin 1 receptor antagonist reduces an ongoing ileal pouch inflammation and the response to a subsequent inflammatory stimulus. Am. J. Physiol. Gastrointest. Liver Physiol. 285: G1259-G1267.
101. BERG, D.J. et al. 2002. Rapid development of colitis in NSAID-treated IL-10-deficient mice. Gastroenterology 123: 1527-1542.
102. STURIALE, S. et al. 1999. Neutral endopeptidase (EC 3.4.24.11) terminates colitis by degrading substance P. Proc. Natl. Acad. Sci. USA 96: 11653-11658.
103. LIEB, K. et al. 1996. Effects of substance P and selected other neuropeptides on the synthesis of interleukin-1 beta and interleukin-6 in human monocytes: a re-examination. J. Neuroimmunol. 67: 77-81.
104. FIEBICH, B.L. et al. 2000. The neuropeptide substance P activates p38 mitogen-activated protein kinase resulting in IL-6 expression independently from NF-kappa B. J. Immunol. 165: 5606-5611.
105. DEROCQ, J.M. et al. 1996. Effect of substance P on cytokine production by human astrocytic cells and blood mononuclear cells: characterization of novel tachykinin receptor antagonists. FEBS Lett. 399: 321-325.
106. LIEB, K. et al. 1997. The neuropeptide substance P activates transcription factor NF-kappa B and kappa B-dependent gene expression in human astrocytoma cells. J. Immunol. 159: 4952-4958.
107. AZZOLINA, A., A. BONGIOVANNI & N. LAMPIASI. 2003. Substance P induces TNF-alpha and IL-6 production through NF kappa B in peritoneal mast cells. Biochem. Biophys. Acta. 1643: 75-83.
108. KOON, H.W. et al. 2005. Substance P-stimulated interleukin-8 expression in human colonic epithelial cells involves PKC{delta} activation. J. Pharmacol. Exp. Ther 314: 1393-1400.
109. SIMEONIDIS, S. et al. 2003. Regulation of the NK-1 receptor gene expression in human macrophage cells via an NF-kappa B site on its promoter. Proc. Natl. Acad. Sci. USA 100: 2957-2962.
110. WEINSTOCK, J.V. et al. 2003. IL-18 and IL-12 signal through the NF-kappa B pathway to induce NK-1R expression on T cells. J. Immunol. 170: 5003-5007.
111. GUO, C.J. et al. 2004. Interleukin-1beta upregulates functional expression of neurokinin-1 receptor (NK-1R) via NF-kappaB in astrocytes. Glia 48: 259-266.
112. BARDELLI, C. et al. 2005. Expression of functional NK1 receptors in human alveolar macrophages: superoxide anion production, cytokine release and involvement of NF-kappaB pathway. Br. J. Pharmacol. 145: 385-396.
113. REED, K.L. et al. 2005. NF-kappaB activation precedes increases in mRNA encoding neurokinin-1 receptor, proinflammatory cytokines, and adhesion molecules in dextran sulfate sodium-induced colitis in rats. Dig. Dis. Sci. 50: 2366-2378.
114. NILSSON, J., A.M. VON EULER & C.J. DALSGAARD. 1985. Stimulation of connective tissue cell growth by substance P and substance K. Nature 315: 61-63.
115. CASTAGLIUOLO, I. et al. 2000. Epidermal growth factor receptor transactivation mediates substance P-induced mitogenic responses in U-373 MG cells. J. Biol. Chem. 275: 26545-26550.
116. KOON, H.W. et al. 2004. Metalloproteinases and transforming growth factor-alpha mediate substance P-induced mitogen-activated protein kinase activation and proliferation in human colonocytes. J. Biol. Chem. 279: 45519-45527.