Immunologic Research

, Volume 30, Issue 3, pp 339–349 | Cite as

Therapeutic targeting of IL-4-and IL-13-responsive cells in pulmonary fibrosis

  • Claudia Jakubzick
  • Steven L. Kunkel
  • Raj K. Puri
  • Cory M. Hogaboam
Article

Abstract

Severe forms of idiopathic interstitial pneumonia (IIP), such as usual interstitial pneumonia (UIP), can be impervious to modern steroid and immunosuppressive treatment regimens, thereby emphasizing the need for novel effective therapies. Understanding the cytokine networks that may affect immune and structural cell activation and, hence, the progression of these fatal fibrotic diseases, has been a focus in our research. In this regard, we have examined the role of interleukin (IL)-4 and IL-13 and their respective receptor subunits in this process. Examination of clinical surgical lung biopsies (SLBs) showed that IIP is characterized by the abnormal, heightened expression of the receptor subunits that bind IL-4 and IL-13. Specifically, IL-4Rα and IL-13Rα2 (the high-affinity IL-13 receptor subunit) was present in greater abundance in SLBs and fibroblasts from IIP patients compared with normal patients, who exhibited no evidence of pulmonary fibrosis. These clinical findings prompted us to investigate whether the targeting of pulmonary cell types that were highly responsive to IL-4 and IL-13 was a viable therapeutic option in IIP. Using a chimeric protein comprised of human IL-13 and a truncated version of an exotoxin from Pseudomonas (abbreviated IL13-PE), we observed that IL13-PE selectively targeted human pulmonary fibroblasts grown from IIP SLBs, whereas it had a minimal effect on fibroblasts grown from biopsies from normal patients. In murine models characterized by abnormal airway or interstitial fibrotic responses, the intranasal administration of IL13-PE significantly attenuated the fibrotic response through the targeting of IL-4Rα-and IL-13Rα2-expressing pulmonary cells, including monocytes, macrophages, and pulmonary fibroblasts. Together, these data demonstrate that IL-4 and IL-13 are required for the initiation and maintenance of pulmonary fibrosis, and highlight the importance of further investigation of anti-fibrotic therapeutics that prevent the action of both cytokines during clinical pulmonary fibrosis.

Key words

Idiopathic pulmonary fibrosis IL-13 IL-4 IL-13 receptor IL-4 receptor 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Green FH: Overview of pulmonary fibrosis. Chest 2002;122:334S-339S.PubMedCrossRefGoogle Scholar
  2. 2.
    Travis W, Matsui K, Moss J, Ferrans V: Idiopathic nonspecific interstitial pneumonia: Prognostic significance of cellular and fibrosing patterns. Am J Surg Path 2000;24:19–33.PubMedCrossRefGoogle Scholar
  3. 3.
    Katzenstein A, Myers J: Idiopathic pulmonary fibrosis. Clinical relevance of pathologic classification. Am J Respir Crit Care Med 1998;157:1301–1315.PubMedGoogle Scholar
  4. 4.
    Myers JL: NSIP, UIP, and the ABCs of idiopathic interstitial pneumonias. Eur Respir J 1998;12:1003–1004.PubMedCrossRefGoogle Scholar
  5. 5.
    American Thoracic Society, European Respiratory Society (ATS/ERS) international multidisciplinary consensus classification of idiopathic interstitial pneumonias. Am J Respir Crit Care Med 2002;165:277–304.Google Scholar
  6. 6.
    Nagai S, Kitaichi M, Itoh H, Nishimura K, Colby T: Idiopathic nonspecific interstitial pneumonia/fibrosis: comparison with idiopathic pulmonary fibrosis and BOOP. Eur Respir J 1998;12:1010–1019.PubMedCrossRefGoogle Scholar
  7. 7.
    Daniil Z, Gilchrist F, Nicholson A, Hansell D, Harris J, Colby T, duBois R: A histologic pattern of nonspecific interstitial pneumonia is associated with a better prognosis than usual interstitial pneumonia in patients with cryptogenic fibrosing alveolitis. Am J Respir Crit Care Med 1999;160:899–905.PubMedGoogle Scholar
  8. 8.
    Hampton J, Martinez F, Orens J, Toews G, Lynch III J: Corticosteroids in idiopathic pulmonary fibrosis (IPF): toxicity may outweight benefits. Am J Respir Crit Care Med 1994;149:A878.Google Scholar
  9. 9.
    Flaherty KR, Toews GB, Travis WD, Colby TV, Kazerooni EA, Gross BH, et al.: Clinical significance of histological classification of idiopathic interstitial pneumonia. Eur Respir J 2002;19:275–283.PubMedCrossRefGoogle Scholar
  10. 10.
    Lasky JA, Brody AR: Interstitial fibrosis and growth factors. Environ Health Perspect 2000;108 Suppl 4:751–762.PubMedCrossRefGoogle Scholar
  11. 11.
    Allen JT, Spiteri MA: Growth factors in idiopathic pulmonary fibrosis: relative roles. Respir Res 2002;3:13.PubMedCrossRefGoogle Scholar
  12. 12.
    Coker RK, Laurent GJ: Pulmonary fibrosis: cytokines in the balance. Eur Respir J 1998;11:1218–1221.PubMedCrossRefGoogle Scholar
  13. 13.
    Wallace WA, Ramage EA, Lamb D, Howie SE: A type 2 (Th2-like) pattern of immune response predominates in the pulmonary interstitium of patients with cryptogenic fibrosing alveolitis (CFA). Clin Exp Immunol 1995;101:436–441.PubMedGoogle Scholar
  14. 14.
    Wallace WA, Howie SE: Immunoreactive interleukin 4 and interferon-gamma expression by type II alveolar epithelial cells in interstitial lung disease. J Pathol 1999;187:475–480.PubMedCrossRefGoogle Scholar
  15. 15.
    Lukacs NW, Hogaboam C, Chensue SW, Blease K, Kunkel SL: Type 1/type 2 cytokine paradigm and the progression of pulmonary fibrosis. Chest 2001;120:5S-8S.PubMedCrossRefGoogle Scholar
  16. 16.
    Gurujeyalakshmi G, Giri SN: Molecular mechanisms of anti-fibrotic effect of interferon gamma in bleomycinmouse model of lung fibrosis: down regulation of TGF-beta and procollagen I and III gene expression. Exp Lung Res 1995;21:791–808.PubMedCrossRefGoogle Scholar
  17. 17.
    Segel MJ, Cohen PY, Izbicki G, Or R, Christensen TG, Wallach-Dayan SB, Breuer R: The role of interferon-{gamma} in the evolution of murine bleomycin lung fibrosis. Am J Physiol Lung Cell Mol Physiol 2003Google Scholar
  18. 18.
    Ziesche R, Hofbauer E, Wittmann K, Petkov V, Block L: A preliminary study of long-term treatment with interferon gamma-1b and low-dose prednisone in patients with idiopathic pulmonary fibrosis. N Engl J Med 1999;341:1264–1269.PubMedCrossRefGoogle Scholar
  19. 19.
    Prasse A, Muller KM, Kurz C, Hamm H, Virchow JC, Jr.: Does interferon-gamma improve pulmonary function in idiopathic pulmonary fibrosis? Eur Respir J 2003;22:906–911.PubMedCrossRefGoogle Scholar
  20. 20.
    Raghu G, Brown KK, Bradford WZ, Starko K, Noble PW, Schwartz DA, King TE, Jr.: A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis. N Engl J Med 2004;350:125–133.PubMedCrossRefGoogle Scholar
  21. 21.
    Postlethwaite AE, Holness MA, Katai H, Raghow R: Human fibroblasts synthesize elevated levels of extracellular matrix proteins in response to interleukin-4. J Clin Invest 1992;90:1479–1485.PubMedGoogle Scholar
  22. 22.
    Gharaee-Kermani M, Denholm EM, Phan SH: Costimulation of fibroblast collagen and transforming growth factor betal gene expression by monocyte chemoattractant protein-1 via specific receptors. J Biol Chem 1996;271:17779–17784.PubMedCrossRefGoogle Scholar
  23. 23.
    Hogaboam CM, Bone-Larson CL, Lipinski S, Lukacs NW, Chensue SW, Strieter RM, Kunkel SL. Differential monocyte chemoattractant protein-1 and chemokine receptor 2 expression by murine lung fibroblasts derived from Th1- and Th2-type pulmonary granuloma models. J Immunol 1999;163:2193–2201.PubMedGoogle Scholar
  24. 24.
    Makhluf HA, Stepniakowska J, Hoffman S, Smith E, LeRoy EC, Trojanowska M. IL-4 upregulates tenascin synthesis in scleroderma and healthy skin fibroblasts. J Invest Dermatol 1996;107:856–859.PubMedCrossRefGoogle Scholar
  25. 25.
    Postlethwaite AE, Seyer JM: Fibroblast chemotaxis induction by human recombinant interleukin-4. Identification by synthetic peptide analysis of two chemotactic domains residing in amino acid sequences 70–88 and 89–122. J Clin Invest 1991;87:2147–2152.PubMedGoogle Scholar
  26. 26.
    Jakubzick C, Choi ES, Kunkel SL, Joshi BH, Puri RK, Hogaboam CM. Impact of interleukin-13 responsiveness on the synthetic and proliferative properties of Th1-and Th2-type pulmonary granuloma fibroblasts. Am J Pathol 2003;162:1475–1486.PubMedGoogle Scholar
  27. 27.
    Zhu Z, Ma B, Zheng T, Homer RJ, Lee CG, Charo IF, et al.: IL-13-induced chemokine responses in the lung: role of CCR2 in the pathogenesis of IL-13-induced inflammation and remodeling. J Immunol 2002;168:2953–2462.PubMedGoogle Scholar
  28. 28.
    Moore BB, Paine R, 3rd, Christensen PJ, Moore TA, Sitterding S, Ngan R, et al.: Protection from pulmonary fibrosis in the absence of CCR2 signaling. J Immunol 2001;167:4368–4377.PubMedGoogle Scholar
  29. 29.
    Belperio JA, Dy M, Burdick MD, Xue YY, Li K, Elias JA, Keane MP. Interaction of IL-13 and C10 in the pathogenesis of bleomycin-induced pulmonary fibrosis. Am J Respir Cell Mol Biol 2002;27:419–427.PubMedGoogle Scholar
  30. 30.
    Doucet C, Brouty-Boye D, Pottin-Clemenceau C, Canonica GW, Jasmin C, Azzarone B: Interleukin (IL) 4 and IL-13 act on human lung fibroblasts. Implication in asthma. J Clin Invest 1998;101:2129–2139.PubMedGoogle Scholar
  31. 31.
    Doucet C, Brouty-Boye D, Pottin-Clemenceau C, Jasmin C, Canonica GW, Azzarone B: IL-4 and IL-13 specifically increase adhesion molecule and inflammatory cytokine expression in human lung fibroblasts. Int Immunol 1998;10:1421–1433.PubMedCrossRefGoogle Scholar
  32. 32.
    Sempowski GD, Beckmann MP, Derdak S, Phipps RP: Subsets of murine lung fibroblasts express membrane-bound and soluble IL-4 receptors. Role of IL-4 in enhancing fibroblast proliferation and collagen synthesis. J Immunol 1994;152:3606–3614.PubMedGoogle Scholar
  33. 33.
    Zhu Z, Homer RJ, Wang Z, Chen Q, Geba GP, Wang J, et al.: Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production. J Clin Invest 1999;103:779–788.PubMedGoogle Scholar
  34. 34.
    Lee CG, Homer RJ, Zhu Z, Lanone S, Wang X, Koteliansky V, et al.: Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor beta(1). J Exp Med 2001;194:809–821.PubMedCrossRefGoogle Scholar
  35. 35.
    Blease K, Jakubzick C, Westwick J, Lukacs N, Kunkel SL, Hogaboam CM: Therapeutic effect of IL-13 immunoneutralization during chronic experimental fungal asthma. J Immunol 2001;166:5219–5224.PubMedGoogle Scholar
  36. 36.
    Blease K, Jakubzick C, Schuh JM, Joshi BH, Puri RK, Hogaboam CM: IL-13 fusion cytotoxin ameliorates chronic fungal-induced allergic airway disease in mice. J Immunol 2001;167:6583–6592.PubMedGoogle Scholar
  37. 37.
    Chiaramonte MG, Donaldson DD, Cheever AW, Wynn TA: An IL-13 inhibitor blocks the development of hepatic fibrosis during a T-helper type 2-dominated inflammatory response. J Clin Invest 1999;104:777–785.PubMedCrossRefGoogle Scholar
  38. 38.
    Chiaramonte MG, Cheever AW, Malley JD, Donaldson DD, Wynn TA: Studies of murine schistosomiasis reveal interleukin-13 blockade as a treatment for established and progressive liver fibrosis. Hepatology 2001;34:273–282.PubMedCrossRefGoogle Scholar
  39. 39.
    Lee JH, Kaminski N, Dolganov G, Grunig G, Koth L, Solomon C, et al.: Interleukin-13 induces dramatically different transcriptional programs in three human airway cell types. Am J Respir Cell Mol Biol 2001;25:474–485.PubMedGoogle Scholar
  40. 40.
    Homer RJ, Zheng T, Chupp G, He S, Zhu Z, Chen Q, et al.: Pulmonary type II cell hypertrophy and pulmonary lipoproteinosis are features of chronic IL-13 exposure. Am J Physiol Lung Cell Mol Physiol 2002;283:L52-L59.PubMedGoogle Scholar
  41. 41.
    Hancock A, Armstrong L, Gama R, Millar A: Production of interleukin 13 by alveolar macrophages from normal and fibrotic lung. Am J Respir Cell Mol Biol 1998;18;60–65.PubMedGoogle Scholar
  42. 42.
    Oriente A, Fedarko NS, Pacocha SE, Huang SK, Lichtenstein LM, Essayan DM: Interleukin-13 modulates collagen homeostasis in human skin and keloid fibroblasts. J Pharmacol Exp Ther 2000;292:988–994.PubMedGoogle Scholar
  43. 43.
    Richter A, Puddicombe SM, Lordan JL, Bucchieri F, Wilson SJ, Djukanovic R, et al.: The contribution of interleukin (IL)-4 and IL-13 to the epithelial-mesenchymal trophic unit in asthma. Am J Respir Cell Mol Biol 2001;25:385–391.PubMedGoogle Scholar
  44. 44.
    Wynn TA: IL-13 effector functions. Annu Rev Immunol 2003;21:425–456.PubMedCrossRefGoogle Scholar
  45. 45.
    Chiaramonte MG, Mentink-Kane M, Jacobson BA, Cheever AW, Whitters MJ, Goad ME, et al.: Regulation and function of the interleukin 13 receptor alpha 2 during a T helper cell type 2-dominant immune response. J Exp Med 2003;197:687–701.PubMedCrossRefGoogle Scholar
  46. 46.
    Wood N, Whitters MJ, Jacobson BA, Witek J, Sypek JP, Kasaian M, et al.: Enhanced interleukin (IL)-13 responses in mice lacking IL-13 receptor alpha 2. J Exp Med 2003;197:703–709.PubMedCrossRefGoogle Scholar
  47. 47.
    Mentink-Kane MM, Cheever AW, Thompson RW, Hari DM, Kabatereine NB, Vennervald BJ, et al.: IL-13 receptor {alpha} 2 down-modulates granulomatous inflammation and prolongs host survival in schistosomiasis. Proc Natl Acad Sci USA 2004;101:586–590.PubMedCrossRefGoogle Scholar
  48. 48.
    Kawakami K, Taguchi J, Murata T, Puri RK: The interleukin-13 receptor alpha2 chain: an essential component for binding and internalization but not for interleukin-13-induced signal transduction through the STAT6 pathway. Blood 2001;97:2673–2679.PubMedCrossRefGoogle Scholar
  49. 49.
    Toru H, Pawankar R, Ra C, Yata J, Nakahata T: Human mast cells produce IL-13 by high-affinity IgE receptor cross-linking: enhanced IL-13 production by IL-4-primed human mast cells. J Allergy Clin Immunol 1998;102:491–502.PubMedCrossRefGoogle Scholar
  50. 50.
    Murata T, Obiri NI, Debinski W, Puri RK: Structure of IL-13 receptor: analysis of subunit composition in cancer and immune cells. Biochem Biophys Res Commun 1997;238:90–94.PubMedCrossRefGoogle Scholar
  51. 51.
    Murata T, Husain SR, Mohri H, Puri PK: Two different IL-13 receptor chains are expressed in normal human skin fibroblasts, and IL-4 and IL-13 mediate signal transduction through a common pathway. Int Immunol 1998;10:1103–1110.PubMedCrossRefGoogle Scholar
  52. 52.
    McKenzie AN, Culpepper JA, de Waal Malefyt R, Briere F, Punnonen J, Aversa G, et al.: Interleukin 13, a T-cell-derived cytokine that regulates human monocyte and B-cell function. Proc Natl Acad Sci USA 1993;90:3735–3739.PubMedCrossRefGoogle Scholar
  53. 53.
    McKenzie AN: Regulation of T helper type 2 cell immunity by interleukin-4 and interleukin-13. Pharmacol Ther 2000;88:143–151.PubMedCrossRefGoogle Scholar
  54. 54.
    Bochner BS, Klunk DA, Sterbinsky SA, Coffman RL, Schleimer RP. IL-13 selectively induces vascular cell adhesion molecule-1 expression in human endothelial cells. J Immunol 1995;154:799–803.PubMedGoogle Scholar
  55. 55.
    Zheng T, Zhu Z, Liu W, Lee CG, Chen Q, Homer RJ, Elias JA: Cytokine regulation of IL-13Ralpha2 and IL-13Ralpha1 in vivo and in vitro. J Allergy Clin Immunol 2003;111:720–728.PubMedCrossRefGoogle Scholar
  56. 56.
    Kawakami K, Kawakami M, Joshi BH, Puri PK: Interleukin-13 receptor-targeted cancer therapy in an immunodeficient animal model of human head and neck cancer. Cancer Res 2001;61:6194–6200.PubMedGoogle Scholar
  57. 57.
    Kawakami M, Kawakami K, Puri RK: Apoptotic pathways of cell death induced by an interleukin-13 receptortargeted recombinant cytotoxin in head and neck cancer cells. Cancer Immunol Immunother 2002;50:691–700.PubMedCrossRefGoogle Scholar
  58. 58.
    Hogaboam CM, Steinhauser ML, Chensue SW, Kunkel SL: Novel roles for chemokines and fibroblasts in interstitial fibrosis. Kidney Int 1998;54:2152–2159.PubMedCrossRefGoogle Scholar
  59. 59.
    Selman M, Pardo A: Idiopathic pulmonary fibrosis: an epithelial/fibroblastic cross-talk disorder. Respir Res 2002;3:3.PubMedCrossRefGoogle Scholar
  60. 60.
    Lynch JP, 3rd, White E, Flaherty K: Corticosteroids in idiopathic pulmonary fibrosis. Curr Opin Pulm Med 2001;7:298–308.PubMedCrossRefGoogle Scholar
  61. 61.
    Flaherty KR, Toews GB, Lynch JP, 3rd, Kazerooni EA, Gross BH, Strawderman RL, et al.: Steroids in idiopathic pulmonary fibrosis: a prospective assessment of adverse reactions, response to therapy, and survival. Am J Med 2001;110:278–282.PubMedCrossRefGoogle Scholar
  62. 62.
    Gauldie J, Kolb M, Sime PJ: A new direction in the pathogenesis of idiopathic pulmonary fibrosis? Respir Res 2002;3:1.PubMedCrossRefGoogle Scholar
  63. 63.
    van den Blink B, Jansen HM, Peppelenbosch MP: Idiopathic pulmonary fibrosis: molecular mechanisms and possible therapeutic strategies. Arch Immunol Ther Exp (Warsz) 2000;48:539–545.Google Scholar
  64. 64.
    Gharaee-Kermani M, Nozaki Y, Hatano K, Phan SH: Lung interleukin-4 gene expression in a murine model of bleomycin-induced pulmonary fibrosis. Cytokine 2001;15:138–147.PubMedCrossRefGoogle Scholar
  65. 65.
    King TE, Jr., Schwarz MI, Brown K, Tooze JA, Colby TV, Waldron JA, et al.: Idiopathic pulmonary fibrosis: relationship between histopathologic features and mortality. Am J Respir Crit Care Med 2001;164:1025–1032.PubMedGoogle Scholar

Copyright information

© Humana Press Inc 2004

Authors and Affiliations

  • Claudia Jakubzick
    • 2
  • Steven L. Kunkel
    • 2
  • Raj K. Puri
    • 1
  • Cory M. Hogaboam
    • 2
  1. 1.Laboratory of Molecular Tumor Biology, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and ResearchUS Food and Drug AdministrationBethesda
  2. 2.Department of PathologyUniversity of Michigan Medical SchoolAnn Arbor

Personalised recommendations