Targeting Th2 Cells in Asthmatic Airways

  • Gaetano Caramori
  • Kazuhiro Ito
  • Paolo Casolari
  • Marco Contoli
  • Alberto Papi
  • Ian M. Adcock
Part of the Allergy Frontiers book series (ALLERGY, volume 6)


Asthma represents a profound worldwide public health problem. The most effective anti-asthmatic drugs currently available include inhaled β2 -agonists and glucocorti-coids; these control asthma in about 90–95% of patients. However, the future therapies will need to focus on the 5–10% patients who do not respond well to these treatments and who account for ~50% of the health care costs of asthma [1, 2]. Strategies for the primary prevention of asthma remain in the realm of speculation and hypothesis [3]. Drug development for asthma has been directed at improving currently available drugs and finding new compounds that target the Th2-driven airway inflammatory response. Several new compounds have been developed to target specific components of the inflammatory process in asthma [e.g., anti-IgE antibodies (omalizumab), cytokines and/or chemokines antagonists, immunomodu-lators, antagonists of adhesion molecules], although they have not yet been proven to be particularly effective. In fact, only omalizumab has reached the market; it may be most cost-effective for patients with severe persistent asthma and frequent severe exacerbations requiring hospital care [3– 5]. In this chapter, we will review the role of current antiasthma drugs and future new chemical entities that can target Th2 cells in asthmatic airways. Some of these new Th2-oriented strategies may, in the future, not only control symptoms and modify the natural course of asthma, but also potentially prevent or cure the disease.


Airway Inflammation Allergy Clin Immunol Respir Crit Airway Hyperresponsiveness Asthmatic Airway 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Barnes PJ, Jonsson B, Klim JB (1996) The costs of asthma. Eur Respir J 9:636–642.PubMedCrossRefGoogle Scholar
  2. 2.
    Gaga M, Zervas E, Grivas S, Castro M, Chanez P (2007) Evaluation and management of severe asthma. Curr Med Chem 14:1049–1059.PubMedCrossRefGoogle Scholar
  3. 3.
    Global Initiative for Asthma. Global strategy for Asthma Management and Prevention. NHLBI/WHO Workshop report. 2002. NIH Publication No 02-3659: 1-200. Last update 2006. Freely available online at (accessibility verified 15 July 2007).
  4. 4.
    Strunk RC, Bloomberg GR (2006) Omalizumab for asthma. N Engl J Med 354:2689–2695.PubMedCrossRefGoogle Scholar
  5. 5.
    Avila PC (2007) Does anti-IgE therapy help in asthma? Efficacy and controversies. Annu Rev Med 58:185–203.PubMedCrossRefGoogle Scholar
  6. 6.
    Kips JC, Anderson GP, Fredberg JJ, Herz U, Inman MD, Jordana M, Kemeny DM, Lotvall J, Pauwels RA, Plopper CG, Schmidt D, Sterk PJ, Van Oosterhout AJ, Vargaftig BB, Chung KF (2003) Murine models of asthma. Eur Respir J 22:374–382.PubMedCrossRefGoogle Scholar
  7. 7.
    Barnes PJ, Adcock IM (2003) How do corticosteroids work in asthma?Ann Intern Med 139:359–370.PubMedGoogle Scholar
  8. 8.
    Caramori G, Adcock I (2003) Pharmacology of airway inflammation in asthma and COPD. Pulm Pharmacol Ther 16:247–277.PubMedCrossRefGoogle Scholar
  9. 9.
    Caramori G, Pandit A, Papi A (2005) Is there a difference between chronic airway inflammation in chronic severe asthma and chronic obstructive pulmonary disease? Curr Opin Allergy Clin Immunol 5:77–83.PubMedGoogle Scholar
  10. 10.
    Loke TK, Sousa AR, Corrigan CJ, Lee TH (2002) Glucocorticoid-resistant asthma. Curr Allergy Asthma Rep 2:144–150.PubMedCrossRefGoogle Scholar
  11. 11.
    Adcock IM, Lane J (2003) Corticosteroid-insensitive asthma: molecular mechanisms. J Endocrinol 178:347–355.PubMedCrossRefGoogle Scholar
  12. 12.
    Barnes PJ, Chung KF, Page CP (1998) Inflammatory mediators of asthma: an update. Pharmacol Rev 50:515–596.PubMedGoogle Scholar
  13. 13.
    Miyaura H, Itawa M (2002) Direct and indirect inhibition of Th1 development by progesterone and glucocorticoids. J Immunol 168:1087–1094.PubMedGoogle Scholar
  14. 14.
    Karagiannidis C, Ruckert B, Hense G, Willer G, Menz G, Blaser K, Schmidt-Weber CB (2005) Distinct leucocyte redistribution after glucocorticoid treatment among difficult-to-treat asthmatic patients. Scand J Immunol 61:187–196.PubMedCrossRefGoogle Scholar
  15. 15.
    Peek EJ, Richards DF, Faith A, Lavender P, Lee TH, Corrigan CJ, Hawrylowicz CM (2005) Interleukin-10-secreting “regulatory” T cells induced by glucocorticoids and beta2-agonists. Am J Respir Cell Mol Biol 33:105–111.PubMedCrossRefGoogle Scholar
  16. 16.
    Jee YK, Gilour J, Kelly A, Bowen H, Richards D, Soh C, Smith P, Hawrylowicz C, Cousins D, Lee T, Lavender P (2005) Repression of interleukin-5 transcription by the glucocorticoid receptor targets GATA3 signaling and involves histone deacetylase recruitment. J Biol Chem 280:23243–23250.PubMedCrossRefGoogle Scholar
  17. 17.
    Crocker IC, Church MK, Newton S, Townley RG (1998) Glucocorticoids inhibit proliferation and interleukin-4 and interleukin-5 secretion by aeroallergen-specific T-helper type 2 cell lines. Ann Allergy Asthma Immunol 80:509–516.PubMedGoogle Scholar
  18. 18.
    Powell N, Till SJ, Kay AB, Corrigan CJ (2001) The topical glucocorticoids beclomethasone dipropionate and fluticasone propionate inhibit human T-cell allergen-induced production of IL-5, IL-3 and GM-CSF mRNA and protein. Clin Exp Allergy 31:69–76.PubMedGoogle Scholar
  19. 19.
    Goleva E, Dunlap A, Leung DY (2004) Differential control of TH1 versus TH2 cell responses by the combination of low-dose steroids with beta2-adrenergic agonists. J Allergy Clin Immunol 114:183–191.PubMedCrossRefGoogle Scholar
  20. 20.
    Di Lorenzo G, Pacor ML, Pellitteri ME, Gangemi S, Di Blasi P, Candore G, Colombo A, Lio D, Caruso C (2002) In vitro effects of fluticasone propionate on IL-13 production by mitogen-stimulated lymphocytes. Mediators Inflamm 11:187–190.PubMedCrossRefGoogle Scholar
  21. 21.
    Melis M, Siena L, Pace E, giomarkaj M, Profita M, Piazzoli A, Todaro M, Stassi G, Bonsignore G, Vignola AM (2002) Fluticasone induces apoptosis in peripheral T-lymphocytes: a comparison between asthmatic and normal subjects. Eur Respir J 19:257–266.PubMedCrossRefGoogle Scholar
  22. 22.
    Pace E, Gagliardo R, Melis M, La Grutta S, Siena L, Monsignore G, Giomarkaj M, Bousquet J, Vignola AM (2004) Synergistic effects of fluticasone propionate and salmeterol on in vitro T-cell activation and apoptosis in asthma. J Allergy Clin Immunol 114:1216–1223.PubMedCrossRefGoogle Scholar
  23. 23.
    Barnes PJ (2003) Theophylline: new perspectives for an old drug. Am J Respir Crit Care Med 167:813–818.PubMedCrossRefGoogle Scholar
  24. 24.
    Barnes PJ (2005) Theophylline in chronic obstructive pulmonary disease: new horizons. Proc Am Thorac Soc 2:334–339; discussion 340–341.PubMedCrossRefGoogle Scholar
  25. 25.
    Sullivan P, Bekir S, Jaffar Z, Page C, Jeffery P, Costello J (1994) Anti-inflammatory effects of low-dose oral theophylline in atopic asthma. Lancet 343:1006–1008.PubMedCrossRefGoogle Scholar
  26. 26.
    Jaffar ZH, Sullivan P, Page C, Costello J (1996) Low-dose theophylline modulates T-lymphocyte activation in allergen-challenged asthmatics. Eur Respir J 9:456–462.PubMedCrossRefGoogle Scholar
  27. 27.
    Djukanovic R, Finnerty JP, Lee C, Wilson S, Madden J, Holgate ST (1995) The effects of theophylline on mucosal inflammation in asthmatic airways: biopsy results. Eur Respir J 8:831–833.PubMedGoogle Scholar
  28. 28.
    Finnerty JP, Lee C, Wilson S, Madden J, Djukanovic R, Holgate ST (1996) Effects of theo-phylline on inflammatory cells and cytokines in asthmatic subjects: a placebo-controlled parallel group study. Eur Respir J 9:1672–1677.PubMedCrossRefGoogle Scholar
  29. 29.
    Nie HX, Yang J, Hu SP, Wu XJ (2002) Effects of theophylline on CD4+ T lymphocyte, interleukin-5, and interferon gamma in induced sputum of asthmatic subjects. Acta Pharmacol Sin 23:267–272.PubMedGoogle Scholar
  30. 30.
    Kidney J, Dominguez M, Taylor PM, Rose M, Chung KF, Barnes PJ (1995) Immunomodulation by theophylline in asthma: demonstration by withdrawal of therapy. Am J Respir Crit Care Med 151:1907–1914.PubMedGoogle Scholar
  31. 31.
    Hidi R, Timmermans S, Liu E, Schudt C, Dent G, Holgate ST, Djukanovic R (2000) Phosphodiesterase and cyclic adenosine monophosphate-dependent inhibition of T-lymphocyte chemotaxis. Eur Respir J 15:342–349.PubMedCrossRefGoogle Scholar
  32. 32.
    Scordamaglia, A, et al. (1988) Theophylline and the immune response: in vitro and in vivo effects. Clin Immunol Immunopathol 48:238–246.PubMedCrossRefGoogle Scholar
  33. 33.
    Choy DK, Ko F, Li ST, Lp LS, Leung R, Hui D, Lai KN, Lai CK (1999) Effects of theophyl-line, dexamethasone and salbutamol on cytokine gene expression in human peripheral blood CD4+ T-cells. Eur Respir J 14:1106–1112.PubMedCrossRefGoogle Scholar
  34. 34.
    Crocker IC, Townley RG, Khan MM (1996) Phosphodiesterase inhibitors suppress proliferation of peripheral blood mononuclear cells and interleukin-4 and -5 secretion by human T-helper type 2 cells. Immunopharmacology 31:223–235.PubMedCrossRefGoogle Scholar
  35. 35.
    Lin CC, Lin CY, Liaw SF, Chen A (2002) Pulmonary function changes and immunomodula-tion of Th 2 cytokine expression induced by aminophylline after sensitization and allergen challenge in brown Norway rats. Ann Allergy Asthma Immunol 88:215–222.PubMedCrossRefGoogle Scholar
  36. 36.
    Holgate ST, Sampson AP (2000) Antileukotriene therapy. Future directions. Am J Respir Crit Care Med 161(suppl):S147–S153.PubMedGoogle Scholar
  37. 37.
    Tohda Y, Nakahara H, Kubo H, Haraguchi R, Fukuoka M, Nakajima S (1999) Effects of ONO-1078 (pranlukast) on cytokine production in peripheral blood mononuclear cells of patients with bronchial asthma. Clin Exp Allergy 29:1532–1536.PubMedCrossRefGoogle Scholar
  38. 38.
    Matsuse H, Kondo Y, Machida I, Kawano T, Saeki S, Tomari S, Obase Y, Fukushima C, Mizuta Y, Kohno S (2006) Effects of anti-inflammatory therapies on recurrent and low-grade respiratory syncytial virus infections in a murine model of asthma. Ann Allergy Asthma Immunol 97:55–60.PubMedCrossRefGoogle Scholar
  39. 39.
    Wu AY, Chik SC, Chan AW, Li Z, Tsang KW, Li W (2003) Anti-inflammatory effects of high-dose montelukast in an animal model of acute asthma. Clin Exp Allergy 33:359–366.PubMedCrossRefGoogle Scholar
  40. 40.
    Nag S, Lamkhioued B, Renzi PM (2002) Interleukin-2-induced increased airway responsiveness and lung Th2 cytokine expression occur after antigen challenge through the leukotriene pathway. Am J Respir Crit Care Med 165:1540–1545.PubMedCrossRefGoogle Scholar
  41. 41.
    Ciprandi G, Frati F, Marcucci F, Sensi L, Tosca MA, Milanese M, Ricca V (2003) Nasal cytokine modulation by montelukast in allergic children: a pilot study. Allerg Immunol (Paris) 35:295–299.Google Scholar
  42. 42.
    Ramer-Quinn DS, Baker RA, Sanders VM (1997) Activated T helper 1 and T helper 2 cells differentially express the beta-2-adrenergic receptor: a mechanism for selective modulation of T helper 1 cell cytokine production. J Immunol 159:4857–4867.PubMedGoogle Scholar
  43. 43.
    Sanders VM, Baker RA, Ramer-Quinn DS, Kasprowicz DJ, Fuchs BA, Street NE (1997) Differential expression of the beta2-adrenergic receptor by Th1 and Th2 clones: implications for cytokine production and B cell help. J Immunol 158:4200–4210.PubMedGoogle Scholar
  44. 44.
    Panina-Bordignon P, Mazzeo D, Lucia PD, D'Ambrosio D, Lang R, Fabbri L, Self C, Sinigaglia F (1997) Beta2-agonists prevent Th1 development by selective inhibition of inter-leukin 12. J Clin Invest 100:1513–1519.PubMedCrossRefGoogle Scholar
  45. 45.
    Holen E, Elsayed S (1998) Effects of beta2 adrenoceptor agonists on T-cell subpopulations. APMIS 106:849–857.PubMedCrossRefGoogle Scholar
  46. 46.
    Wallin A, Sandstrom T, Cioppa GD, Holgate S, Wilson S (2002) The effects of regular inhaled formoterol and budesonide on preformed Th-2 cytokines in mild asthmatics. Respir Med 96:1021–1025.PubMedCrossRefGoogle Scholar
  47. 47.
    Farrar JR, Rainey DK, Norris AA (1995) Pharmacologic modulation of Th1 and Th2 cell subsets by nedocromil sodium. Int Arch Allergy Immunol 107:414–415.PubMedCrossRefGoogle Scholar
  48. 48.
    Davies H, Olson L, Gibson P (2000) Methotrexate as a steroid sparing agent for asthma in adults. Cochrane Database Syst Rev 2:CD000391.PubMedGoogle Scholar
  49. 49.
    Kay AB (2006) The role of T lymphocytes in asthma. Chem Immunol Allergy 91:59–75.PubMedCrossRefGoogle Scholar
  50. 50.
    Evans DJ, Cullinan P, Geddes DM (2001) Cyclosporin as an oral corticosteroid sparing agent in stable asthma. Cochrane Database Syst Rev 2:CD002993.PubMedGoogle Scholar
  51. 51.
    Barnes PJ (2006) New therapies for asthma. Trends Mol Med 12:515–20.PubMedCrossRefGoogle Scholar
  52. 52.
    Caramori G, Ito K, Adcock IM (2004) Targeting Th2 cells in asthmatic patients. Curr Drug Targets Inflamm Allergy 3:243–255.PubMedCrossRefGoogle Scholar
  53. 53.
    Bateman ED, Izquierdo L, Harnest U, Hofbauer P, Magyar P, Schmid-Wirlitsch C, Leichtl S, Bredenboker D (2006) Efficacy and safety of roflumilast in the treatment of asthma.Ann Allergy Asthma Immunol 96:679–686.PubMedCrossRefGoogle Scholar
  54. 54.
    Landells LJ, Szilagy CM, Jones NA, Banner KH, Allen JM, Doherty A, O'Connor BJ, Spina D, Page CP (2001) Identification and quantification of phosphodiesterase 4 subtypes in CD4 and CD8 lymphocytes from healthy and asthmatic subjects. Br J Pharmacol 133:722–729.PubMedCrossRefGoogle Scholar
  55. 55.
    Essayan DM, Kagey-Sobotka A, Lichtenstein LM, Huang SK (1997) Differential regulation of human antigen-specific Th1 and Th2 lymphocyte responses by isozyme selective cyclic nucleotide phosphodiesterase inhibitors. J Pharmacol Exp Ther 282:505–512.PubMedGoogle Scholar
  56. 56.
    Essayan DM, Kagey-Sobotka A, Lichtenstein LM, Huang SK (1997) Regulation of interleu-kin-13 by type 4 cyclic nucleotide phosphodiesterase (PDE) inhibitors in allergen-specific human T lymphocyte clones. Biochem Pharmacol 53:1055–1060.PubMedCrossRefGoogle Scholar
  57. 57.
    Bielekova B, Lincoln A, McFarland H, Martin R (2000) Therapeutic potential of phosphodi-esterase-4 and -3 inhibitors in Th1-mediated autoimmune diseases. J Immunol 164:1117–1124.PubMedGoogle Scholar
  58. 58.
    Marcoz P, Prigent AF, Lagarde M, Nemoz G (1993) Modulation of rat thymocyte proliferative response through the inhibition of different cyclic nucleotide phosphodiesterase isoforms by means of selective inhibitors and cGMP-elevating agents. Mol Pharmacol 44:1027–1035.PubMedGoogle Scholar
  59. 59.
    Sommer N, Martin R, McFarland HF, Quigley L, Cannella B, Raine CS, Scott DE, Loschmann PA, Racke MK (1997) Therapeutic potential of phosphodiesterase type 4 inhibition in chronic autoimmune demyelinating disease. J Neuroimmunol 79:54–61.PubMedCrossRefGoogle Scholar
  60. 60.
    Adcock IM, Caramori G (2004) Chemokines and asthma. Curr Drug Targets Inflamm Allergy 3:257–261.PubMedCrossRefGoogle Scholar
  61. 61.
    Charo IF, Ransohoff RM (2006) The many roles of chemokines and chemokine receptors in inflammation. N Engl J Med 354:610–621.PubMedCrossRefGoogle Scholar
  62. 62.
    Leckie MJ, ten Brinke A, Khan J, Diamant Z, O'Connor BJ, Walls CM, Mathur AK, Cowley HC, Chung KF, Djukanovic R, Hansel TT, Holgate ST, Sterk PJ, Barnes PJ (2000) Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 356:2144–2148.PubMedCrossRefGoogle Scholar
  63. 63.
    Erin EM, Williams TJ, Barnes PJ, Hansel TT (2002) Eotaxin receptor (CCR3) antagonism in asthma and allergic disease. Curr Drug Targets Inflamm Allergy 1:201–214.PubMedCrossRefGoogle Scholar
  64. 64.
    Batt DG, Houghton GC, Roderick J, Santella JB 3rd, Wacker DA, Welch PK, Orlovsky YI, Wadman EA, Trzaskos JM, Davies P, Decicco CP, Carter PH (2005) N-Arylalkylpiperidine urea derivatives as CC chemokine receptor-3 (CCR3) antagonists. Bioorg Med Chem Lett 15:787–791.PubMedCrossRefGoogle Scholar
  65. 65.
    De Lucca GV, Kim UT, Johnson C, Vargo BJ, Welch PK, Covington M, Davies P, Solomon KA, Newton RC, Trainor GL, Decicco CP, Ko SS (2002) Discovery and structure-activity relationship of N-(ureidoalkyl)-benzyl-piperidines as potent small molecule CC chemokine receptor-3 (CCR3) antagonists. J Med Chem 45:3794–3804.CrossRefGoogle Scholar
  66. 66.
    De Lucca GV, Kim UT, Vargo BJ, Duncia JV, Santella JB 3rd, Gardner DS, Zheng C, Liauw A, Wang Z, Emmett G, Wacker DA, Welch PK, Covington M, Stowell NC, Wadman EA, Das AM, Davies P, Yeleswaram S, Graden DM, Solomon KA, Newton RC, Trainor GL, Decicco CP, Ko SS (2005) Discovery of CC chemokine receptor-3 (CCR3) antagonists with picomolar potency. J Med Chem 48:2194–2211.CrossRefGoogle Scholar
  67. 67.
    De Lucca GV (2006) Recent developments in CCR3 antagonists. Curr Opin Drug Discov Devel 9:516–524.Google Scholar
  68. 68.
    Nakamura T, Ohbayashi M, Toda M, Hall DA, Horgan CM, Ono SJT (2005) A specific CCR3 chemokine receptor antagonist inhibits both early and late phase allergic inflammation in the conjunctiva. Immunol Res 33:213–221.PubMedCrossRefGoogle Scholar
  69. 69.
    Pruitt JR, Batt DG, Wacker DA, et al. (2007) CC chemokine receptor-3 (CCR3) antagonists: Improving the selectivity of DPC168 by reducing central ring lipophilicity. Bioorg Med Chem Lett 17:2992–2997.PubMedCrossRefGoogle Scholar
  70. 70.
    Suzuki K, Morokata T, Morihira K, Sato I, Takizawa S, Kaneko M, Takahashi K, Shimizu Y (2006) In vitro and in vivo characterization of a novel CCR3 antagonist, YM-344031. Biochem Biophys Res Commun 339:1217–1223.PubMedCrossRefGoogle Scholar
  71. 71.
    Wegmann M, Goggel R, Sel S, Sel S, Erb KJ, Kalkbrenner F, Renz H, Garn H (2007) Effects of a low-molecular-weight CCR-3 antagonist on chronic experimental asthma. Am J Respir Cell Mol Biol 36:61–67.PubMedCrossRefGoogle Scholar
  72. 72.
    Suzuki K, Morokata T, Morihira K, Sato I, Takizawa S, Kaneko M, Takahashi K, Shimizu Y (2007) A dual antagonist for chemokine CCR3 receptor and histamine H(1) receptor. Eur J Pharmacol 563:224–232.PubMedCrossRefGoogle Scholar
  73. 73.
    Das AM, Vaddi KG, Solomon KA, Krauthauser C, Jiang X, McIntyre KW, Yang XX, Wadman E, Welch P, Covington M, Graden D, Yeleswaram K, Trzaskos JM, Newton RC, Mandlekar S, Ko SS, Carter PH, Davies P (2006) Selective inhibition of eosinophil influx into the lung by small molecule CC chemokine receptor 3 antagonists in mouse models of allergic inflammation. J Pharmacol Exp Ther 318:411–417.PubMedCrossRefGoogle Scholar
  74. 74.
    Fryer AD, Stein LH, Nie Z, Curtis DE, Evans CM, Hodgson ST, Jose PJ, Belmonte KE, Fitch E, Jacoby DB (2006) Neuronal eotaxin and the effects of CCR3 antagonist on airway hyper-reactivity and M2 receptor dysfunction. J Clin Invest 116:228–236.PubMedCrossRefGoogle Scholar
  75. 75.
    Forssmann U, Hartung I, Balder R, Fuchs B, Escher SE, Spodsberg N, Dulkys Y, Walden M, Heitland A, Braun A, Forssmann WG, Elsner J (2004) n-Nonanoyl-CC chemokine ligand 14, a potent CC chemokine ligand 14 analogue that prevents the recruitment of eosinophils in allergic airway inflammation. J Immunol 173:3456–3466.PubMedGoogle Scholar
  76. 76.
    Manns J, Rieder S, Escher S, Eilers B, Forssmann WG, Elsner J, Forssmann U (2007) The allergy-associated chemokine receptors CCR3 and CCR5 can be inactivated by the modified chemokine NNY-CCL11. Allergy 62:17–24.PubMedCrossRefGoogle Scholar
  77. 77.
    Munitz A, Bachelet I, Levi-Schaffer F (2006) Reversal of airway inflammation and remodeling in asthma by a bispecific antibody fragment linking CCR3 to CD300a. J Allergy Clin Immunol 118:1082–1089.PubMedCrossRefGoogle Scholar
  78. 78.
    Conroy DM, Jopling LA, Lloyd CM, Hodge MR, Andrew DP, Williams TJ, Pease JE, Sabroe I (2003) CCR4 blockade does not inhibit allergic airways inflammation. J Leukoc Biol 74:558–563.PubMedCrossRefGoogle Scholar
  79. 79.
    Allen S, Newhouse B, Anderson AS, Fa'uber B, Allen A, Chantry D, Eberhardt C, Odino J, Burgess LE (2004) Discovery and SAR of trisubstituted thiazolidinones as CCR4 antagonists. Bioorg Med Chem Lett 14:1619–1624.PubMedCrossRefGoogle Scholar
  80. 80.
    Newhouse B, Allen S, Fa'uber B, Anderson AS, Eary CT, Hansen JD, Schiro J, Gaudino JJ, Laird E, Chantry D, Eberhardt C, Burgess LE (2004) Racemic and chiral lactams as potent, selective and functionally active CCR4 antagonists. Bioorg Med Chem Lett 14:5537–5542.PubMedCrossRefGoogle Scholar
  81. 81.
    Purandare AV, Gao A, Wan H, Somerville JE, Burke C, Seachord C, Vaccaro W, Wityak J, Poss MA (2005) Identification of chemokine receptor CCR4 antagonist. Bioorg Med Chem Lett 15:2669–2672.PubMedCrossRefGoogle Scholar
  82. 82.
    Purandare AV, Wan H, Gao A, Somerville JE, Burke C, Vaccaro W, Yang X, McIntyre KW, Poss MA (2006) Optimization of CCR4 antagonists: side-chain exploration. Bioorg Med Chem Lett 16:204–207.PubMedCrossRefGoogle Scholar
  83. 83.
    Purandare AV, Somerville JE (2006) Antagonists of CCR4 as immunomodulatory agents. Curr Top Med Chem 6:1335–1344.PubMedGoogle Scholar
  84. 84.
    Purandare AV, Wan H, Somerville JE, Burke C, Vaccaro W, Yang X, McIntyre KW, Poss MA (2007) Core exploration in optimization of chemokine receptor CCR4 antagonists. Bioorg Med Chem Lett 17:679–682.PubMedCrossRefGoogle Scholar
  85. 85.
    Chung CD, Kuo F, Kumer J, Motani AS, Lawrence CE, Henderson WR Jr, Venkataraman C (2003) CCR8 is not essential for the development of inflammation in a mouse model of allergic airway disease. J Immunol 170:581–587.PubMedGoogle Scholar
  86. 86.
    Goya I, Villares R, Zaballos A, Gutierrez J, Kremer L, Gonzalo JA, Varona R, Carramolino L, Serrano A, Pallares P, Criado LM, Kolbeck R, Torres M, Coyle AJ, Gutierrez-Ramos JC, Martinez-A C, Marquez G (2003) Absence of CCR8 does not impair the response to ovalbu-min-induced allergic airway disease. J Immunol 170:2138–2146.PubMedGoogle Scholar
  87. 87.
    Fox JM, Najarro P, Smith GL, Struyf S, Proost P, Pease JE (2006) Structure/function relationships of CCR8 agonists and antagonists. Amino-terminal extension of CCL1 by a single amino acid generates a partial agonist. J Biol Chem 281:36652–36661.PubMedCrossRefGoogle Scholar
  88. 88.
    Ghosh S, Elder A, Guo J, Mani U, Patane M, Carson K, Ye Q, Bennett R, Chi S, Jenkins T, Guan B, Kolbeck R, Smith S, Zhang C, LaRosa G, Jaffee B, Yang H, Eddy P, Lu C, Uttamsingh V, Horlick R, Harriman G, Flynn D (2006) Design, synthesis, and progress toward optimization of potent small molecule antagonists of CC chemokine receptor 8 (CCR8). J Med Chem 49:2669–2672.PubMedCrossRefGoogle Scholar
  89. 89.
    Marro ML, Daniels DA, Andrews DP, Chapman TD, Gearing KL (2006) In vitro selection of RNA aptamers that block CCL1 chemokine function. Biochem Biophys Res Commun 349:270–276.PubMedCrossRefGoogle Scholar
  90. 90.
    Norman P (2007) CCR8 antagonists. Exp Opin Ther Patents 17:465–469.CrossRefGoogle Scholar
  91. 91.
    Sugimoto H, Shichijo M, Iino T, Manabe Y, Watanabe A, Shimazaki M, Gantner F, Bacon KB (2003) An orally bioavailable small molecule antagonist of CRTH2, ramatroban (BAY u3405), inhibits prostaglandin D2-induced eosinophil migration in vitro. J Pharmacol Exp Ther 305:347–352.PubMedCrossRefGoogle Scholar
  92. 92.
    Uller L, Mathiesen JM, Alenmyr L, Korsgren M, Ulven T, Hogberg T, Andersson G, Persson CG, Kostenis E (2007) Antagonism of the prostaglandin D2 receptor CRTH2 attenuates asthma pathology in mouse eosinophilic airway inflammation. Respir Res 8:16.PubMedCrossRefGoogle Scholar
  93. 93.
    Armer RE, Ashton MR, Boyd EA, Brennan CJ, Brookfield FA, Gazi L, Gyles SL, Hay PA, Hunter MG, Middlemiss D, Whittaker M, Xue L, Pettipher R (2005) Indole-3-acetic acid antagonists of the prostaglandin D2 receptor CRTH2. J Med Chem 48:6174–6177.PubMedCrossRefGoogle Scholar
  94. 94.
    Birkinshaw TN, Teague SJ, Beech C, Bonnert RV, Hill S, Patel A, Reakes S, Sanganee H, Dougall IG, Phillips TT, Salter S, Schmidt J, Arrowsmith EC, Carrillo JJ, Bell FM, Paine SW, Weaver R (2006) Discovery of potent CRTh2 (DP2) receptor antagonists. Bioorg Med Chem Lett 16:4287–4290.PubMedCrossRefGoogle Scholar
  95. 95.
    Ly TW, Bacon KB (2005) Small-molecule CRTH2 antagonists for the treatment of allergic inflammation: an overview. Expert Opin Investig Drugs 14:769–773.PubMedCrossRefGoogle Scholar
  96. 96.
    Mathiesen, JM, Ulven T, Martini L, Gerlach LO, Heinemann A, Kostenis E (2005) Identification of indole derivatives exclusively interfering with a G protein-independent signaling pathway of the prostaglandin D2 receptor CRTH2. Mol Pharmacol 68:393–402.PubMedGoogle Scholar
  97. 97.
    Pettipher R, Hansel TT, Armer R (2007) Antagonism of the prostaglandin D2 receptors DP1 and CRTH2 as an approach to treat allergic diseases. Nat Rev Drug Discov 6:313–325.PubMedCrossRefGoogle Scholar
  98. 98.
    Ulven T, Receveur JM, Grimstrup M, Rist O, Frimurer TM, Gerlach LO, Mathiesen JM, Kostenis E, Uller L, Hogberg T (2006) Novel selective orally active CRTH2 antagonists for allergic inflammation developed from in silico derived hits. J Med Chem 49:6638–6641.PubMedCrossRefGoogle Scholar
  99. 99.
    Ulven T, Kostenis E (2006) Targeting the prostaglandin D2 receptors DP and CRTH2 for treatment of inflammation. Curr Top Med Chem 6:1427–1444.PubMedGoogle Scholar
  100. 100.
    Chvatchko Y, Proudfoot AE, Buser R, Juillard P, Alouani S, Kosco-Vilbois M, Coyle AJ, Nibbs RJ, Graham G, Offord RE, Wells TN (2003) Inhibition of airway inflammation by amino-terminally modified RANTES/CC chemokine ligand 5 analogues Is not mediated through CCR3. J Immunol 171:5498–5506.PubMedGoogle Scholar
  101. 101.
    Dorsam G, Graeler MH, Seroogy C, Kong Y, Voice JK, Goetzl EJ (2003) Transduction of multiple effects of sphingosine 1-phosphate (S1P) on T cell functions by the S1P1 G protein-coupled receptor. J Immunol 171:3500–3507.PubMedGoogle Scholar
  102. 102.
    Sawicka E, Zuany-Amorim C, Manlius C, Trifilieff A, Brinkmann V, Kemeny DM, Walker C (2003) Inhibition of Th1- and th2-mediated airway inflammation by the sphingosine 1-phosphate receptor agonist FTY720. J Immunol 171:6206–6214.PubMedGoogle Scholar
  103. 103.
    Idzko M, Hammad H, van Nimwegen M, Kool M, Muller T, Soullie T, Willart MA, Hijdra D, Hoogsteden HC, Lambrecht BN (2006) Local application of FTY720 to the lung abrogates experimental asthma by altering dendritic cell function. J Clin Invest 116:2935–2944.PubMedCrossRefGoogle Scholar
  104. 104.
    Yoshino T, Ishikawa J, Ohga K, Morokata T, Takezawa R, Morio H, Okada Y, Honda K, Yamada T (2007) YM-58483, a selective CRAC channel inhibitor, prevents antigen-induced airway eosinophilia and late phase asthmatic responses via Th2 cytokine inhibition in animal models. Eur J Pharmacol 560:225–233.PubMedCrossRefGoogle Scholar
  105. 105.
    Barnes PJ (2006) Transcription factors in airway diseases. Lab Invest 86:867–872.PubMedCrossRefGoogle Scholar
  106. 106.
    Caramori G, Ito K, Adcock IM (2004) Transcription factors in asthma and COPD. IDrugs 7:764–770.PubMedGoogle Scholar
  107. 107.
    Adcock IM, Chung KF, Caramori G, Ito K (2006) Kinase inhibitors and airway inflammation. Eur J Pharmacol 533:118–132.PubMedCrossRefGoogle Scholar
  108. 108.
    Caramori G, Adcock IM, Ito K (2004) Anti-inflammatory inhibitors of IkappaB kinase in asthma and COPD. Curr Opin Investig Drugs 5:1141–1147.PubMedGoogle Scholar
  109. 109.
    Fichtner-Feigl S, Fuss IJ, Preiss JC, Strober W, Kitani A (2005) Treatment of murine Th1-and Th2-mediated inflammatory bowel disease with NF-kappa B decoy oligonucleotides. J Clin Invest 115:3057–3071.PubMedCrossRefGoogle Scholar
  110. 110.
    Nguyen C, Teo JL, Matsuda A, Eguchi M, Chi EY, Henderson WR Jr, Kahn M (2003) Chemogenomic identification of Ref-1/AP-1 as a therapeutic target for asthma. Proc Natl Acad Sci U S A 100:1169–1173.PubMedCrossRefGoogle Scholar
  111. 111.
    Desmet C, Gosset P, Henry E, Garze V, Faisca P, Vo s N, Jaspar F, Melotte D, Lambrecht B, Desmecht D, Pajak B, Moser M, Lekeux P, Bureau F (2005) Treatment of experimental asthma by decoy-mediated local inhibition of activator protein-1. Am J Respir Crit Care Med 172:671–678.PubMedCrossRefGoogle Scholar
  112. 112.
    Erpenbeck VJ, Hohlfeld JM, Discher M, Krentel H, Hagenberg A, Braun A, Krug N (2003) Increased messenger RNA expression of c-maf and GATA-3 after segmental allergen challenge in allergic asthmatics. Chest 123(suppl 3):370S–371S.CrossRefGoogle Scholar
  113. 113.
    Erpenbeck VJ, Hagenberg A, Krentel H, Discher M, Braun A, Hohlfeld JM, Krug N (2006) Regulation of GATA-3, c-maf and T-bet mRNA expression in bronchoalveolar lavage cells and bronchial biopsies after segmental allergen challenge. Int Arch Allergy Immunol 139:306–316.PubMedCrossRefGoogle Scholar
  114. 114.
    Kiwamoto T, Ishii Y, Morishima Y, Yoh K, Maeda A, Ishizaki K, Iizuka T, Hegab AE, Matsuno Y, Homma S, Nomura A, Sakamoto T, Takahashi S, Sekizawa K (2006) Transcription factors T-bet and GATA-3 regulate development of airway remodeling. Am J Respir Crit Care Med 174:142–151.PubMedCrossRefGoogle Scholar
  115. 115.
    Finotto S, De Sanctis GT, Lehr HA, Herz U, Buerke M, Schipp M, Bartsch B, Atreya R, Schmitt E, Galle PR, Renz H, Neurath MF (2001) Treatment of allergic airway inflammation and hyperresponsiveness by antisense-induced local blockade of GATA-3 expression. J Exp Med 193:1247–1260.PubMedCrossRefGoogle Scholar
  116. 116.
    Mikhak Z, Fleming CM, Medoff BD, Thomas SY, Tager AM, Campanella GS, Luster AD (2006) STAT1 in peripheral tissue differentially regulates homing of antigen-specific Th1 and Th2 cells. J Immunol 176:4959–4967.PubMedGoogle Scholar
  117. 117.
    Lim S, Caramori G, Tomita K, Jazrawi E, Oates T, Chung KF, Barnes PJ, Adcock IM (2004) Differential expression of IL-10 receptor by epithelial cells and alveolar macrophages. Allergy 59:505–514.PubMedCrossRefGoogle Scholar
  118. 118.
    Sampath D, Castro M, Look DC, Holtzman MJ (1999) Constitutive activation of an epithelial signal transducer and activator of transcription (STAT) pathway in asthma. J Clin Invest 103:1353–1361.PubMedCrossRefGoogle Scholar
  119. 119.
    Quarcoo D, Weixler S, Groneberg D, Joachim R, Ahrens B, Wagner AH, Hecker M, Hamelmann E (2004) Inhibition of signal transducer and activator of transcription 1 attenuates allergen-induced airway inflammation and hyperreactivity. J Allergy Clin Immunol 114:288–295.PubMedCrossRefGoogle Scholar
  120. 120.
    Mathew A, MacLean JA, DeHaan E, Tager AM, Green FH, Luster AD (2001) Signal transducer and activator of transcription 6 controls chemokine production and T helper cell type 2 cell trafficking in allergic pulmonary inflammation. J Exp Med 193.Google Scholar
  121. 121.
    Wills-Karp M (2004) Interleukin-13 in asthma pathogenesis. Immunol Rev 202:175–190.PubMedCrossRefGoogle Scholar
  122. 122.
    Christodoulopoulos P, Cameron L, Nakamura Y, Lemiere C, Muro S, Dugas M, Boulet LP, Laviolette M, Olivenstein R, Hamid Q (2001) Th2 cytokine-associated transcription factors in atopic and nonatopic asthma: evidence for differential signal transducer and activator of transcription 6 expression. J Allergy Clin Immunol 107:586–591.PubMedCrossRefGoogle Scholar
  123. 123.
    Ghaffar O, Christodoulopoulos P, Lamkhioued B, Wright E, Ihaku D, Nakamura Y, Frenkiel S, Hamid Q (2000) In vivo expression of signal transducer and activator of transcription factor 6 (STAT6) in nasal mucosa from atopic allergic rhinitis: effect of topical corticosteroids. Clin Exp Allergy 30:86–93.PubMedCrossRefGoogle Scholar
  124. 124.
    Mullings RE, Wilson SJ, Puddicombe SM, Lordan JL, Bucchieri F, Djukanovic R, Howarth PH, Harper S, Holgate ST, Davies DE (2001) Signal transducer and activator of transcription 6 (STAT-6) expression and function in asthmatic bronchial epithelium. J Allergy Clin Immunol 108:832–838.PubMedCrossRefGoogle Scholar
  125. 125.
    Caramori G, Lim S, Tomita K, Ito K, Oates T, Chung K, Barnes PJ, Adcock IM (2000) STAT6 expression in T-cells subsets, alveolar macrophages and bronchial biopsies from normal and asthmatic subjects. Eur Respir J 16(suppl 31):162s, abstract.Google Scholar
  126. 126.
    Peng Q, Matsuda T, Hirst SJ (2004) Signaling pathways regulating interleukin-13-stimulated chemokine release from airway smooth muscle. Am J Respir Crit Care Med 169:596–603.PubMedCrossRefGoogle Scholar
  127. 127.
    Nakano T, Inoue H, Fukuyama S, Matsumoto K, Matsumura M, Tsuda M, Matsumoto T, Aizawa H, Nakanishi Y (2006) Niflumic acid suppresses interleukin-13-induced asthma phenotypes. Am J Respir Crit Care Med 173:1216–1221.PubMedCrossRefGoogle Scholar
  128. 128.
    Shum BO, Mackay CR, Gorgun CZ, Frost MJ, Kumar RK, Hotamisligil GS, Rolph MS (2006) The adipocyte fatty acid-binding protein aP2 is required in allergic airway inflammation. J Clin Invest 116:2183–2192.PubMedCrossRefGoogle Scholar
  129. 129.
    Kim JI, Ho IC, Grusby MJ, Glimcher LH (1999) The transcription factor c-Maf controls the production of IL-4 but not other Th2 cytokine. Immunity 10:745–751.PubMedCrossRefGoogle Scholar
  130. 130.
    Kishikawa H, Sun J, Choi A, Miaw SC, Ho IC (2001) The cell type-specific expression of the murine IL-13 gene is regulated by GATA-3. J Immunol 167:4414–4420.PubMedGoogle Scholar
  131. 131.
    Nurieva RI, Duong J, Kishikawa H, Dianzani U, Rojo JM, Ho I, Flavell RA, Dong C (2003) Transcriptional regulation of th2 differentiation by inducible costimulator. Immunity 18:801–811.PubMedCrossRefGoogle Scholar
  132. 132.
    Hwang ES, White IA, Ho IC (2002) An IL-4-independent and CD25-mediated function of c-maf in promoting the production of Th2 cytokines. Proc Natl Acad Sci U S A 99:13026–13030.PubMedCrossRefGoogle Scholar
  133. 133.
    Ho IC, Lo D, Glimcher LH (1998) c-maf promotes T helper cell type 2 (Th2) and attenuates Th1 differentiation by both interleukin 4-dependent and -independent mechanisms. J Exp Med 188:1859–1866.PubMedCrossRefGoogle Scholar
  134. 134.
    Taha R, Hamid Q, Cameron L, Olivenstein R (2003) T helper type 2 cytokine receptors and associated transcription factors GATA-3, c-MAF, and signal transducer and activator of transcription factor-6 in induced sputum of atopic asthmatic patients. Chest 123:2074–2082.PubMedCrossRefGoogle Scholar
  135. 135.
    Horsley V, Pavlath GK (2002) NFAT: ubiquitous regulator of cell differentiation and adaptation. J Cell Biol 156:771–774.PubMedCrossRefGoogle Scholar
  136. 136.
    Seminario MC, Guo J, Bochner BS, Beck LA, Georas SN (2001) Human eosinophils constitutively express nuclear factor of activated T cells p and c. J Allergy Clin Immunol 107:143–152.PubMedCrossRefGoogle Scholar
  137. 137.
    Crabtree GR, Olson EN (2002) NFAT signaling: choreographing the social lives of cells. Cell 109(suppl):S67–S79.PubMedCrossRefGoogle Scholar
  138. 138.
    Hogan PG, Chen L, Nardone J, Rao A (2003) Transcriptional regulation by calcium, cal-cineurin, and NFAT. Genes Dev 17:2205–2232.PubMedCrossRefGoogle Scholar
  139. 139.
    Mori A, Kaminuma O, Mikami T, Inoue S, Okumura Y, Akiyama K, Okudaira H (1999) Transcriptional control of the IL-5 gene by human helper T cells: IL-5 synthesis is regulated independently from IL-2 or IL-4 synthesis. J Allergy Clin Immunol 103(suppl):S429–S436.PubMedCrossRefGoogle Scholar
  140. 140.
    Ogawa K, Kaminuma O, Okudaira H, Kikkawa H, Ikezawa K, Sakurai N, Mori A (2002) Transcriptional regulation of the IL-5 gene in peripheral T cells of asthmatic patients. Clin Exp Immunol 130:475–483.PubMedCrossRefGoogle Scholar
  141. 141.
    Keen JC, Sholl L, Wills-Karp M, Georas SN (2001) Preferential activation of nuclear factor of activated T cells c correlates with mouse strain susceptibility to allergic responses and interleukin-4 gene expression. Am J Respir Cell Mol Biol 24:58–65.PubMedGoogle Scholar
  142. 142.
    Diehl S, Chow CW, Weiss L, Palmetshofer A, Twardzik T, Rounds L, Serfling E, Davis RJ, Anguita J, Rincon M (2002) Induction of NFATc2 expression by interleukin 6 promotes T helper type 2 differentiation. J Exp Med 196:39–49.PubMedCrossRefGoogle Scholar
  143. 143.
    Hodge MR, Ranger AM, Charles de la Brousse F, Hoey T, Grusby MJ, Glimcher LH (1996) Hyperproliferation and dysregulation of IL-4 expression in NF-Atp-deficient mice. Immunity 4:397–405.PubMedCrossRefGoogle Scholar
  144. 144.
    Rengarajan J, Mowen KA, McBride KD, Smith ED, Singh H, Glimcher LH (2002) Interferon regulatory factor 4 (IRF4) interacts with NFATc2 to modulate interleukin 4 gene expression. J Exp Med 195:1003–1012.PubMedCrossRefGoogle Scholar
  145. 145.
    Rengarajan J, Tang B, Glimcher LH (2002) NFATc2 and NFATc3 regulate T(H)2 differentiation and modulate TCR-responsiveness of naive T(H) cells. Nat Immunol 3:48–54.PubMedCrossRefGoogle Scholar
  146. 146.
    van Rietschoten JG, Smits HH, van de Wetering D, Westland R, Verweij CL, den Hartog MT, Wierenga EA (2001) Silencer activity of NFATc2 in the interleukin-12 receptor beta 2 proximal promoter in human T helper cells. J Biol Chem 276:34509–34516.PubMedCrossRefGoogle Scholar
  147. 147.
    Xanthoudakis S, Viola JP, Shaw KT, Luo C, Wallace JD, Bozza PT, Luk DC, Curran T, Rao A (1996) An enhanced immune response in mice lacking the transcription factor NFAT1. Science 272:892–895.PubMedCrossRefGoogle Scholar
  148. 148.
    Chen J, Amasaki Y, Kamogawa Y, Nagoya M, Arai N, Arai K, Miyatake S (2003) Role of NFATx (NFAT4/NFATc3) in expression of immunoregulatory genes in murine peripheral CD4+ T cells. J Immunol 170:3109–3117.PubMedGoogle Scholar
  149. 149.
    Ranger AM, Oukka M, Rengarajan J, Glimcher LH (1998) Inhibitory function of two NFAT family members in lymphoid homeostasis and Th2 development. Immunity 9:627–635.PubMedCrossRefGoogle Scholar
  150. 150.
    Chen Y, Smith ML, Chiou GX, Ballaron S, Sheets MP, Gubbins E, Warrior U, Wilkins J, Surowy C, Nakane M, Carter GW, Trevillyan JM, Mollison K, Djuric SW (2002) TH1 and TH2 cytokine inhibition by 3,5-bis(trifluoromethyl)pyrazoles, a novel class of immuno-modulators. Cell Immunol 220:134–142.PubMedCrossRefGoogle Scholar
  151. 151.
    Djuric SW, BaMaung NY, Basha A, Liu H, Luly JR, Madar DJ, Sciotti RJ, Tu NP, Wagenaar FL, Wiedeman PE, Zhou X, Ballaron S, Bauch J, Chen YW, Chiou XG, Fey T, Gauvin D, Gubbins E, Hsieh GC, Marsh KC, Mollison KW, Pong M, Shaughnessy TK, Sheets MP, Smith M, Trevillyan JM, Warrior U, Wegner CD, Carter GW (2000) 3,5-Bis(trifluoromethyl) pyrazoles: a novel class of NFAT transcription factor regulator. J Med Chem 43:2975–2981.PubMedCrossRefGoogle Scholar
  152. 152.
    Kubo M, Hanada T, Yoshimura A (2003) Suppressors of cytokine signaling and immunity. Nat Immunol 4:1169–1176.PubMedCrossRefGoogle Scholar
  153. 153.
    Harada M, Nakashima K, Hirota T, Shimizu M, Doi S, Fujita K, Shirakawa T, Enomoto T, Yoshikawa M, Moriyama H, Matsumoto K, Saito H, Suzuki Y, Nakamura Y, Tamari M (2007) Functional polymorphism in the suppressor of cytokine signaling 1 gene associated with adult asthma. Am J Respir Cell Mol Biol 36:491–496.PubMedCrossRefGoogle Scholar
  154. 154.
    Kubo M, Inoue H (2006) Suppressor of cytokine signaling 3 (SOCS3) in Th2 cells evokes Th2 cytokines, IgE, and eosinophilia. Curr Allergy Asthma Rep 6:32–39.PubMedCrossRefGoogle Scholar
  155. 155.
    Inoue H, Kubo M (2004) SOCS proteins in T helper cell differentiation: implications for allergic disorders? Expert Rev Mol Med 6:1–11.PubMedCrossRefGoogle Scholar
  156. 156.
    Inoue H, Fukuyama S, Matsumoto K, Kubo M, Yoshimura A (2007) Role of endogenous inhibitors of cytokine signaling in allergic asthma. Curr Med Chem 14:181–189.PubMedCrossRefGoogle Scholar
  157. 157.
    Seki Y, Inoue H, Nagata N, Hayashi K, Fukuyama S, Matsumoto K, Komine O, Hamano S, Himeno K, Inagaki-Ohara K, Cacalano N, O'Garra A, Oshida T, Saito H, Johnston JA, Yoshimura A, Kubo M.(2003) SOCS-3 regulates onset and maintenance of T(H)2-mediated allergic responses. Nat Med 9:1047–54.PubMedCrossRefGoogle Scholar
  158. 158.
    Seki Y, Hayashi K, Matsumoto A, Seki N, Tsukada J, Ransom J, Naka T, Kishimoto T, Yoshimura A, Kubo M (2002) Expression of the suppressor of cytokine signaling-5 (SOCS5) negatively regulates IL-4-dependent STAT6 activation and Th2 differentiation. Proc Natl Acad Sci USA 99:13003–13008.PubMedCrossRefGoogle Scholar
  159. 159.
    Ozaki A, Seki Y, Fukushima A, Kubo M (2005) The control of allergic conjunctivitis by suppressor of cytokine signaling (SOCS) 3 and SOCS-5 in a murine model. J Immunol 175:5489–5497.PubMedGoogle Scholar
  160. 160.
    Brender C, Columbus R, Metcalf D, Handman E, Starr R, Huntington N, Tarlinton D, Odum N, Nicholson SE, Nicola NA, Hilton DJ, Alexander WS (2004) SOCS-5 is expressed in primary B and T lymphoid cells but is dispensable for lymphocyte production and function. Mol Cell Biol 24:6094–103.PubMedCrossRefGoogle Scholar
  161. 161.
    Ohshima M, Yokoyama A, Ohnishi H, Hamada H, Kohno N, Higaki J, Naka T (2007) Overexpression of suppressor of cytokine signalling-5 augments eosinophilic airway inflammation in mice. Clin Exp Allergy 37:735–742.PubMedCrossRefGoogle Scholar
  162. 162.
    Hammad H, De Heer HJ, Soullie T, Angeli V, Trottein F, Hoogsteden HC, Lambrecht BN (2004) Activation of peroxisome proliferator-activated receptor-gamma in dendritic cells inhibits the development of eosinophilic airway inflammation in a mouse model of asthma. Am J Pathol 164:263–271.PubMedGoogle Scholar
  163. 163.
    Woerly G, Honda K, Loyens M, Papin JP, Auwerx J, Staels B, Capron M, Dombrowicz D (2003) Peroxisome proliferator-activated receptors alpha and gamma down-regulate allergic inflammation and eosinophil activation. J Exp Med 198:411–421.PubMedCrossRefGoogle Scholar
  164. 164.
    Trifilieff A, Bench A, Hanley M, Bayley D, Campbell E, Whittaker P (2003) PPAR-alpha and -gamma but not -delta agonists inhibit airway inflammation in a murine model of asthma: in vitro evidence for an NF-kappaB-independent effect. Br J Pharmacol 139:163–171.PubMedCrossRefGoogle Scholar
  165. 165.
    Mueller C, Weaver V, Vanden Heuvel JP, August A, Cantorna MT (2003) Peroxisome pro-liferator-activated receptor gamma ligands attenuate immunological symptoms of experimental allergic asthma. Arch Biochem Biophys 418:186–196.PubMedCrossRefGoogle Scholar
  166. 166.
    Kim SR, Lee KS, Park HS, Park SJ, Min KH, Jin SM, Lee YC (2005) Involvement of IL-10 in peroxisome proliferator-activated receptor gamma-mediated anti-inflammatory response in asthma. Mol Pharmacol 68:1568–1575.PubMedGoogle Scholar
  167. 167.
    Honda K, Marquillies P, Capron M, Dombrowicz D (2004) Peroxisome proliferator-activated receptor gamma is expressed in airways and inhibits features of airway remodeling in a mouse asthma model. J Allergy Clin Immunol 113:882–888.PubMedCrossRefGoogle Scholar
  168. 168.
    Lee KS, Park SJ, Hwang PH, Yi HK, Song CH, Chai OH, Kim JS, Lee MK, Lee YC (2005) PPAR-gamma modulates allergic inflammation through up-regulation of PTEN. FASEB J 19:1033–1035.PubMedCrossRefGoogle Scholar
  169. 169.
    Lee KS, Park SJ, Kim SR, Min KH, Jin SM, Lee HK, Lee YC (2006) Modulation of airway remodeling and airway inflammation by peroxisome proliferator-activated receptor gamma in a murine model of toluene diisocyanate-induced asthma. J Immunol 177:5248–5257.PubMedGoogle Scholar
  170. 170.
    Lee KS, Kim SR, Park SJ, Park HS, Min KH, Jin SM, Lee MK, Kim UH, Lee YC (2006) Peroxisome proliferator activated receptor-gamma modulates reactive oxygen species generation and activation of nuclear factor-kappaB and hypoxia-inducible factor 1alpha in allergic airway disease of mice. J Allergy Clin Immunol 118:120–127.PubMedCrossRefGoogle Scholar
  171. 171.
    Spears M, McSharry C, Thomson NC (2006) Peroxisome proliferator-activated receptor-gamma agonists as potential anti-inflammatory agents in asthma and chronic obstructive pulmonary disease. Clin Exp Allergy 36:1494–1504.PubMedCrossRefGoogle Scholar
  172. 172.
    Belvisi MG, Hele DJ, Birrell MA (2006) Peroxisome proliferator-activated receptor gamma agonists as therapy for chronic airway inflammation. Eur J Pharmacol 533:101–109.PubMedCrossRefGoogle Scholar
  173. 173.
    Khanna S, Sobria ME, Bharatam PV (2005) Additivity of molecular fields: CoMFA study on dual activators of PPARalpha and PPARgamma. J Med Chem 48:3015–3025.PubMedCrossRefGoogle Scholar
  174. 174.
    Ueki S, Usami A, Oyamada H, Saito N, Chiba T, Mahemuti G, Ito W, Kato H, Kayaba H, Chihara J (2006) Procaterol upregulates peroxisome proliferator-activated receptor-gamma expression in human eosinophils. Int Arch Allergy Immunol 140(suppl 1):S35–S41.CrossRefGoogle Scholar
  175. 175.
    Usami A, Ueki S, Ito W, Kobayashi Y, Chiba T, Mahemuti G, Oyamada H, Kamada Y, Fujita M, Kato H, Saito N, Kayaba H, Chihara J (2006) Theophylline and dexamethasone induce peroxisome proliferator-activated receptor-gamma expression in human eosinophils. Pharmacology 77:33–37.PubMedCrossRefGoogle Scholar
  176. 176.
    Adcock IM, Caramori G (2004) Kinase targets and inhibitors for the treatment of airway inflammatory diseases: the next Generation of drugs for severe asthma and COPD? Biodrugs 18:167–180.PubMedCrossRefGoogle Scholar
  177. 177.
    Schafer PH, Wadsworth SA, Wang L, Siekierka SJ (1999) p38 alpha mitogen-activated protein kinase is activated by CD28-mediated signaling and is required for IL-4 production by human CD4+CD45RO+ T cells and Th2 effector cells. J Immunol 162:7110–7119.PubMedGoogle Scholar
  178. 178.
    Duan W, Chan JH, McKay K, Crosby JR, Choo HH, Leung BP, Karras JG, Wong WS (2005) Inhaled p38alpha mitogen-activated protein kinase antisense oligonucleotide attenuates asthma in mice. Am J Respir Crit Care Med 171:571–578.PubMedCrossRefGoogle Scholar
  179. 179.
    Duan W, Wong WS (2006) Targeting mitogen-activated protein kinases for asthma. Curr Drug Targets 7:691–698.PubMedCrossRefGoogle Scholar
  180. 180.
    Lane SJ, Adcock IM, Richards D, Hawrylowicz C, Barnes PJ, Lee TH (1998) Corticosteroid-resistant bronchial asthma is associated with increased c-fos expression in monocytes and T lymphocytes. J Clin Invest 102:2156–2164.PubMedCrossRefGoogle Scholar
  181. 181.
    Huang TJ, Adcock IM, Chung KF (2001) A novel transcription factor inhibitor, SP100030, inhibits cytokine gene expression, but not airway eosinophilia or hyperresponsiveness in sensitized and allergen-exposed rat. Br J Pharmacol 134:1029–1036.PubMedCrossRefGoogle Scholar
  182. 182.
    Rose MJ, Page C (2004) Glycosaminoglycans and the regulation of allergic inflammation. Curr Drug Targets Inflamm Allergy 3:221–225.PubMedCrossRefGoogle Scholar
  183. 183.
    Ellyard JI, Simson L, Johnston K, Freeman C, Parish CR (2007) Eotaxin selectively binds heparin: An interaction that protects eotaxin from proteolysis and potentiates chemotactic activity in vivo. J Biol Chem 282(20):15238–15247.PubMedCrossRefGoogle Scholar
  184. 184.
    Rashid RM, Lee JM, Fareed J, Young MR (2007) In vitro heparan sulfate modulates the immune responses of normal and tumor-bearing mice. Immunol Invest 36:183–201.PubMedCrossRefGoogle Scholar
  185. 185.
    Lever R, Page C (2001) Glycosaminoglycans, airways inflammation and bronchial hyper-responsiveness. Pulm Pharmacol Ther 14:249–254.PubMedCrossRefGoogle Scholar
  186. 186.
    Diamant Z, Page CP (2000) Heparin and related molecules as a new treatment for asthma. Pulm Pharmacol Ther 13:1–4.PubMedCrossRefGoogle Scholar
  187. 187.
    Page C (2000) The role of proteoglycans in the regulation of airways inflammation and airways remodelling. J Allergy Clin Immunol 105(suppl):S518–S521.PubMedCrossRefGoogle Scholar
  188. 188.
    Ahmed T, Garrigo J, Danta I (1993) Preventing bronchoconstriction in exercise-induced asthma with inhaled heparin. N Engl J Med 329:90–95.PubMedCrossRefGoogle Scholar
  189. 189.
    Ahmed T, Gonzales BJ, Danta I (1999) Prevention of exercise-induced bronchoconstriction by inhaled low-molecular-weight heparin. Am J Respir Crit Care Med 160:576–581.PubMedGoogle Scholar
  190. 190.
    Garrigo J, Danta I, Ahmed T (1996) Time course of the protective effect of inhaled heparin on exercise-induced asthma. Am J Respir Crit Care Med 153:1702–1707.PubMedGoogle Scholar
  191. 191.
    Barnes PJ (2003) Cytokine-directed therapies for the treatment of chronic airway diseases. Cytokine Growth Factor Rev 14:511–522.PubMedCrossRefGoogle Scholar
  192. 192.
    Grunewald SM, Werthmann A, Schnarr B, Klein CE, Brocker EB, Mohrs M, Brombacher F, Sebald W, Duschl A (1998) An antagonistic IL-4 mutant prevents type I allergy in the mouse: inhibition of the IL-4/IL-13 receptor system completely abrogates humoral immune response to allergen and development of allergic symptoms in vivo. J Immunol 160:4004–4009.PubMedGoogle Scholar
  193. 193.
    Lindell D, Gundel R, Fitch N, Harris P (1999) The IL-4 receptor antagonist (Bay 16–9996) reverses airway hyperresponsiveness in a primate model of asthma. Am J Respir Crit Care Med 159(suppl): abstract A230.Google Scholar
  194. 194.
    Steinke JW, Borish L (2001) Th2 cytokines and asthma. Interleukin-4: its role in the patho-genesis of asthma, and targeting it for asthma treatment with interleukin-4 receptor antagonists. Respir Res 2:66–70.Google Scholar
  195. 195.
    Henderson WR, Jr, Chi E Y, Maliszewski CR (2000) Soluble IL-4 receptor inhibits airway inflammation following allergen challenge in a mouse model of asthma. J Immunol 164:1086–1095.PubMedGoogle Scholar
  196. 196.
    Borish LC, Nelson HS, Lanz MJ, Claussen L, Whitmore JB, Agosti JM, Garrison L (1999) Interleukin-4 receptor in moderate atopic asthma. A phase I/II randomized, placebo-controlled trial. Am J Respir Crit Care Med 160:1816–1823.PubMedGoogle Scholar
  197. 197.
    LC, Nelson HS, Corren J, Bensch G, Busse WW, Whitmore JB, Agosti JM (2001) IL-4R Asthma Study Group. Efficacy of soluble IL-4 receptor for the treatment of adults with asthma. J Allergy Clin Immunol 107:963–970.Google Scholar
  198. 198.
    Karras JG, Crosby JR, Guha M, Tung D, Miller DA, Gaarde WA, Geary RS, Monia BP, Gregory SA (2007) Anti-inflammatory activity of inhaled IL-4 receptor-alpha antisense oligonucleotide in mice. Am J Respir Cell Mol Biol 36:276–285.PubMedCrossRefGoogle Scholar
  199. 199.
    Ma Y, Hayglass KT, Becker AB, Halayko AJ, Basu S, Simons FER, Peng Z (2007) Novel cytokine peptide-based vaccines: an interleukin-4 vaccine suppresses airway allergic responses in mice. Allergy 62:675–682.PubMedCrossRefGoogle Scholar
  200. 200.
    Grunig G, Warnock M, Wakil AE, Venkayya R, Brombacher F, Rennick DM, Sheppard D, Mohrs M, Donaldson DD, Locksley RM, Corry DB (1998) Requirement for IL-13 independently of IL-4 in experimental asthma. Science 282:2261–2263.PubMedCrossRefGoogle Scholar
  201. 201.
    Yang G, Volk A, Petley T, Emmell E, Giles-Komar J, Shang X, Li J, Das AM, Shealy D, Griswold DE, Li L (2004) Anti-IL-13 monoclonal antibody inhibits airway hyperresponsive-ness, inflammation and airway remodeling. Cytokine 28:224–232.PubMedCrossRefGoogle Scholar
  202. 202.
    Kasaian MT, Donaldson DD, Tchistiakova L, Marquette K, Tan XY, Ahmed A, Jacobson BA, Widom A, Cook TA, Xu X, Barry AB, Goldman SJ, Abraham WM (2007) Efficacy of IL-13 neutralization in a sheep model of experimental asthma. Am J Respir Cell Mol Biol 36:368–376.PubMedCrossRefGoogle Scholar
  203. 203.
    Izuhara K, Arima K, Kanaji S, Ohta S, Kanaji T (2006) IL-13: a promising therapeutic target for bronchial asthma. Curr Med Chem 13:2291–2298.PubMedCrossRefGoogle Scholar
  204. 204.
    Blanchard C, Mishra A, Saito-Akei H, Monk P, Anderson I, Rothenberg ME (2005) Inhibition of human interleukin-13-induced respiratory and oesophageal inflammation by anti-human-interleukin-13 antibody (CAT-354). Clin Exp Allergy 35:1096–1103.PubMedCrossRefGoogle Scholar
  205. 205.
    Yang G, Li L, Volk A, Emmell E, Petley T, Giles-Komar J, Rafferty P, Lakshminarayanan M, Griswold DE, Bugelski PJ, Das AM (2005) Therapeutic dosing with anti-interleukin-13 monoclonal antibody inhibits asthma progression in mice. J Pharmacol Exp Ther 313:8–15.PubMedCrossRefGoogle Scholar
  206. 206.
    Bree A, Schlerman FJ, Wadanoli M, Tchistiakova L, Marquette K, Tan XY, Jacobson BA, Widom A, Cook TA, Wood N, Vunnum S, Krykbaev R, Xu X, Donladson DD, Goldman SJ, Sypek J, Kasain MT (2007) IL-13 blockade reduces lung inflammation after Ascaris suum challenge in cynomolgus monkeys. J Allergy Clin Immunol 119:1251–1257.PubMedCrossRefGoogle Scholar
  207. 207.
    Ma Y, Hayglass KT, Becker AB, Fan Y, Yang X, Basu S, Srinivasan G, Simons FE, Halayko AJ, Peng Z (2007) Novel recombinant IL-13 peptide-based vaccine reduces airway allergic inflammatory responses in mice. Am J Respir Crit Care Med 176(5):439–445.PubMedCrossRefGoogle Scholar
  208. 208.
    Kips JC, O'Connor BJ, Langley SJ, Woodcock A, Kerstjens HA, Postma DS, Danzig M, Cuss F, Pauwels RA (2003) Effect of SCH55700, a humanized anti-human interleukin-5 antibody, in severe persistent asthma: a pilot study. Am J Respir Crit Care Med 2003;167:1655–1659. [Comment in: Am J Respir Crit Care Med 167:1586–1587].PubMedCrossRefGoogle Scholar
  209. 209.
    Flood-Page PT, Menzies-Gow AN, Kay AB, Robinson DS (2003) Eosinophil's role remains uncertain as anti-interleukin-5 only partially depletes numbers in asthmatic airway. Am J Respir Crit Care Med 2003;167:199–204. [Comment in: Am J Respir Crit Care Med 167:102–103].PubMedCrossRefGoogle Scholar
  210. 210.
    Buttner C, Lun A, Splettstoesser T, Kunkel G, Renz H (2003) Monoclonal anti-interleukin-5 treatment suppresses eosinophil but not T-cell functions. Eur Respir J 21:799–803.PubMedCrossRefGoogle Scholar
  211. 211.
    Mao H, Wen FO, Liu CT, Liang ZA, Wang ZL, Yin KS (2006) Effect of interleukin-5 receptor-alpha short hairpin RNA-expressing vector on bone marrow eosinophilopoiesis in asthmatic mice. Adv Ther 23:938–956.PubMedCrossRefGoogle Scholar
  212. 212.
    Mao H, Wen FO, Li SY, Liang ZA, Liu CT, Yin KS, Wang ZL (2007) A preliminary study towards downregulation of murine bone marrow eosinophilopoiesis mediated by small molecule inhibition of interleukin-5 receptor alpha gene in vitro. Respiration 74:320–328.PubMedCrossRefGoogle Scholar
  213. 213.
    Taga T, Kishimoto T (1997) Gp130 and the interleukin-6 family of cytokines. Annu Rev Immunol 15:797–819.PubMedCrossRefGoogle Scholar
  214. 214.
    Doganci A, Eigenbrod T, Krug N, De Sanctis GT, Hausding M, Erpenbeck VJ, Haddad el-B, Lehr HA, Schmitt E, Bopp T, Kallen KJ, Herz U, Schmitt S, Luft C, Hecht O, Hohlfeld JM, Ito H, Nishimoto N, Yoshikazi K, Kishimoto T, Rose-John S, Renz H, Neurath MF, Galle PR, Finotto S (2005) The IL-6R alpha chain controls lung CD4+CD25+ Treg development and function during allergic airway inflammation in vivo. J Clin Invest 115:313–325. [Erratum in: J Clin Invest 115:1388. Lehr, Hans A; added].PubMedGoogle Scholar
  215. 215.
    McNamara PS, Smyth RL (2005) Interleukin-9 as a possible therapeutic target in both asthma and chronic obstructive airways disease. Drug News Perspect 18:615–621.PubMedCrossRefGoogle Scholar
  216. 216.
    Steenwinckel V, Louahed J, Orabona C, Huax F, Warnier G, McKenzie A, Lison D, Levitt R, Renauld JC (2007) IL-13 mediates in vivo IL-9 activities on lung epithelial cells but not on hematopoietic cells. J Immunol 178:3244–3251.PubMedGoogle Scholar
  217. 217.
    Shimbara A, Christodoulopoulos P, Soussi-Gounni A, Olivenstein R, Nakamura Y, Levitt RC, Nicolaides NC, Holroyd KJ, Tsicopoulos A, Lafitte JJ, Wallaert B, Hamid QA (2000) IL-9 and its receptor in allergic and nonallergic lung disease: increased expression in asthma. J Allergy Clin Immunol 105:108–15.PubMedCrossRefGoogle Scholar
  218. 218.
    Ying S, Meng Q, Kay AB, Robinson DS (2002) Elevated expression of interleukin-9 mRNA in the bronchial mucosa of atopic asthmatics and allergen-induced cutaneous late-phase reaction: relationships to eosinophils, mast cells and T lymphocytes. Clin Exp Allergy 32:866–871.PubMedCrossRefGoogle Scholar
  219. 219.
    Erpenbeck VJ, Hohlfeld JM, Volkmann B, Hagenberg A, Geldmacher H, Braun A, Krug N (2003) Segmental allergen challenge in patients with atopic asthma leads to increased IL-9 expression in bronchoalveolar lavage fluid lymphocytes. J Allergy Clin Immunol 111:1319–27.PubMedCrossRefGoogle Scholar
  220. 220.
    van den Brule S, Heymans J, Havaux X, Renauld JC, Lison D, Huax F, Denis O (2007) Pro-fibrotic effect of IL-9 overexpression in a model of airway remodeling. Am J Respir Cell Mol Biol 37(2):202–209.PubMedCrossRefGoogle Scholar
  221. 221.
    Fallon PG, Jolin HE, Smith P, Emson CL, Townsend MJ, Fallon R, Smith P, McKenzie AN (2002) IL-4 induces characteristic Th2 responses even in the combined absence of IL-5, IL-9, and IL-13. Immunity 17:7–17.PubMedCrossRefGoogle Scholar
  222. 222.
    Townsend JM, Fallon GP, Matthews JD, Smith P, Jolin EH, McKenzie NA (2000) IL-9-deficient mice establish fundamental roles for IL-9 in pulmonary mastocytosis and goblet cell hyperplasia but not T cell development. Immunity 13:573–578.PubMedCrossRefGoogle Scholar
  223. 223.
    Cheng G, Arima M, Honda K, Hirata H, Eda F, Yoshida N, Fukushima F, Ishii Y, Fukuda T (2002) Anti-interleukin-9 antibody treatment inhibits airway inflammation and hyperreactiv-ity in mouse asthma model. Am J Respir Crit Care Med 166:409–416.PubMedCrossRefGoogle Scholar
  224. 224.
    Kung TT, Luo B, Crawley Y, Garlisi CG, Devito K, Minnicozzi M, Egan RW, Kreutner W, Chapman RW (2001) Effect of anti-mIL-9 antibody on the development of pulmonary inflammation and airway hyperresponsiveness in allergic mice. Am J Respir Cell Mol Biol 25:600–605.PubMedGoogle Scholar
  225. 225.
    Sitkauskiene B, Radinger M, Bossios A, Johansson AK, Sakalauskas R, Lotvall J (2005) Airway allergen exposure stimulates bone marrow eosinophilia partly via IL-9. Respir Res 6:33.PubMedCrossRefGoogle Scholar
  226. 226.
    Lee CG, Homer RJ, Cohn L, Link H, Jung S, Craft JE, Graham BS, Johnson TR, Elias JA (2002) Transgenic overexpression of interleukin (IL)-10 in the lung causes mucus metaplasia, tissue inflammation, and airway remodeling via IL-13-dependent and -independent pathways. J Biol Chem 277:35466–35474.PubMedCrossRefGoogle Scholar
  227. 227.
    Tomita K, Lim S, Hanazawa T, Usmani O, Stirling R, Chung KF, Barnes PJ, Adcock IM (2002) Attenuated production of intracellular IL-10 and IL-12 in monocytes from patients with severe asthma. Clin Immunol 102:258–266.PubMedCrossRefGoogle Scholar
  228. 228.
    Xystrakis E, Kusumakar S, Boswell S, Peek E, Urry Z, Richards DF, Adikibi T, Pridgeon C, Dallman M, Loke TK, Robinson DS, Barrat FJ, O'Garra A, Lavender P, Lee TH, Corrigan C, Hawrylowicz CM (2006) Reversing the defective induction of IL-10-secreting regulatory T cells in glucocorticoid-resistant asthma patients. J Clin Invest 116:146–155.PubMedCrossRefGoogle Scholar
  229. 229.
    Lim S, Crawley E, Woo P, Barnes PJ (1998) Haplotype associated with low interleukin-10 production in patients with severe asthma. Lancet 352:113.PubMedCrossRefGoogle Scholar
  230. 230.
    Ogawa H, Nishimura N, Nishioka Y, Azuma M, Yanagawa H, Sone S (2003) Adenoviral interleukin-12 gene transduction into human bronchial epithelial cells: up-regulation of pro-inflammatory cytokines and its prevention by corticosteroids. Clin Exp Allergy 33:921–929.PubMedCrossRefGoogle Scholar
  231. 231.
    Bryan SA, O'Connor BJ, Matti S, Leckie MJ, Kanabar V, Khan J, Warrington SJ, Renzetti L, Ranes A, Bock JA (2000) Effects of recombinant human interleukin-12 on eosinophils, airway hyperresponsiveness, and the late asthmatic response. Lancet 356:2149–2153.PubMedCrossRefGoogle Scholar
  232. 232.
    Matsuse H, Kong X, Hu J, Wolf SF, Lockey RF, Mohapatra SS (2003) Intranasal IL-12 produces discreet pulmonary and systemic effects on allergic inflammation and airway reactivity. Int Immunopharmacol 3:457–468.PubMedCrossRefGoogle Scholar
  233. 233.
    Christensen U, Haagerup A, Binderup HG, Vestbo J, Kruse TA, Borgium AD (2006) Family based association analysis of the IL2 and IL15 genes in allergic disorders. Eur J Hum Genet 14:227–235.PubMedCrossRefGoogle Scholar
  234. 234.
    Kurz T, Strauch K, Dietrich H, Braun S, Hierl S, Jerkic SP, Wienker TF, Deichmann KA, Heinzmann A (2004) Multilocus haplotype analyses reveal association between 5 novel IL-15 polymorphisms and asthma. J Allergy Clin Immunol 113:896–901.PubMedCrossRefGoogle Scholar
  235. 235.
    Muro S, Taha R, Tsicopoulos A, Olivenstein R, Tonnel AB, Christodoulopoulos P, Wallaert B, Hamid Q (2001) Expression of IL-15 in inflammatory pulmonary diseases. J Allergy Clin Immunol 108:970–975.PubMedCrossRefGoogle Scholar
  236. 236.
    Ishimitsu R, Nishimura H, Yajima T, Watase T, Kawauchi H, Yoshikai Y (2001) Overexpression of IL-15 in vivo enhances Tc1 response, which inhibits allergic inflammation in a murine model of asthma. J Immunol 166:1991–2001.PubMedGoogle Scholar
  237. 237.
    Ruckert R, Brandt K, Braun A, Hoymann HG, Herz U, Budagian V, Durkop H, Renz H, Bulfone-Paus S (2005) Blocking IL-15 prevents the induction of allergen-specific T cells and allergic inflammation in vivo. J Immunol 174:5507–5515.PubMedGoogle Scholar
  238. 238.
    Wei H, Zhang J, Xiao W, Feng J, Sun R, Tian Z (2005) Involvement of human natural killer cells in asthma pathogenesis: natural killer 2 cells in type 2 cytokine predominance. J Allergy Clin Immunol 115:841–847.PubMedCrossRefGoogle Scholar
  239. 239.
    O'Sullivan S, Cormican L, Burke CM, Poulter LW (2004) Fluticasone induces T cell apop-tosis in the bronchial wall of mild to moderate asthmatics. Thorax 59:657–661.PubMedCrossRefGoogle Scholar
  240. 240.
    Bombardieri M, McInnes IB, Pitzalis C (2007) Interleukin-18 as a potential therapeutic target in chronic autoimmune/inflammatory conditions. Expert Opin Biol Ther 7:31–40.PubMedCrossRefGoogle Scholar
  241. 241.
    Maecker HT, Hansen G, Walter DM, DeKruyff RH, Levy S, Umetsu DT (2001) Vaccination with allergen-IL-18 fusion DNA protects against, and reverses established, airway hyperre-activity in a murine asthma model. J Immunol 166:959–965.PubMedGoogle Scholar
  242. 242.
    Tsutsui H, Yoshimoto T, Hayashi N, Mizutani H, Nakanishi K (2004) Induction of allergic inflammation by interleukin-18 in experimental animal models. Immunol Rev 202:115–138.PubMedCrossRefGoogle Scholar
  243. 243.
    Sugimoto T, Ishikawa Y, Yoshimoto T, Hayashi N, Fujimoto J, Nakanishi K (2004) Interleukin 18 acts on memory T helper cells type 1 to induce airway inflammation and hyperresponsiveness in a naive host mouse. J Exp Med 199:535–545.PubMedCrossRefGoogle Scholar
  244. 244.
    Kumano K, Nakao A, Nakajima H, Hayashi F, Kurimoto M, Okamura H, Saito Y, Iwamoto I (1999) Interleukin-18 enhances antigen-induced eosinophil recruitment into the mouse airways. Am J Respir Crit Care Med 160:873–878.PubMedGoogle Scholar
  245. 245.
    Wild JS, Sigounas A, Sur N, Siddiqui MS, Alam R, Kurimoto M, Sur S (2000) IFN-gamma-inducing factor (IL-18) increases allergic sensitization, serum IgE, Th2 cytokines, and airway eosinophilia in a mouse model of allergic asthma. J Immunol 164:2701–2710.PubMedGoogle Scholar
  246. 246.
    Wong CK, Ho CY, Ko FW, Chan CH, Ho AS, Hui DS, Lam CW (2001) Proinflammatory cytokines (IL-17, IL-6, IL-18 and IL-12) and Th cytokines (IFN-gamma, IL-4, IL-10 and IL-13) in patients with allergic asthma. Clin Exp Immunol 125:177–183.PubMedCrossRefGoogle Scholar
  247. 247.
    Tanaka H, Miyazaki N, Oashi K, Teramoto S, Shiratori M, Hashimoto M, Ohmichi M, Abe S (2001) IL-18 might reflect disease activity in mild and moderate asthma exacerbation. J Allergy Clin Immunol 107:331–336.PubMedCrossRefGoogle Scholar
  248. 248.
    Ho LP, Davis M, Denison A, Wood FT, Greening AP (2002) Reduced interleukin-18 levels in BAL specimens from patients with asthma compared to patients with sarcoidosis and healthy control subjects. Chest 121:1421–1426.PubMedCrossRefGoogle Scholar
  249. 249.
    McKay A, Komai-Koma M, MacLeod KJ, Campbell CC, Kitson SM, Chaudhuri R, Thomson L, McSharry C, Liew FY, Thomson NC (2004) Interleukin-18 levels in induced sputum are reduced in asthmatic and normal smokers. Clin Exp Allergy 34:904–910.PubMedCrossRefGoogle Scholar
  250. 250.
    Sheppard P, Kindsvogel W, Xu W, Henderson K, Schlutsmeyer S, Whitmore TE, Kuestner R, Garrigues U, Birks C, Roraback J, Ostrander C, Dong D, Shin J, Presnell S, Fox B, Haldeman B, Cooper E, Taft D, Gilbert T, Grant FJ, Tackett M, Krivan W, McKnight G, Clegg C, Foster D, Klucher KM (2003) IL-28, IL-29 and their class II cytokine receptor IL-28R. Nat Immunol 4:63–68.PubMedCrossRefGoogle Scholar
  251. 251.
    Langer JA, Cutrone EC, Kotenko S (2004) The Class II cytokine receptor (CRF2) family: overview and patterns of receptor-ligand interactions. Cytokine Growth Factor Rev 15:33–48.PubMedCrossRefGoogle Scholar
  252. 252.
    Dumoutier L, Leemans C, Lejeune D, Kotenko SV, Renauld JC (2001) Cutting edge: STAT activation by IL-19, IL-20 and mda-7 through IL-20 receptor complexes of two types. J Immunol 167:3545–3549.PubMedGoogle Scholar
  253. 253.
    Kotenko SV, Langer JA (2004) Full house: 12 receptors for 27 cytokines. Int Immunopharmacol 4:593–608.PubMedCrossRefGoogle Scholar
  254. 254.
    Donnelly RP, Sheikh F, Kotenko SV, Dickensheets H (2004) The expanded family of class II cytokines that share the IL-10 receptor-2 (IL-10R2) chain. J Leukoc Biol 76:314–321.PubMedCrossRefGoogle Scholar
  255. 255.
    Krause CD, Pestka S (2005) Evolution of the Class 2 cytokines and receptors, and discovery of new friends and relatives. Pharmacol Ther 106:299–346.PubMedCrossRefGoogle Scholar
  256. 256.
    Uze G, Monneron D (2007) IL-28 and IL-29: newcomers to the interferon family. Biochimie 89:729–734.PubMedCrossRefGoogle Scholar
  257. 257.
    Gallagher G, Eskdale J, Jordan W, Peat J, Campbell J, Boniotto M, Lennon GP, Dickensheets H, Donnelly RP (2004) Human interleukin-19 and its receptor: a potential role in the induction of Th2 responses. Int Immunopharmacol 4:615–626.PubMedCrossRefGoogle Scholar
  258. 258.
    Gallagher G, Dickensheets H, Eskdale J, Izotova LS, O. Mirochnitchenko OV, Peat JD, Vazquez N, Pestka S, Donnelly RP, Kotenko SV (2000) Cloning, expression and initial characterization of interleukin-19 (IL-19), a novel homologue of human interleukin-10 (IL-10). Genes Immun 1:442.PubMedCrossRefGoogle Scholar
  259. 259.
    Liao YC, Liang WG, Chen FW, Hsu JH, Yang MJJ, Chang S (2002) IL-19 induces production of IL-6 and TNF- a and results in cell apoptosis through TNF- a. J Immunol 169:4288.PubMedGoogle Scholar
  260. 260.
    Liao SC, Cheng YC, Wang YC, Wang CW, Yang SM, Yu CK, Shieh CC, Cheng KC, Lee MF, Chiang SR, Shieh JM, Chang MS (2004) IL-19 induced Th2 cytokines and was up-regulated in asthma patients. J Immunol 173:6712–6718.PubMedGoogle Scholar
  261. 261.
    Zhong H, Wu Y, Belardinelli L, Zeng D (2006) A2B adenosine receptors induce IL-19 from bronchial epithelial cells, resulting in TNF-alpha increase. Am J Respir Cell Mol Biol 35:587–592.PubMedCrossRefGoogle Scholar
  262. 262.
    Sivakumar P V, Foster DC, Clegg CH (2004) Interleukin-21 is a T-helper cytokine that regulates humoral immunity and cell-mediated anti-tumour responses. Immunology 112:177–182.PubMedCrossRefGoogle Scholar
  263. 263.
    Habib T, Nelson A, Kaushansky K (2003) IL-21: a novel IL-2-family lymphokine that modulates B, T, and natural killer cell responses. J Allergy Clin Immunol 112:1033–1045.PubMedCrossRefGoogle Scholar
  264. 264.
    Ozaki KR, Spolski CG, Feng C-F, et al. (2002) A critical role for IL-21 in regulating immu-noglobulin production. Science 298:1630–1634.PubMedCrossRefGoogle Scholar
  265. 265.
    Shang XZ, Ma KY, Radewonuk J, Li J, Song XY, Griswold DE, Emmell E, Li T (2006) IgE isotype switch and IgE production are enhanced in IL-21-deficient but not IFN-gamma-deficient mice in a Th2-biased response. Cell Immunol 241:66–74.PubMedCrossRefGoogle Scholar
  266. 266.
    Kasaian MT, Whitters MJ, Carter LL, Lowe LD, Jussif JM, Deng B, Johnson KA, Witek JS, Senices M, Konz RF, Wurster AL, Donaldson DD, Collins M, Young DA, Grusby MJ (2002) IL-21 limits NK cell responses and promotes antigen-specific T cell activation: a mediator of the transition from innate to adaptive immunity. Immunity 16:559–569.PubMedCrossRefGoogle Scholar
  267. 267.
    Curti BD (2006) Immunomodulatory and antitumor effects of interleukin-21 in patients with renal cell carcinoma. Expert Rev Anticancer Ther 6:905–909.PubMedCrossRefGoogle Scholar
  268. 268.
    Fina D, Fantini MC, Pallone F, Monteleone G (2007) Role of interleukin-21 in inflammation and allergy. Inflamm Allergy Drug Targets 6:63–68.PubMedCrossRefGoogle Scholar
  269. 269.
    Wolk K, Sabat R (2006) Interleukin-22: a novel T- and NK-cell derived cytokine that regulates the biology of tissue cells. Cytokine Growth Factor Rev 17:367–380.PubMedCrossRefGoogle Scholar
  270. 270.
    Oral HB, Kotenko SV, Yilmaz M, Mani O, Zumkehr J, Blaser K, Akdis CA, Akdis M (2006) Regulation of T cells and cytokines by the interleukin-10 (IL-10)-family cytokines IL-19, IL-20, IL-22, IL-24 and IL-26. Eur J Immunol 36:380–388.PubMedCrossRefGoogle Scholar
  271. 271.
    Whittington HA, Armstrong L, Uppington KM, Millar AB (2004) Interleukin-22: a potential immunomodulatory molecule in the lung. Am J Respir Cell Mol Biol 31:220–226.PubMedCrossRefGoogle Scholar
  272. 272.
    Heijink IH, van Oosterhout AJM (2006) Strategies for targeting T-cells in allergic diseases and asthma. Pharmacol Ther 112:489–500.PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2010

Authors and Affiliations

  • Gaetano Caramori
    • 1
  • Kazuhiro Ito
    • 2
  • Paolo Casolari
    • 1
  • Marco Contoli
    • 1
  • Alberto Papi
    • 1
  • Ian M. Adcock
    • 2
  1. 1.Dipartimento di Medicina Clinica e Sperimentale, Centro di Ricerca su Asma e BPCOUniversità di FerraraFerraraItaly
  2. 2.Airway Disease Section, National Heart and Lung InstituteImperial College of LondonLondonUK

Personalised recommendations