Background: The basic pathological features of bronchial asthma can be explained on the basis of chronic airway inflammation, involving inflammatory cells such as T cells (particularly type 2 helper T, Th2, cells) and mast cells, and airway remodeling. Many aspects of airway remodeling remain unclear at the molecular level. Recent attention has focused on the role of transforming growth factor (TGF)-β, a fibrogenic cytokine, in airway remodeling. Currently available evidence suggests that airway remodeling is caused by an imbalance in regulatory mechanisms mediated by Smads, a family of signal-transducing molecules. Objectives: We studied the effects of the Th2 cytokines interleukin (IL)-5 and granulocyte-macrophage colony-stimulating factor (GM-CSF), and the regulatory cytokine IL-10 on the expression of inhibitory Smad7 protein in bronchial epithelial cells. Methods: Real-time reverse-transcriptase polymerase chain reaction was employed. Results: Stimulation with IL-10 upregulated the expression of Smad7 compared with control. Neither IL-5 nor GM-CSF induced Smad7 expression. Smad7 expression was upregulated by IL-10 plus either IL-5 or GM-CSF. IL-10 inhibited the expression of TGF-β-inducible early gene, which is known to downregulate Smad7 expression. Conclusions: Our results suggest that IL-10 acts as a regulatory cytokine in the inhibition of airway inflammation.

Keywords:
Bronchial asthma, IL-10, Smad7, TGF-β signaling
1.
Makino S, Ohta K, Nishima S, Morikawa A: Asthma Prevention and Management Guidelines 200, Japan. Int Arch Allergy Immunol 2005;136:(suppl 1):1–50.
2.
National Heart, Lung, and Blood Institute: Global Strategy for Asthma Management and Prevention, revised 2002. Bethesda, US Department of Health and Human Services; 2002, NIH Pub No. 02-3659.
3.
Holgate ST: Unmet clinical needs in asthma. Clin Exp Allergy 2000;30(suppl 1):1.
4.
Bousquet J, Jeffery PK, Busse WW, et al: Asthma. From bronchoconstriction to airways inflammation and remodeling. Am J Respir Crit Care Med 2000;161:1720–1745.
5.
Vignola AM, Kips J, Bousquet J: Tissue remodeling as a feature of persistent asthma. J Allergy Clin Immunol 2000;105:1041–1053.
6.
Ohno I, Nitta Y, Yamauchi K, et al: Eosinophils as a potential source of platelet-derived growth factor B-chain (PDGF-B) in nasal polyposis and bronchial asthma. Am J Respir Cell Mol Biol 1995;13:639–647.
7.
Boulay ME, Prince P, Deschesnes F, et al: Metalloproteinase-9 in induced sputum correlates with the severity of the late allergen-induced asthmatic response. Respiration 2004;71:216–224.
8.
Chen XQ, Yang J, Hu SP, et al: Increased expression of CD86 and reduced production of IL-12 and IL-10 by monocyte-derived dendritic cells from allergic asthmatics and their effects on Th1-and Th2-type cytokine balance. Respiration 2006;73:34–40.
9.
Massague J: TGF-β signal transduction. Annu Rev Biochem 1998;67:753–791.
10.
Nakao A, Imamura T, Souchenlnytskyi S, et al: TGF-β receptor-mediated signaling through Smad2, Smad3 and Smad4. EMBO J 1997;16:5353–5362.
11.
Heldin CH, Miyazono K, ten Dijke P: TGF-β signaling from cell membrane to nucleus through Smad proteins. Nature 1997;390:465–471.
12.
Nakao A, Afrankhte M, Moren A, et al: Identification of Smad7, a TGFβ-inducible antagonist of TGF-β signalling. Nature 1997;389: 631–635
13.
Nakao A, Fuji M, Matsumura R, et al: Transient gene transfer and expression of Smad7 prevents bleomycin-induced lung fibrosis in mice. J Clin Invest 1999;104:5–11.
14.
Sagara H, Okada T, Okumura K, et al: Activation of TGF-β/Smad2 signaling is associated with airway remodeling in asthma. J Allergy Clin Immunol 2002;110:249–254.
15.
Jackson AL, Warner NL: Preparation, staining and analysis by flow cytometry of peripheral blood leukocytes; in Rose NR, Friedman M, Fahey HL (eds): Manual of Clinical Laboratory Immunology, ed 3. Washington, American Society for Microbiology, 1986, pp 226–235.
16.
Chomczynski P: A reagent for the single-step simultaneous isolation of RNA, DNA, and protein from cell and tissue samples. Biotechniques 1993;15:532–536.
17.
Ohno I, Nitta Y, Yamauchi K, et al: Transforming growth factor-β1 gene expression by eosinophils in asthmatic airway inflammation. Am J Respir Cell Mol Biol 1996;15:404–409.
18.
Minshall EM, Leung DY, Martin RJ, et al: Eosinophil-associated TGF-β1 mRNA expression and airways fibrosis in bronchial asthma. Am J Respir Cell Mol Biol 1997;17:326–333.
19.
Vignola A, Chanez P, Chiappara G, et al: Transforming growth factor-β expression in mucosa biopsies in asthma and chronic bronchitis. Am J Respir Crit Care Med 1997;156:591–599.
20.
Massague J: How cells read TGF-β signals. Nat Rev Mol Cell Biol 2000;1:169–178.
21.
Moustakas A, Souchelnyskyi S, Heldin CH: Smad regulation in TGF-β signal transduction. J Cell Sci 2001;14:4359–4369.
22.
Nakao A, Sagara H, Setoguchi Y, et al: Expression of Smad7 in bronchial epithelial cells is inversely correlated to basement membrane thickness and airway hyperresponsiveness in asthma. J Allergy Clin Immunol 2002;110:873–878.
23.
Johnsen SA, Subramaniam M, Katagiri T, et al: Transcriptional regulation of Smad2 is required for enhancement of TGFβ/Smad signaling by TGFβ inducible early gene. J Cell Biochem 2002;87:233–241.
24.
Prete GD, Carli MD, Almerigogna F, et al: Human IL-10 is produced by both type1 helper (Th1) and type2 helper (Th2) T cell clones and inhibits their antigen-specific proliferation and cytokine production. J Immunol 1993;150:353–360.
25.
Zuany-Amorim C, Haile S, Leduc D, et al: Interleukin-10 inhibits antigen-induced cellular recruitment into the airways of sensitized mice. J Clin Invest 1995;95:2644–2651.
26.
Grung G, Corry DB, Leach MW, et al: Interleukin-10 is a natural suppressor of cytokine production and inflammation in a murine model of allergic bronchopulmonary aspergillosis. J Exp Med 1997;185:1089–1099.
27.
Groux H, Bigler M, de Vries JE, et al: Interleukin-10 induces a long-term antigen-specific anergic state in human CD4+T cells. J Exp Med 1996;184:19–29.
28.
D’Andrea A, Aste-Amezaga M, Valiante NM, et al: Interleukin-10 (IL-10) inhibits human lymphocyte interferon gamma-production by suppressing natural killer cell stimulatory factor/IL-12 synthesis in accessory cells. J Exp Med 1993;178:1041–1048.
29.
Borish L, Aarons A, Rumbyrt J, et al: Interleukin-10 regulation in normal subjects and patients with asthma. J Allergy Clin Immunol 996;97:1288–1296.
© 2007 S. Karger AG, Basel
2007
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.