Abstract
Th2 type cytokines such as interleukin (IL)-4, IL-5, IL-9, and IL-13 are important mediators in allergic inflammation. The present review will focus on the role of IL-9 in allergic inflammation. The structure and genomic architecture of IL-9 and its receptor, the source of IL-9 and its regulation as well as its effects on different cell types will be reviewed. Furthermore, the specific role of IL-9 in allergic diseases and the potential therapeutic approach of blocking IL-9 will be discussed.
References
1.
Modi WS, Pollock DD, Mock BA, Banner C, Renauld JC, Van Snick J: Regional localization of the human glutaminase (GLS) and interleukin-9 (IL9) gene by in situ hybridization. Cytogenet Cell Gen 1991;57:114–116.
2.
Nicolaides NC, Holroyd KJ, Ewart SL, Eleff SM, Kiser MB, Dragwa CR, Sullivan CD, Grasso L, Zhang LY, Messler CJ, Zhou T, Kleeberger SR, Buetow KH, Levitt RC: Interleukin 9: A candidate gene for asthma. Proc Natl Acad Sci USA 1997;94:13175–13180.
3.
Postma DS, Bleecker ER, Amelung PJ, Holroyd KJ, Xu J, Panhuysen CI, Meyers DA, Levitt RC: Genetic susceptibility to asthma – bronchial hyperresponsiveness coinherited with a major gene for atopy. N Engl J Med 1995;333:894–900.
4.
Van Leeuwen BH, Martinson ME, Webb GC, Young IG: Molecular organization of the cytokine gene cluster, involving human IL-3, IL-4, IL-5, and GM-CSF genes, on human chromosome 5. Blood 1989;31:265–270.
5.
Mock BA, Krall M, Kozak CA, Nesbitt MN, McBride OW, Renauld JC, Van Snick J: IL-9 maps to mouse chromosome 13 and human chromosome 5. Immunogenetics 1990;31:265–270.
6.
Renauld JC, Goethals A, Houssiau F, Merz H, Van Roost E, Van Snick J: Human P40/IL-9. Expression in activated CD4+ T cells, genomic organization, and comparison with the mouse gene. J Immunol 1990;144:4235–4241.
7.
Zhu YX, Kang LY, Luo W, Li CCH, Yang L, Yang YC: Multiple transcription factors are required for activation of human interleukin 9 gene in T cells. J Biol Chem 1996;271:15815–15822.
8.
Kimura Y, Takeshitak T, Kondo M, Ishii N, Nakamura M, Van Snick J, Sugamura K: Sharing of the IL-2 receptor γ chain with the functional IL-9 receptor complex. Int Immunol 1995;7:115–120.
9.
Kermouni A, Van Roost E, Arden KC, Vermeesch JR, Weiss C, Godelaine D, Flint J, Lurquin C, Szikora JP, Higgs DR: The IL-9 receptor gene (IL9R): genomic structure, chromosomal localization in the pseudoautosomal region of the long arm of the sex chromosomes, and identification of IL9R pseudogenes at 9qter, 10pter, and 18pter. Genomics 1995;29:371–382.
10.
Vermeesch JR, Petit P, Kermouni A, Renauld JC, Van Den Berghe H, Marynen P: The IL-9 receptor gene, located in the Xq/Yq pseudoautosomal region, has an autosomal origin, escapes X inactivation and is expressed from the Y. Hum Mol Genet 1997;6:1–8.
11.
Demoulin JB, Uyttenhove C, Van Roost E, DeLestre B, Donckers D, Van Snick J, Renauld JC: A single tyrosine of the interleukin-9 (IL-9) receptor is required for STAT activation, antiapoptotic activity, and growth regulation by IL-9. Mol Cell Biol 1996;16:4710–4716.
12.
Bauer JH, Liu KD, You Y, Lai SY, Goldsmith MA: Heteromerization of the gamma c chain with the interleukin-9 receptor alpha unit leads to STAT activation and prevention of apoptosis. J Biol Chem 1998;273:9255–9260.
13.
Demoulin JB, Van Roost E, Stevens M, Groner B, Renauld JC: Distinct roles for STAT1, STAT3, and STAT5 in differentiation gene induction and apoptosis inhibition by interleukin-9. J Biol Chem 1999;274:25855–25861.
14.
Demoulin JB, Uyttenhove C, Lejeune D, Miu A, Groner B, Renauld JC: STAT5 activation is required for interleukin-9-dependent growth and transformation of lymphoid cells. Cancer Res 2000;60:3971–3977.
15.
Shimbara A, Christodoulopoulos P, Soussi-Gounni A, Olivenstein R, Nakamura Y, Levitt RC, Nicolaides NC, Holroyd KJ, Tsicopoulos A, Lafitte JJ, Wallaert B, Hamid Q: IL-9 and its receptor in allergic and nonallergic lung disease: Increased expression in asthma. J Allergy Clin Immunol 2000;105:108–115.
16.
Erpenbeck VJ, Hohlfeld JM, Volkmann B, Hagenberg A, Geldmacher H, Braun A, Krug N: Segmental allergen challenge in patients with atopic asthma leads to increased IL-9 expression in bronchoalveolar lavage fluid lymphocytes. J Allergy Clin Immunol 2003;111:1319–1327.
17.
Uyttenhove C, Simpson RJ, Van Snick J: Functional and structural characterization of P40, a mouse glycoprotein with T cell growth factor activity. Proc Natl Acad Sci USA 1988;85:6943–6948.
18.
Schmitt E, Beuscher HU, Huels C, Monteyne P, Van Brandwijk R, Van Snick J, Ruede E: IL-1 serves as a secondary signal for IL-9 expression. J Immunol 1991;147:3848–3854.
19.
Monteyne P, Renauld JC, Van Broeck J, Dunne DW, Brombacher F, Coutelier JP: IL-4-independent regulation of in vivo IL-9 expression. J Immunol 1997;159:2616–2623.
20.
Houssiau FA, Renauld JC, Fibbe WE, Van Snick J: IL-2 dependence of IL-9 expression in human T lymphocytes. J Immunol 1992;106:3147–3151.
21.
Houssiau F, Schandene L, Stevens M, Cambiaso C, Goldman M, Van Snick J, Renauld JC: A cascade of cytokines is responsible for IL-9 expression in human T cells. J Immunol 1995;154:2624–2630.
22.
Schmitt E, Germann T, Goedert S, Hoehn P, Huels C, Koelsch S, Kuhn R, Muller W, Palm N, Rude E: IL-9 production of naive CD4+ T cells depends on IL-2, is synergistically enhanced by a combination of TGF-beta and IL-4, and is inhibited by IFN-gamma. J Immunol 1994;153:3989–3996.
23.
Ying S, Meng Q, Kay AB, Robinson DS: Elevated expression of interleukin-9 mRNA in the bronchial mucosa of atopic asthmatics and allergen-induced cutaneous late-phase reaction: Relationship to eosinophils, mast cells and T lymphocytes. Clin Exp Allergy 2002;32:866–871.
24.
Soussi-Gounni A, Nutku E, Koussih L, Aris F, Louahed J, Levitt RC, Nicolaides NC, Hamid Q: IL-9 expression by human eosinophils: Regulation by IL-1β and TNF-α. J Allergy Clin Immunol 2000;106:460–466.
25.
Metcalfe DD, Baram D, Mekori YA: Mast cells. Physiol Rev 1997;77:1033–1079.
26.
Hultner L, Kolsch S, Stassen M, Kaspers U, Kremer JP, Mailhammer R, Moeller J, Broszeit H, Schmitt E: In activated mast cells, IL-1 upregulates the production of several Th2-related cytokines including IL-9. J Immunol 2000;164:5556–5563.
27.
Stassen M, Arnold M, Hultner L, Muller C, Neudorfl, C, Reineke T, Schmitt E: Murine bone marrow-derived mast cells as potent producers of IL-9:Costimulatory function of IL-10 and kit ligand in the presence of IL-1. J Immunol 2000;164:5549–5555.
28.
Matsuzawa S, Sakashita K, Kinoshita T, Ito S, Yamashita T, Koike K: IL-9 enhances the growth of human mast cell progenitors under stimulation with stem cell factor. J Immunol 2003;170:3461–3467.
29.
Chalmers GW, MacLeod KJ, Thomson L, Little SA, McSharry C, Thomson NC: Smoking and airway inflammation in patients with mild asthma. Chest 2001;120:1917–1922.
30.
Van Snick J, Goethals A, Renauld JC, Van Roost E, Uyttenhove C, Rubira MR, Moritz RL, Simpson RJ: Cloning and characterization of a cDNA for a new mouse T cell growth factor (P40). J Exp Med 1989;169:363–368.
31.
Gessner A, Blum H, Rollinghoff M: Differenatial regulation of IL-9 expression after infection with Leishmania major in susceptible and resistant mice. Immunobiology 1993;189:419–435.
32.
Renauld JC, Van der Lugt N, Vink A, Van Roon M, Godfraind C, Warnier G, Merz H, Feller A, Berns A, Van Snick J: Thymic lymphomas in interleukin 9 transgenic mice. Oncogene 1994;9:1327–1332.
33.
Merz H, Houssiau FA, Orscheschek K, Renauld JC, Fliedner A, Herin M, Noel H, Kadin M, Mueller-Hermelink HK, Van Snick J: Interleukin-9 expression in human malignant lymphomas: Unique association with Hodgkin’s disease and large cell anaplastic lymphoma. Blood 1991;78:1311–1317.
34.
Temann U, Geba G, Rankin J, Flavell R: Expression of interleukin-9 in the lungs of transgenic mice causes airway inflammation, mast cell hyperplasia, and bronchial hyperresponsiveness. J Exp Med 1998;188:1307–1320.
35.
Perdow-Hickman S, Salgame P: Rescue of human T cells by interleukin-9 (IL-9) from IL-2 deprivation-induced apoptosis: Correlation with α subunit expression of the IL-9 receptor. J Interferon Cytokine Res 2000;20:603–608.
36.
McLane MP, Haczku A, Van den Rijn M, Weiss C, Ferrante V, MacDonald D, Renauld JC, Nicolaides NC, Holroyd KJ, Levitt RC: Interleukin-9 promotes allergen-induced eosinophilic inflammation and airway hyperrepsonsiveness in transgenic mice. Am J Respir Cell Mol Biol 1998;19:713–720.
37.
Vink A, Warnier G, Brombacher F, Renauld JC: Interleukin-9-induced in vivo expansion of the B-1 lymphocyte population. J Exp Med 1999;189:1413–1423.
38.
Dugas B, Renauld JC, Pene J, Bonnefoy JY, Petit-Frere C, Braquet P, Bousquet J, Van Snick J, Mencia-Huerta JM: Interleukin-9 potentiates the interleukin-4-induced immunoglobulin (IgG, IgM and IgE) production by normal human B lymphocytes. Eur J Immunol 1993;23:1687–1692.
39.
Jeannin P, Delneste Y, Lecoanet-Henchoz S, Gretener D, Bonnefoy JY: Interleukin-7 (IL-7) enhances class switching to IgE and IgG4 in the presence of T cells via IL-9 and sCD23. Blood 1998;91:1355–1361.
40.
Dong Q, Louahed J, Vink A, Sullivan CD, Messler CJ, Zhou Y, Haczku A, Huaux F, Arras M, Holroyd KJ, Renauld JC, Levitt RC, Nicolaides NC: IL-9 induces chemokine expression in lung epithelial cells and baseline airway eosinophilia in transgenic mice. Eur J Immunol 1999;29:2130–2139.
41.
Louahed J, Zhou Y, Maloy WL, Rani PU, Weiss C, Tomer Y, Vink A, Renauld JC, Van Snick J, Nicolaides NC, Levitt RC, Haczku A: Interleukin 9 promotes influx and local maturation of eosinophils. Blood 2001;97:1035–1042.
42.
Soussi Gounni A, Gregory B, Nutku E, Aris F, Latifa K, Minshall E, North J, Tavernier J, Levitt RC, Nicolaides NC, Robinson D, Hamid Q: Interleukin-9 enhances interleukin-5 receptor expression, differentiation and survival of human eosinophils. Blood 2000;96:2163–2171.
43.
Gordon JR, Burd PR, Galli SJ: Mast cells as a source of multifunctional cytokines. Immunol Today 1990;11:458–464.
44.
Burd PR, Thompson WC, Max EE, Mills FC: Activated mast cell produce interleukin 13. J Exp Med 1995;181:1373–1380.
45.
Bradding P: Human mast cell cytokines. Clin Exp Allergy 1996;26:13–19.
46.
Hultner L, Druez C, Moeller J, Uyttenhove C, Schmitt E, Rude E, Dormer P, Van Snick J: Mast cell growth-enhancing activity (MEA) is structurally related and functionally identical to the mouse T cell growth factor P40/TCGFIII (interleukin 9). Eur J Immunol 1990;20:1413–1416.
47.
Renauld JC, Vink A, Louahed J, Van Snick J: Interleukin-9 is a major anti-apoptotic factor for thymic lymphomas. Blood 1995;85:1300–1305.
48.
Godfraind C, Louahed J, Faulkner H, Vink A, Warnier G, Grencis R, Renauld JC: Intraepithelial infiltration by mast cells with both connective tissue-type and mucosal-type characteristics in gut, trachea, and kidneys of IL-9 transgenic mice. J Immunol 1998;160:3989–3996.
49.
Louahed J, Kermouni A, Van Snick J, Renauld JC: IL-9 induces expression of granzymes and high-affinity IgE receptor in murine T helper clones. J Immunol 1995;154:5061–5070.
50.
Cassatella MA: The production of cytokines by polymorphonuclear neutrophils. Immunol Today 1995;16:21–26.
51.
Sibille Y, Reynolds HY: Macrophages and polymorphonuclear neutrophils in lung defense and injury. Am Rev Respir Dis 1990;141:471–501.
52.
Boshetto P, Mapp CE, Picotti G, Fabbri LM: Neutrophils and asthma. Eur Respir J 1989;6:S456–S459.
53.
Girard D, Boiani N, Beaulieu AD: Human neutrophils express the interleukin-15 receptor alpha chain (IL-15Ralpha) but not the IL-9Ralpha component. Clin Immunol Immunopathol 1998;88:232–240.
54.
Soussi Gounni A, Koussih L, Nutku E, Cameron L, Lamkhioued B, Nicolaides NC, Levitt RC, Hamid Q: Functional expression of IL-9 receptor by human neutrophils from asthmatic donors: Role in IL-8 release. J Immunol 2001;166:2768–2774.
55.
Little FF, Cruikshank WW, Center DM: IL-9 stimulates release of chemotactic factors from human bronchial epithelial cells. Am J Respir Cell Mol Biol 2001;25:347–352.
56.
Tsukadaira A, Okubo Y, Koyama S, Sato E, Nagase H, Agematsu K, Nakazawa K: Human bronchial epithelium expresses interleukin-9 receptors and releases neutrophil chemotactic factor. Exp Lung Res 2002;28:123–139.
57.
Longphre M, Li D, Gallup M, Drori E, Ordonez CL, Redman T, Wenzel S, Bice DE, Fahy JV, Basbaum C: Allergen-induced IL-9 directly stimulates mucin transcription in respiratory epithelial cells. J Clin Invest 1999;104:1375–1382.
58.
Louahed J, Toda M, Jen J, Hamid Q, Renauld JC, Levitt RC, Nicolaides NC: Interleukin-9 upregulates mucus expression in the airways. Am J Respir Cell Mol Biol 2000;22:649–656.
59.
Vermeer PD, Harson R, Einwalter LA, Moninger T, Zabner J: Interleukin-9 induces goblet cell hyperplasia during repair of human airway epithelia. Am J Respir Cell Mol Biol 2003;28:286–295.
60.
Nakanishi A, Morita S, Iwashita H, Sagiya Y, Ashida Y, Shirafuji H, Fujisawa Y, Nishimura O, Fujino M: Role of gob-5 in mucus overproduction and airway hyperresponsiveness in asthma. Proc Natl Acad Sci USA 2001;98:5175–5180.
61.
Zhou Y, Dong Q, Louahed J, Dragwa C, Savio D, Huang M, Weiss C, Tomer Y, McLane MP, Nicolaides NC, Levitt RC: Characterization of a calcium-activated chloride channel as a shared target of Th2 cytokine pathways and its potential involvement in asthma. Am J Respir Cell Mol Biol 2001;25:486–491.
62.
Toda M, Tulic MK, Levitt RC, Hamid Q: A calcium-activated chloride channel (hCLCA1) is strongly related to IL-9 expression and mucus production in bronchial epithelium of patients with asthma. J Allergy Clin Immunol 2002 109:246–250.
63.
Soussi Gounni A, Muro S, Levitt RC, Hamid Q: Role of IL-9 in smooth muscle cells function (abstract). J Allergy Clin Immunol 2001;107:S48.
64.
Baraldo S, Faffe DS, Moore PE, Whitehead T, McKenna M, Silverman ES, Panettieri RA Jr, Shore SA: Interleukin-9 influences chemokine release in airway smooth muscle: Role of ERK. Am J Physiol Lung Cell Mol Physiol 2003;284:L1093–L1102.
65.
Hirst SJ, Hallsworth MP, Peng Q, Lee TH: Selective induction of eotaxin release by interleukin-13 or interleukin-4 in human airway smooth muscle cells is synergistic with interleukin-1β and is mediated by the interleukin-4 receptor α-chain. Am J Respir Crit Care Med 2002;165:1161–1171.
66.
Laporte JC, Moore PE, Baraldo S, Jouvin MH, Church TL, Schwartzman IN, Panettieri RA Jr, Kinet JP, Shore SA: Direct effects of interleukin-13 on signaling pathways for physiological responses in cultured human airway smooth muscle cells. Am J Respir Crit Care Med 2001;164:141–148.
67.
Stetkiewicz P, Wills-Karp M, Sypek J: IL-13, IL-4, and TNFα regulate IL-4 and IL-13 receptor expressionn and eotaxin production in human bronchial smooth muscle (abstract). Am J Respir Crit Care Med 2001;163:A778.
68.
Noguchi E, Shibasaki M, Arinami T, Takeda K, Maki T, Miyamoto T, Kawashima T, Kobayashi K, Hamaguchi H: Evidence for linkage between asthma/atopy in childhood and chromosome 5q31-q33 in a Japanese population. Am J Respir Crit Care Med 1997;156:1390–1393.
69.
Bottcher MF, Jenmalm MC, Bjorksten B: Immune responses to birch in young children during their first 7 years of life. Clin Exp Allergy 2002;32:1690–1698.
70.
Jenmalm MC, Van Snick J, Cormont F, Salman B: Allergen-induced Th1 and Th2 cytokine secretion in relation to specific allergen sensitization and atopic symptoms in children. Clin Exp Allergy 2001;31:1528–1535.
71.
Levitt RC, McLane MP, MacDonald D, Ferrante V, Weiss C, Zhou Y, Holroyd KJ, Nicolaides NC: IL-9 pathway in asthma: new therapeutic targets for allergic inflammatory disorders. J Allergy Clin Immunol 1999;103:S484-S491.
72.
Lamblin C, Gosset P, Salez F, Vandezande LM, Perez T, Darras J, Janin A, Tonnel AB, Wallaert B: Eosinophilic airway inflammation in nasal polyposis. J Allergy Clin Immunol 1999;104:85–92.
73.
Kung TT, Lou B, Crawley Y, Garlisi CG, Devito K, Minnicozzi M, Egan RW, Kreutner W, Chapman RW: Effect of anti-mIL-9 antibody on the development of pulmonary inflammation and airway hyperresponsiveness in allergic mice. Am J Respir Cell Mol Biol 2001;25:600–605.
74.
Cheng G, Arima M, Honda K, Hirata H, Eda F, Yoshida N, Fukushima F, Ishii Y, Fukuda T: Anti-interleukin-9 antibody treatment inhibits airway inflammation and hyperreactivity in mouse asthma model. Am J Respir Crit Care Med 2002;166:409–416.
75.
Richard M, Grencis RK, Humphreys NE, Renauld JC, Van Snick J: Anti-IL-9 vaccination prevents worm expulsion and blood eosinophilia in Trichuris muris-infected mice. Proc Natl Acad Sci USA 2000;97:767–772.
76.
McMillan SJ, Bishop B, Townsend MJ, McKenzie AN, Lloyd CM: The absence of interleukin 9 does not affect the development of allergen-induced pulmonary inflammation nor airway hyperreactivity. J Exp Med 2002;195:51–57.
© 2004 S. Karger AG, Basel
2004
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.
