Background: Pranlukast, a cysteinyl leukotriene receptor 1 (CysLTR1) antagonist, inhibits not only airway smooth muscle contraction, but also allergic inflammation. The aim of this study was to determine the mechanism of pranlukast-induced interleukin-5 (IL-5) inhibition in allergic inflammation. Methods: Surgically resected human lung tissue was passively sensitized in vitro with mite-allergen-sensitized sera, followed by stimulation with mite allergen after pretreatment of the tissue with pranlukast, dexamethasone, or both. The IL-5 protein level in the culture medium was measured, and in situ hybridization of IL-5 and CysLTR1 mRNA was performed using lung tissues. Results: Pretreatment of lung tissues with pranlukast alone significantly decreased the amount of IL-5 protein in the culture medium by 40%. The combination of pranlukast and dexamethasone synergistically enhanced this effect. Quantitative in situ hybridization with image analysis revealed abundant expression of IL-5 mRNA in eosinophils, lymphocytes, and mast cells in sensitized and allergen-stimulated lung tissues. CysLTR1 mRNA was detected in macrophages, smooth muscle cells, eosinophils, and mast cells, but was less expressed in lymphocytes. Pranlukast-induced inhibition of IL-5 mRNA expression was noted in various cells, irrespective of their CysLTR1 mRNA expression status. In addition, cysteinyl leukotrienes per se failed to upregulate the IL-5 production. Conclusion: Our results indicate that pranlukast inhibits IL-5 synthesis via a mechanism distinct from CysLTR1 antagonism.

1.
National Heart, Lung and Blood Institute: International Consensus Report on Diagnosis and Management of Asthma. Bethesda, National Institutes of Health, 1992.
2.
National Heart, Lung and Blood Institute: Global Strategy for Asthma Management and Prevention Issued January, 1995. NIH Publication No. 02-3659, revised 2002. Bethesda, National Institutes of Health, 2002.
3.
Obata T, Okada Y, Motoishi M, Nakagawa N, Terawaki T, Aishita H: In vitro antagonism of ONO-1078, a newly developed anti-asthma agent, against peptide leukotrienes in isolated guinea pig tissues. Jpn J Pharmacol 1992;60:227–237.
4.
Drazen JM: Comparative contractile responses to sulfidopeptide leukotrienes in normal and asthmatic human subjects. Ann N Y Acad Sci 1988;524:289–297.
5.
Tamaoki J, Kondo M, Sakai N, Nakata J, Takemura H, Nagai A, Takizawa T, Konno K: Leukotriene antagonist prevents exacerbation of asthma during reduction of high-dose inhaled corticosteroid. The Tokyo Joshi-Idai Asthma Research Group. Am J Respir Crit Care Med 1997;155:1235–1240.
6.
Yamaguchi K, Tanifuji Y, Pan LH, Yoshida T, Sakurai S, Goto S, Kuroda S, Kobayashi H, Inoue H: Effects of pranlukast, a leukotriene receptor antagonist, on airway inflammation in mild asthmatics. J Asthma 2001;38:51–57.
7.
Diamant Z, Hitermann JT, van Rensen EL, Callenbach PM, Veselic-Charvat M, van der Veen H, Sont JK, Sterk PJ: The effect of inhaled leukotriene D4 and methacholine on sputum cell differentials in asthma. Am J Respir Crit Care Med 1997;155:1247–1253.
8.
Underwood DC, Osborn RR, Newsholme SJ, Torphy TJ, Hay DW: Persistent airway eosinophilia after leukotriene (LT) D4 administration in the guinea pig: Modulation by the LTD4 receptor antagonist, pranlukast, or an interleukin-5 monoclonal antibody. Am J Respir Crit Care Med 1996;154(4 Pt 1):850–857.
9.
Fukushima C, Shimoda T, Matsuse H, Takao A, Sakai H, Asai S, Kohno S, Hara K: Inhibitory effect of thromboxane A2 synthetase inhibitor, DP-1904, on antigen-induced contraction of human lung parenchyma. Ann Allergy Asthma Immunol 1996;77:483–487.
10.
Koji T, Brenner RM: Localization of estrogen receptor messenger ribonucleic acid in rhesus monkey uterus by nonradioactive in situ hybridization with digoxigenin-labeled oligodeoxynucleotides. Endocrinology 1993;132:382–392.
11.
Adams JC: Heavy metal intensification of DAB-based HRP reaction product. J Histochem Cytochem 1981;29:775.
12.
Yoshii A, Koji T, Ohsawa N, Nakane PK: In situ localization of ribosomal RNAs is a reliable reference for hybridizable RNA in tissue sections. J Histochem Cytochem 1995;43:321–328.
13.
Tohda Y, Nakahara H, Kubo H, Haraguchi R, Fukuoka M, Nakajima S: Effect of ONO-1078 (pranlukast) on cytokine production in peripheral blood mononuclear cells of patients with bronchial asthma. Clin Exp Allergy 1999;29:1532–1536.
14.
Heise CE, O’Dowd BF, Figueroa DJ, Sawyer N, Nguyen T, Im DS, Stocco R, Bellefeuille JN, Abramovitz M, Cheng R, Willians DL Jr, Zeng Z, Liu O, Ma L, Clements MK, Coulombe N, Liu Y, Austin CP, George SR, O’Neill GP, Metters KM, Lynch KR, Evans JF: Characterization of the human cysteinyl leukotriene 2 receptor. J Biol Chem 2000;275:30531–30536.
15.
Tomari S, Matsuse H, Machida I, Kondo Y, Kawano T, Obase Y, Fukushima C, Shimoda T, Kohno S: Pranlukast, a cysteinyl leukotriene receptor 1 antagonist, attenuates allergen-specific tumor necrosis factor alpha production and nuclear factor kappa B nuclear translocation in peripheral blood monocytes from atopic asthmatics. Clin Exp Allergy 2003;33:795–801.
16.
Panettieri RA, Tan EM, Ciocca V, Luttmann MA, Leonard TB, Hay DW: Effects of LTD4 on human airway smooth muscle cell proliferation, matrix expression, and contraction in vitro: Differential sensitivity to cysteinyl leukotriene receptor antagonists. Am J Respir Cell Mol Biol 1998;19:453–461.
17.
Vargaftig BB, Singer M: Leukotrienes mediate murine bronchopulmonary hyperreactivity, inflammation, and part of mucosal metaplasia and tissue injury induced by recombinant murine interleukin-13. Am J Respir Cell Mol Biol 2003;28:410–419.
18.
Singer M, Lefort J, Vargaftig BB: Granulocyte depletion and dexamethasone differentially modulate airways hyperreactivity, inflammation, mucus accumulation, and secretion induced by rmIL-13 or antigen. Am J Respir Cell Mol Biol 2002;26:74–84.
19.
Vargaftig BB, Singer M: Leukotrienes, IL-13, and chemokines cooperate to induce BHR and mucus in allergic mouse lungs. Am J Physiol Lung Cell Mol Physiol 2003;284:L260–L269.
20.
Vargaftig BB, Singer M: Leukotrienes mediate part of Ova-induced lung effects in mice via EGFR. Am J Physiol Lung Cell Mol Physiol 2003;285:L808–L818.
21.
Ihaku D, Cameron L, Suzuki M, Molet S, Martin J, Hamid Q: Montelukast, a leukotriene receptor antagonist, inhibits the late airway response to antigen, airway eosinophilia, and IL-5-expressing cells in Brown Norway rats. J Allergy Clin Immunol 1999;104:1147–1154.
22.
Espinosa K, Bosse Y, Stankova J, Rola-Pleszczynski M: CysLT1 receptor upregulation by TGF-beta and IL-13 is associated with bronchial smooth muscle cell proliferation in response to LTD4. J Allergy Clin Immunol 2003;111:1032–1040.
23.
Laviolette M, Malmström K, Lu S, Chervinsky P, Pujet JC, Peszek I, Zhang J, Reiss TF: Montelukast added to inhaled beclomethasone in treatment of asthma. Am J Respir Crit Care Med 1999;160:1862–1868.
24.
Kawano T, Matsuse H, Kondo Y, Machida I, Saeki S, Tomari S, Mitsuta K, Obase Y, Fukushima C, Shimoda T, Kohno S: Cysteinyl leukotrienes induce nuclear factor kappa b activation and RANTES production in a murine model of asthma. J Allergy Clin Immunol 2003;112:369–374.
25.
Bisgaard H: Role of leukotrienes in asthma pathophysiology. Pediatr Pulmonol 2000;30:166–176.
26.
Lynch KR, O’Neill GP, Liu O, Im DS, Sawyer N, Metters KM, Coulombe N, Abramovitz M, Figueroa DJ, Zeng Z, Connolly BM, Bai C, Austin CP, Chateauneuf A, Stocco R, Greig GM, Kargman S, Hooks SB, Hosfield E, Williams DL Jr, Ford-Hutchinson AW, Caskey CT, Evans JF: Characterization of the human cysteinyl leukotriene CysLT1 receptor. Nature 1999;399:789–793.
27.
Mellor EA, Maekawa A, Austen KF, Boyce JA: Cysteinyl leukotriene receptor 1 is also a pyrimidinergic receptor and is expressed by human mast cells. Proc Natl Acad Sci USA 2001;98:7964–7969.
28.
Figueroa DJ, Breyer RM, Defoe SK, Kargman S, Daugherty BL, Waldburger K, Liu Q, Clements M, Zeng Z, O’Neill GP, Jones TR, Lynch KR, Austin CP, Evans JF: Expression of the cysteinyl leukotriene 1 receptor in normal human lung and peripheral blood leukocytes. Am J Respir Crit Care Med 2001;163:226–233.
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.