Background: Mast cells are involved in allergy and inflammation by secreting multiple mediators including histamine, cytokines and platelet-activating factor. Certain histamine 1 receptor antagonists have been reported to inhibit histamine secretion, but the effect on cytokine release from human mast cells triggered by allergic and other stimuli is not well known. We investigated the ability of rupatadine, a potent histamine 1 receptor antagonist that also blocks platelet-activating factor actions, to also inhibit mast cell mediator release. Methods: Rupatadine (1–50 μM) was used before stimulation by: (1) interleukin (IL)-1 to induce IL-6 from human leukemic mast cells (HMC-1 cells), (2) substance P for histamine, IL-8 and vascular endothelial growth factor release from LAD2 cells, and (3) IgE/anti-IgE for cytokine release from human cord blood-derived cultured mast cells. Mediators were measured in the supernatant fluid by ELISA or by Milliplex microbead arrays. Results: Rupatadine (10–50 μM) inhibited IL-6 release (80% at 50 μM) from HMC-1 cells, whether added 10 min or 24 h prior to stimulation. Rupatadine (10–50 μM for 10 min) inhibited IL-8 (80%), vascular endothelial growth factor (73%) and histamine (88%) release from LAD2 cells, as well as IL-6, IL-8, IL-10, IL-13 and tumor necrosis factor release from human cord blood-derived cultured mast cells. Conclusion: Rupatadine can inhibit histamine and cytokine secretion from human mast cells in response to allergic, immune and neuropeptide triggers. These actions endow rupatadine with unique properties in treating allergic inflammation, especially perennial rhinitis and idiopathic urticaria.

Keywords:
Cytokines, Inflammation, Mast cells, Rupatadine, Urticaria
1.
Galli SJ, Nakae S, Tsai M: Mast cells in the development of adaptive immune responses. Nat Immunol 2005;6:135–142.
2.
Mekori YA, Metcalfe DD: Mast cells in innate immunity. Immunol Rev 2000;173:131–140.
3.
Theoharides TC, Kalogeromitros D: The critical role of mast cell in allergy and inflammation. Ann NY Acad Sci 2006;1088:78–99.
4.
Boesiger J, Tsai M, Maurer M, Yamaguchi M, Brown LF, Claffey KP, Dvorak HF, Galli SJ: Mast cells can secrete vascular permeability factor/vascular endothelial cell growth factor and exhibit enhanced release after immunoglobulin E-dependent upregulation of Fcε receptor I expression. J Exp Med 1998;188:1135–1145.
5.
Papanicolaou D, Wilder RL, Manolagas SC, Chrousos G: The pathophysiologic roles of interleukin-6 in human disease. Ann Intern Med 1998;128:127–137.
6.
Salamon P, Shoham NG, Gavrieli R, Wolach B, Mekori YA: Human mast cells release interleukin-8 and induce neutrophil chemotaxis on contact with activated T cells. Allergy 2005;60:1316–1319.
7.
Grutzkau A, Kruger-Krasagakes S, Baumeister H, Schwarz C, Kogel H, Welker P, Lippert U, Henz BM, Moller A: Synthesis, storage and release of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) by human mast cells: implications for the biological significance of VEGF206. Mol Biol Cell 1998;9:875–884.
8.
Kay AB: Allergy and allergic diseases: first of two parts. N Engl J Med 2001;344:30–37.
9.
Paus R, Theoharides TC, Arck PC: Neuroimmunoendocrine circuitry of the ‘brain-skin connection’. Trends Immunol 2006;27:32–39.
10.
Estelle F, Simons R: The antiallergic effects of antihistamines (H1-receptor antagonists). J Allergy Clin Immunol 1992;90:705–715.
11.
Keam SJ, Plosker GL: Rupatadine: a review of its use in the management of allergic disorders. Drugs 2007;67:457–474.
12.
Merlos M, Giral M, Balsa D, Ferrando R, Queralt M, Puigdemont A, Garcia-Rafanell J, Forn J: Rupatadine, a new potent, orally active dual antagonist of histamine and platelet-activating factor (PAF). J Pharmacol Exp Ther 1997;280:114–121.
13.
Katiyar S, Prakash S: Pharmacological profile, efficacy and safety of rupatadine in allergic rhinitis. Prim Care Respir J 2008;8–12. DOI: 10.3132/pcrj.2008.00043.
14.
Picado C: Rupatadine: pharmacological profile and its use in the treatment of allergic disorders. Expert Opin Pharmacother 2006;7:1989–2001.
15.
Izquierdo I, Merlos M, Garcia-Rafanell J: Rupatadine: a new selective histamine H1 receptor and platelet-activating factor (PAF) antagonist. A review of pharmacological profile and clinical management of allergic rhinitis. Drugs Today (Barc) 2003;39:451–468.
16.
Stuebner P, Horak F, Zieglmayer R, Arnaiz E, Leuratti C, Perez I, Izquierdo I: Effects of rupatadine vs placebo on allergen-induced symptoms in patients exposed to aeroallergens in the Vienna Challenge Chamber. Ann Allergy Asthma Immunol 2006;96:37–44.
17.
Fantin S, Maspero J, Bisbal C, Agache I, Donado E, Borja J, Mola O, Izquierdo I: A 12-week placebo-controlled study of rupatadine 10 mg once daily compared with cetirizine 10 mg once daily, in the treatment of persistent allergic rhinitis. Allergy 2008;63:924–931.
18.
Dubertret L, Zalupca L, Cristodoulo T, Benea V, Medina I, Fantin S, Lahfa M, Perez I, Izquierdo I, Arnaiz E: Once-daily rupatadine improves the symptoms of chronic idiopathic urticaria: a randomised, double-blind, placebo-controlled study. Eur J Dermatol 2007;17:223–228.
19.
Martinez-Cocera C, De Molina M, Marti-Guadano E, Pola J, Conde J, Borja J, Perez I, Arnaiz E, Izquierdo I: Rupatadine 10 mg and cetirizine 10 mg in seasonal allergic rhinitis: a randomised, double-blind parallel study. J Investig Allergol Clin Immunol 2005;15:22–29.
20.
Mullol J, Bousquet J, Bachert C, Canonica WG, Gimenez-Arnau A, Kowalski ML, Marti-Guadano E, Maurer M, Picado C, Scadding G, Van Cauwenberge P: Rupatadine in allergic rhinitis and chronic urticaria. Allergy 2008;63(suppl 87):5–28.
21.
Butterfield JH, Weiler D, Dewald G, Gleich GJ: Establishment of an immature mast cell line from a patient with mast cell leukemia. Leuk Res 1988;12:345–355.
22.
Kirshenbaum AS, Akin C, Wu Y, Rottem M, Goff JP, Beaven MA, Rao VK, Metcalfe DD: Characterization of novel stem cell factor responsive human mast cell lines LAD 1 and 2 established from a patient with mast cell sarcoma/leukemia; activation following aggregation of FcepsilonRI or FcgammaRI. Leuk Res 2003;27:677–682.
23.
Kempuraj D, Saito H, Kaneko A, Fukagawa K, Nakayama M, Toru H, Tomikawa M, Tachimoto H, Ebisawa M, Akasawa A, Miyagi T, Kimura H, Nakajima T, Tsuji K, Nakahata T: Characterization of mast cell-committed progenitors present in human umbilical cord blood. Blood 1999;93:3338–3346.
24.
Kandere-Grzybowska K, Letourneau R, Kempuraj D, Donelan J, Poplawski S, Boucher W, Athanassiou A, Theoharides TC: IL-1 induces vesicular secretion of IL-6 without degranulation from human mast cells. J Immunol 2003;171:4830–4836.
25.
Kempuraj D, Huang M, Kandere K, Boucher W, Leutourneau R, Jeudy S, Fitzgerald K, Spear K, Athanasiou A, Theoharides TC: Azelastine is more potent than olopatadine in inhibiting interleukin-6 and tryptase release from human umbilical cord blood-derived cultured mast cells. Ann Allergy Asthma Immunol 2002;88:501–506.
26.
Queralt M, Brazis P, Merlos M, de Mora F, Puigdemont A: In vitro inhibitory effect of rupatadine on histamine and TNF-alpha release from dispersed canine skin mast cells and the human mast cell line HMC-1. Inflamm Res 2000;49:355–360.
27.
Solans A, Carbo ML, Pena J, Nadl T, Izquierdo I, Merlos M: Influence of food on the bioavailability of rupatadine tablets in healthy volunteers; a single-dose, randomized, open-label, two-way crossover study. Clin Ther 2007;29:900–908.
28.
Lytinas M, Kempuraj D, Huang M, Kandere K, Boucher W, Letourneau R, Jeudy S, Fitzgerald K, Spear K, Athanasiou A, Theoharides TC: Azelastine’s inhibition of histamine and tryptase release from human umbilical cord blood-derived cultured mast cells, as well as rat skin mast cell-induced vascular permeability: comparison with olopatadine. Allergy Asthma Proc 2002;23:45–51.
29.
Kempuraj D, Huang M, Kandere-Grzybowska K, Basu S, Boucher W, Letourneau R, Athanasiou A, Theoharides TC: Azelastine inhibits secretion of IL-6, TNF-α and IL-8 as well as NF-κB activation and intracellular calcium ion levels in normal human mast cells. Int Arch Allergy Immunol 2003;132:231–239.
30.
Galatowicz G, Ajayi Y, Stern ME, Calder VL: Ocular anti-allergic compounds selectively inhibit human mast cell cytokines in vitro and conjunctival cell infiltration in vivo. Clin Exp Allergy 2007;37:1648–1656.
31.
Siraganian RP: Mast cell signal transduction from the high-affinity IgE receptor. Curr Opin Immunol 2003;15:639–646.
32.
Blank U, Rivera J: The ins and outs of IgE-dependent mast-cell exocytosis. Trends Immunol 2004;25:266–273.
33.
Kraft S, Rana S, Jouvin MH, Kinet JP: The role of the FcepsilonRI beta-chain in allergic diseases. Int Arch Allergy Immunol 2004;135:62–72.
34.
Grabbe J, Welker P, Möller A, Dippel E, Ashman LK, Czarnetzki BM: Comparative cytokine release from human monocytes, monocyte-derived immature mast cells and a human mast cell line (HMC-1). J Invest Dermatol 1994;103:504–508.
35.
Bradding P, Okayama Y, Howarth PH, Church MK, Holgate ST: Heterogeneity of human mast cells based on cytokine content. J Immunol 1995;155:297–307.
36.
Krüger-Krasagakes S, Möller AM, Kolde G, Lippert U, Weber M, Henz BM: Production of inteuleukin-6 by human mast cells and basophilic cells. J Invest Dermatol 1996;106:75–79.
37.
Gibbs BF, Wierecky J, Welker P, Henz BM, Wolff HH, Grabbe J: Human skin mast cell rapidly release preformed and newly generated TNF-alpha and IL-8 following stimulation with anti-IgE and other secretagogues. Exp Dermatol 2001;10:312–320.
38.
Theoharides TC, Kempuraj D, Tagen M, Conti P, Kalogeromitros D: Differential release of mast cell mediators and the pathogenesis of inflammation. Immunol Rev 2007;217:65–78.
39.
Cao J, Papadopoulou N, Kempuraj D, Boucher WS, Sugimoto K, Cetrulo CL, Theoharides TC: Human mast cells express corticotropin-releasing hormone (CRH) receptors and CRH leads to selective secretion of vascular endothelial growth factor. J Immunol 2005;174:7665–7675.
© 2009 S. Karger AG, Basel
2009
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.