Abstract
Substance P (SP) is an important neuropeptide involved in neurogenic inflammation and most of its pathophysiological functions are mediated through binding to the neurokinin-1 receptor. SP exerts various proinflammatory actions on immune-cells, including macrophages. Several compounds such as cytokines have the capacity to activate and stimulate macrophages to produce arachidonic acid oxygenation and lipoxygenation products. Leukotriene B4 (LTB4) is one of the most important mediators of leukocyte activation in acute and chronic inflammatory reactions. LTB4 stimulates chemotaxis, lysosomal enzyme release, and cell aggregation. In this report, we studied the effect of SP on rat adherent granuloma macrophages (RAGMs). The chronic granuloma in rat was induced by dorsal injections of a potassium permanganate (KMnO4) saturated crystal solution (200 μl of a 1:40 dilution). After 7 days, all rats developed a subcutaneous granuloma in the injection site from which infiltrated macrophages were extracted, isolated, and cultured in vitro. We tested the hypothesis that SP stimulates the production of LTB4 in RAGMs and increases lipoxygenase expression. Here we show that the cell-free supernatant of RAGMs stimulated with SP (10 μM), resulted in statistically significant increases of LTB4. Preincubation of RAGMs with NDGA (nordihydroguaiaretic acid (10 μM), completely abolished the production of LTB4 in the supernatants and lipoxygenase expression on RAGMs challenged with SP, or the cation ionophore A23187 (positive control). Similar effects were obtained when the cells were pretreated with dexamethasone (10 μM). Our results suggest that SP is able to stimulate the release of LTB4 and lipoxygenase expression in macrophages from chronic inflammatory granuloma and provide further evidence for a neuroinflammatory pathway.
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Andoh T, Yageta Y, Konno M, Yamaguchi-Miyamoto T, Takahata H, Nojima H, Nemoto H, Kuraishi Y (2008) Evidence for separate involvement of different mu-opioid receptor subtypes in itch and analgesia induced by supraspinal action of opioids. J Pharmacol Sci 106:667–670
Angelini F, Di Matteo G, Balestrero S, Brunetti E, Mancino G, Rossi P, Galli E (2007) Nuclear factor kappaB activity is increased in peripheral blood mononuclear cells of children affected by atopic and non-atopic eczema. Int J Immunopathol Pharmacol 20:59–67
Anogianaki A, Castellani ML, Madhappan B, Salini V, Vecchiet J, Tetè S, Frydas S, Perrella A, De Lutiis MA, Neri G, Cerulli G, Caraffa A, Conti P (2007) RANTES (CCL5) potentiates calcium ionophore in the production of LTB4 in rat adherent macrophages from granuloma induced by KMnO4: inhibition by NDGA. Pharmacol Res 57:49–55
Arimoto T, Takano H, Inoue K, Yanagisawa R, Yoshino S, Yamaki K, Yoshikawa T (2007) Pulmonary exposure to diesel exhaust particle components enhances circulatory chemokines during lung inflammation. Int J Immunopathol Pharmacol 20:197–201
Banche G, Allizond V, Mandras N, Garzaro M, Cavallo GP, Baldi C, Scutera S, Musso T, Roana J, Tullio V, Carlone NA, Cuffini AM (2007) Improvement of clinical response in allergic rhinitis patients treated with an oral immunostimulating bacterial lysate: in vivo immunological effects. Int J Immunopathol Pharmacol 20:129–138
Baraniuk JN, Kaliner MA (1990) Neuropeptides and nasal secretion. J Allergy Clin Immunol 86:620–627
Birklein F, Schmelz M (2008) Neuropeptides, neurogenic inflammation and complex regional pain syndrome (CRPS). Neurosci Lett 437:199–202
Bocchietto E, Paolucci C, Breda D, Sabbioni E, Burastero SE (2007) Human monocytoid THP-1 cell line versus monocyte-derived human immature dendritic cells as in vitro models for predicting the sensitising potential of chemicals. Int J Immunopathol Pharmacol 20:259–265
Bosello S, Pers JO, Rochas C, Devauchelle V, De Santis M, Daridon C, Saraux A, Ferraccioli GF, Youinou P (2007) BAFF and rheumatic autoimmune disorders: implications for disease management and therapy. Int J Immunopathol Pharmacol 20:1–8
Boyce JA (2007) Mast cells and eicosanoid mediators: a system of reciprocal paracrine and autocrine regulation. Immunol Rev 217:168–185
Bruzzese V (2008) Rheumatoid arthritis: time disjoints. Eur J Inflamm 6:93–94
Chang WC, Di Capite J, Singaravelu K, Nelson C, Halse V, Parekh AB (2008) Local Ca2+ influx through Ca2+ release-activated Ca2+ (CRAC) channels stimulates production of an intracellular messenger and an intercellular pro-inflammatory signal. J Biol Chem 283:4622–4631
Chiorino G, Mello Grand M, Scatolini M, Ostano P (2008) From single gene to integrative molecular concept MAPS: pitfalls and potentials of microarray technology. J Biol Regul Homeost Agents 22:7–16
Dasari P, Nicholson IC, Zola H (2008) Toll-like receptors. J Biol Regul Homeost Agents 22:17–26
Eligini S, Habib A, Lebret M, Créminon C, Lévy-Toledano S, Maclouf J (2001) Induction of cyclo-oxygenase-2 in human endothelial cells by SIN-1 in the absence of prostaglandin production. Br J Pharmacol 133:1163–1171
Evans DL, Lynch KG, Benton T, Dubé B, Gettes DR, Tustin NB, Lai JP, Metzger D, Douglas SD (2008) Selective serotonin reuptake inhibitor and substance P antagonist enhancement of natural killer cell innate immunity in human immunodeficiency virus/acquired immunodeficiency syndrome. Biol Psychiatry 63:899–905
Ferdinande L, Demetter P, Perez-Novo C, Waeytens A, Taildeman J, Rottiers I, Rottiers P, De Vos M, Cuvelier CA (2008) Inflamed intestinal mucosa features a specific epithelial expression pattern of indoleamine 2, 3-dioxygenase. Int J Immunopathol Pharmacol 21:289–295
Feuerstein G, Hallenbeck JM (1987) Prostaglandins, leukotrienes, and platelet-activating factor in shock. Annu Rev Pharmacol Toxicol 27:301–313
Foschino-Barbaro MP, Carpagnano GE, Spanevello A, Cagnazzo MG, Barnes PJ (2007) Inflammation, oxidative stress and systemic effects in mild chronic obstructive pulmonary disease. Int J Immunopathol Pharmacol 20:753–763
Gallicchio M, Rosa AC, Benetti E, Collino M, Dianzani C, Fantozzi R (2006) Substance P-induced cyclooxygenase-2 expression in human umbilical vein endothelial cells. Br J Pharmacol 147:681–689
García-Horsman JA, Männistö PT, Venäläinen JI (2007) On the role of prolyl oligopeptidase in health and disease. Neuropeptides 41:1–24
Gigante A, Torcianti M, Boldrini E, Manzotti S, Falcone G, Greco F, Mattioli-Belmonte M (2008) Vitamin K and D association stimulates in vitro osteoblast differentiation of fracture site derived human mesenchymal stem cells. J Biol Regul Homeost Agents 22(1):35–44
Hansson GK (2005) Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 352:1685–1695
Hong D, Byers MR, Oswald RJ (1993) Dexamethasone treatment reduces sensory neuropeptides and nerve sprouting reactions in injured teeth. Pain 55:171–181
Ingber A, Cohen Y, Krimsky M, Yedgar S (2007) A novel treatment of contact dermatitis by topical application of phospholipase A2 inhibitor: a double-blind placebo-controlled pilot study. Int J Immunopathol Pharmacol 20:191–195
Inoue K, Takano H, Yanagisawa R, Sakurai M, Abe S, Yoshino S, Yamaki K, Yoshikawa T (2007) Effects of nanoparticles on lung physiology in the presence or absence of antigen. Int J Immunopathol Pharmacol 20:737–744
Inoue K, Takano H, Ohnuki M, Yanagisawa R, Sakurai M, Shimada A, Mizushima K, Yoshikawa T (2008) Size effects of nanomaterials on lung inflammation and coagulatory disturbance. Int J Immunopathol Pharmacol 21:197–206
Katsanos GS, Anogeianaki A, Orso C, Tete S, Salini V, Antinolfi P, Sabatino G (2008a) Impact of substance P on cellular immunity. J Biol Regul Homeost Agents 22:93–98
Katsanos GS, Anogianaki A, Castellani ML, Ciampoli C, De Amicis D, Orso C, Pollice R, Vecchiet J, Tete S, Salini V, Caraffa A, Patruno A, Shaik YB, Kempuraj D, Doyle R, Antinolfi PL, Cerulli G, Conti CM, Fulcheri M, Neri G, Sabatino G (2008b) Biology of neurotensin: revisited study. Int J Immunopathol Pharmacol 21:255–259
Katsanos GS, Anogeianaki A, Orso C, Tetè S, Salini V, Antinolfi PL, Sabatino G (2008c) Substance P: an inflammatory peptide. Eur J Inflamm 6(2):59–64
Keeble JE, Brain SD (2004) A role for substance P in arthritis? Neurosci Lett 361:176–179
Khalil Z, Helme RD (1989) Sympathetic neurons modulate plasma extravasation in the rat through a non-adrenergic mechanism. Clin Exp Neurol 26:45–50
Lai JP, Ho WZ, Kilpatrick LE, Wang X, Tuluc F, Korchak HM, Douglas SD (2006) Full-length and truncated neurokinin-1 receptor expression and function during monocyte/macrophage differentiation. Proc Natl Acad Sci USA 103:7771–7776
Lavagno L, Ferrero E, Ortolan E, Malavasi F, Funaro A (2007) CD157 is part of a supramolecular complex with CD11b/CD18 on the human neutrophil cell surface. J Biol Regul Homeost Agents 21:5–11
Magarelli N, Savastano MA, Palmieri D, Zappacosta R, Lattanzio G, Salini V, Orso CA, Guglielmi G, Colosimo C (2007) Poly-L-lactic acid beta-tricalcium phosphate screws: a preliminary in vivo biocompatibility study. Int J Immunopathol Pharmacol 20:207–211
Mori G, Brunetti G, Colucci S, Ciccolella F, Coricciati M, Pignataro P, Oranger A, Ballini A, Farronato D, Mastrangelo F, Tetè S, Grassi FR, Grano M (2007) Alteration of activity and survival of osteoblasts obtained from human periodontitis patients: role of TRAIL. J Biol Regul Homeost Agents 21:105–114
Newton R, Seybold J, Kuitert LM, Bergmann M, Barnes PJ (1998) Repression of cyclooxygenase-2 and prostaglandin E2 release by dexamethasone occurs by transcriptional and post-transcriptional mechanisms involving loss of polyadenylated mRNA. Biol Chem 273:32312–32321
Nishimura Y, Nishiike-Wada T, Wada Y, Miura Y, Otsuki T, Iguchi H (2007) Long-lasting production of TGF-beta1 by alveolar macrophages exposed to low doses of asbestos without apoptosis. Int J Immunopathol Pharmacol 20:661–671
Pacheco P, Vieira-de-Abreu A, Gomes RN, Barbosa-Lima G, Wermelinger LB, Maya-Monteiro CM, Silva AR, Bozza MT, Castro-Faria-Neto HC, Bandeira-Melo C, Bozza PT (2007) Monocyte chemoattractant protein-1/CC chemokine ligand 2 controls microtubule-driven biogenesis and leukotriene B4-synthesizing function of macrophage lipid bodies elicited by innate immune response. J Immunol 179:8500–8508
Panasiti V, Devirgiliis V, Mancini M, Curzio M, Rossi M, Fioriti D, Pietropaolo V, Nicosia R, Gallinelli C, Chiarini F, Pecorini G, Calvieri S (2008) A cutaneous infection caused by Brevundimonas vesicularis: a case report. Int J Immunopathol Pharmacol 21:437–445
Pannone G, Sanguedolce F, De Maria S, Farina E, Lo Muzio L, Serpico R, Emanuelli M, Rubini C, De Rosa G, Staibano S, Macchia L, Bufo P (2007) Cyclooxygenase isozymes in oral squamous cell carcinoma: a real-time RT-PCR study with clinic pathological correlations. Int J Immunopathol Pharmacol 20:317–324
Peters K, Unger RE, Gatti AM, Sabbioni E, Tsaryk R, Kirkpatrick CJ (2007) Metallic nanoparticles exhibit paradoxical effects on oxidative stress and pro-inflammatory response in endothelial cells in vitro. Int J Immunopathol Pharmacol 20:685–695
Piancatelli D, Bellotta L, Del Beato T, Duse M, Della Penna MR (2008) Total IL-12 levels are increased in paediatric atopic dermatitis: correlations with age and disease severity. Int J Immunopathol Pharmacol 21:359–365
Raffaelli L, Serini S, Piccioni E, Manicone PF, Berardi D, Perfetti G, Calviello G (2008) N-3 polyunsaturated fatty acid effect in periodontal disease: state of art and possible mechanisms involved. Int J Immunopathol Pharmacol 21:261–266
Reinke EK, Johnson MJ, Ling C, Karman J, Lee J, Weinstock JV, Sandor M, Fabry Z (1998) Substance P receptor mediated maintenance of chronic inflammation in EAE. Am J Physiol 274:L970–L979
Sardella G, De Luca L, Francavilla V, Accapezzato D, Di Roma A, Gianoglio O, Colantonio R, Mancone M, Fedele F, Paroli M (2007) Effect of coronary percutaneous revascularization on interferon-gamma and interleukin-10 producing CD4+ T cells during acute myocardial infarction. Int J Immunopathol Pharmacol 20:791–799
Shanmugham LN, Petrarca C, Castellani ML, Frydas S, Vecchiet J, Conti P, Tete S (2006) Rantes potentiates human macrophage aggregation and activation responses to calcium ionophore (A23187) and activates arachidonic acid pathways. J Biol Regul Homeost Agents 20(1–2):15–23
Steinhilber D (1994) 5-Lipoxygenase: enzyme expression and regulation of activity. Pharm Acta Helv 69:3–14
Stoppini L, Barja F, Mathison R, Baertschi J (1984) Spinal substance P transmits bradykinin but not osmotic stimuli from hepatic portal vein to hypothalamus in rat. Neuroscience 11:903–912
Sturiale S, Barbara G, Qiu B, Figini M, Geppetti P, Gerard N, Gerard C, Grady EF, Bunnett NW, Collins SM (1999) Neutral endopeptidase (EC 3.4.24.11) terminates colitis by degrading substance P. Proc Natl Acad Sci USA 96:11653–11658
Sun J, Ramnath RD, Tamizhselvi R, Bhatia M (2008) Neurokinin A engages Neurokinin-1 receptor to induce NF-{kappa}B-dependent gene expression in murine macrophages: implications of ERK1/2 and PI3K/Akt pathways. Am J Physiol Cell Physiol 295:C679–C691
Tang HB, Inoue A, Iwasa M, Hide I, Nakata Y (2006) Substance P release evoked by capsaicin or potassium from rat cultured dorsal root ganglion neurons is conversely modulated with bradykinin. J Neurochem 97:1412–1418
Tetè S, Mastrangelo F, Carone L, Nargi E, Costanzo G, Vinci R, Burruano F, Tortorici S, Dadorante V, Caciagli F, Traini T, Gherlone E, Caraffa A, Salini V, Conti P, Ciccarelli R (2007) Morphostructural analysis of human follicular stem cells on highly porous bone hydroxyapatite scaffold. Int J Immunopathol Pharmacol 20:819–826
Tortorici S, Mauro A, Burruano F, Difalco P, Leone A, Gerbino A, Buscemi M, Conti P, Mastrangelo F, Tete S (2008) Matrix metalloproteinase-2 matrix metalloproteinase-9 and inducible nitric oxide synthase in oral leukoplakia: immunohistochemistry and RT-PCR analysis. J Biol Regul Homeost Agents 22:125–130
Uracz W, Uracz D, Olszanecki R, Gryglewski RJ (2002) Interleukin 1beta induces functional prostaglandin E synthase in cultured human umbilical vein endothelial cells. Physiol Pharmacol 53:643–654
Weller CL, Collington SJ, Brown JK, Miller HR, Al-Kashi A, Clark P, Jose PJ, Hartnell A, Williams TJ (2005) Leukotriene B4, an activation product of mast cells, is a chemoattractant for their progenitors. J Exp Med 201:1961–1971
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Castellani, M.L., Conti, P., Felaco, M. et al. Substance P Upregulates LTB4 in Rat Adherent Macrophages from Granuloma Induced by KMnO4 . Neurotox Res 15, 49–56 (2009). https://doi.org/10.1007/s12640-009-9004-6
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DOI: https://doi.org/10.1007/s12640-009-9004-6