Current Allergy and Asthma Reports

, Volume 7, Issue 2, pp 151–156 | Cite as

Tumor necrosis factor inhibitors for the treatment of asthma



Asthma is a unique form of chronic airway inflammation characterized by reversible airway obstruction, airway hyperresponsiveness and the production of specific inflammatory mediators. Local activation of both immune and nonimmune cells in the lung triggers the release of these immunomodulator molecules. Among them, tumor necrosis factor (TNF)-α, a multipotent pro-inflammatory mediator, plays a critical role in immunoregulation of asthma by contributing to bronchopulmonary inflammation and airway hyperresponsiveness. Blocking TNF-α activity has already shown outstanding efficacy in other chronic inflammatory diseases including rheumatoid arthritis, Crohn’s disease, and psoriasis. The successful treatment of these other chronic inflammatory diseases provides hope that TNF inhibitors may have application for the treatment of asthma. Recent developments in animal models and clinical trials in patients with severe asthma provide strong support for the concept that blocking TNF-α activity represents a new approach in asthma therapy. In this review, we address the multipotential role of TNF-α in asthma and the efficacy and safety of TNF-α blocking agents in asthma.


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References and Recommended Reading

  1. 1.
    Braman SS: The global burden of asthma [review]. Chest 2006, 130(1 suppl):4S–12.PubMedCrossRefGoogle Scholar
  2. 2.
    World Health Organization: Facts about asthma. In WHO Fact Sheet 2006. Available at: Accessed September 20, 2006.
  3. 3.
    Masoli M, Fabian D, Holt S, et al.: The global burden of asthma: executive summary of the GINA Dissemination Committee report. Allergy 2004, 59:469–478.PubMedCrossRefGoogle Scholar
  4. 4.
    Beasley R: The burden of asthma with specific reference to the United States. J Allergy Clin Immunol 2002, 109:S482–S489.PubMedCrossRefGoogle Scholar
  5. 5.
    Wagelie-Steffen AL, Kavanaugh AF, Wasserman SI: Biologic therapies for the treatment of asthma. Clin Chest Med 2006, 27:133–147.PubMedCrossRefGoogle Scholar
  6. 6.
    Erzurum SC: Inhibition of tumor necrosis factor alpha for refractory asthma. N Engl J Med 2006, 354:754–758.PubMedCrossRefGoogle Scholar
  7. 7.
    Russo C, Polosa R: TNF-alpha as a promising therapeutic target in chronic asthma: a lesson from rheumatoid arthritis. Clin Sci (Lond) 2005, 109:135–142.Google Scholar
  8. 8.
    Buhl R: Anti-IgE antibodies for the treatment of asthma. Curr Opin Pulm Med 2005, 11:27–34.PubMedCrossRefGoogle Scholar
  9. 9.
    Poole JA, Matangkasombut P, Rosenwasser LJ: Targeting the IgE molecule in allergic and asthmatic diseases: review of the IgE molecule and clinical efficacy. J Allergy Clin Immunol 2005, 115:S376–S385.PubMedCrossRefGoogle Scholar
  10. 10.
    Barnes PJ: Cytokine modulators as novel therapies for asthma. Annu Rev Pharmacol Toxicol 2002, 42:81–98.PubMedCrossRefGoogle Scholar
  11. 11.
    Howarth PH, Babu KS, Arshad HS, et al.: Tumour necrosis factor (TNFalpha) as a novel therapeutic target in symptomatic corticosteroid dependent asthma. Thorax 2005, 60:1012–1018.PubMedCrossRefGoogle Scholar
  12. 12.
    Kim J, McKinley L, Natarajan S, et al.: Anti-tumor necrosis factor-alpha antibody treatment reduces pulmonary inflammation and methacholine hyper-responsiveness in a murine asthma model induced by house dust. Clin Exp Allergy 2006, 36:122–132.PubMedCrossRefGoogle Scholar
  13. 13.
    Hanauer SB, Sandborn WJ, Rutgeerts P, et al.: Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn’s disease: the CLASSIC-I trial. Gastroenterology 2006, 130:323–333.PubMedCrossRefGoogle Scholar
  14. 14.
    Scott DL, Kingsley GH: Tumor necrosis factor inhibitors for rheumatoid arthritis. N Engl J Med 2006, 355:704–712.PubMedCrossRefGoogle Scholar
  15. 15.
    Carswell EA, Old LJ, Kassel RL, et al.: An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci U S A 1975, 72:3666–3670.PubMedCrossRefGoogle Scholar
  16. 16.
    Beutler B, Mahoney J, Le Trang N, et al.: Purification of cachectin, a lipoprotein lipase-suppressing hormone secreted by endotoxin-induced RAW 264.7 cells. J Exp Med 1985, 161:984–995.PubMedCrossRefGoogle Scholar
  17. 17.
    Wollenberg GK, DeForge LE, Bolgos G, et al.: Differential expression of tumor necrosis factor and interleukin-6 by peritoneal macrophages in vivo and in culture. Am J Pathol 1993, 143:1121–1130.PubMedGoogle Scholar
  18. 18.
    Call DR, Nemzek JA, Ebong SJ, et al.: Differential local and systemic regulation of the murine chemokines KC and MIP2. Shock 2001, 15:278–284.PubMedGoogle Scholar
  19. 19.
    DeForge LE, Remick DG: Kinetics of TNF, IL-6, and IL-8 gene expression in LPS-stimulated human whole blood. Biochem Biophys Res Commun 1991, 174:18–24.PubMedCrossRefGoogle Scholar
  20. 20.
    Caput D, Beutler B, Hartog K, et al.: Identification of a common nucleotide sequence in the 3′-untranslated region of mRNA molecules specifying inflammatory mediators. Proc Natl Acad Sci U S A 1986, 83:1670–1674.PubMedCrossRefGoogle Scholar
  21. 21.
    Hsi ED, Remick DG: Rapid determination of cell-associated tumor necrosis factor production by flow cytometry. Lab Invest 1993, 68:740–745.PubMedGoogle Scholar
  22. 22.
    Black RA: Tumor necrosis factor-alpha converting enzyme. Int J Biochem Cell Biol 2002, 34:1–5.PubMedCrossRefGoogle Scholar
  23. 23.
    Haack M, Pollmacher T, Mullington JM: Diurnal and sleep-wake dependent variations of soluble TNF-and IL-2 receptors in healthy volunteers. Brain Behav Immun 2004, 18:361–367.PubMedCrossRefGoogle Scholar
  24. 24.
    Leeuwenberg JF, Dentener MA, Buurman WA: Lipopolysaccharide LPS-mediated soluble TNF receptor release and TNF receptor expression by monocytes. Role of CD14, LPS binding protein, and bactericidal/permeability-increasing protein. J Immunol 1994, 152:5070–5076.PubMedGoogle Scholar
  25. 25.
    Truyens C, Torrico F, Lucas R, et al.: The endogenous balance of soluble tumor necrosis factor receptors and tumor necrosis factor modulates cachexia and mortality in mice acutely infected with Trypanosoma cruzi. Infect Immun 1999, 67:5579–5586.PubMedGoogle Scholar
  26. 26.
    Fisher CJ, Jr., Agosti JM, Opal SM, et al.: Treatment of septic shock with the tumor necrosis factor receptor: Fc fusion protein. The Soluble TNF Receptor Sepsis Study Group. N Engl J Med 1996, 334:1697–1702.PubMedCrossRefGoogle Scholar
  27. 27.
    Waage A, Halstensen A, Espevik T: Association between tumour necrosis factor in serum and fatal outcome in patients with meningococcal disease. Lancet 1987, 1:355–357.PubMedCrossRefGoogle Scholar
  28. 28.
    Holgate ST, Holloway J, Wilson S, et al.: Understanding the pathophysiology of severe asthma to generate new therapeutic opportunities. J Allergy Clin Immunol 2006, 117:496–506; quiz 507.PubMedCrossRefGoogle Scholar
  29. 29.
    Shah A, Church MK, Holgate ST: Tumour necrosis factor alpha: a potential mediator of asthma. Clin Exp Allergy 1995, 25:1038–1044.PubMedCrossRefGoogle Scholar
  30. 30.
    Thomas PS: Tumour necrosis factor-alpha: the role of this multifunctional cytokine in asthma. Immunol Cell Biol 2001, 79:132–140.PubMedCrossRefGoogle Scholar
  31. 31.
    Babu KS, Davies DE, Holgate ST: Role of tumor necrosis factor alpha in asthma. Immunol Allergy Clin North Am 2004, 24:583–597.PubMedCrossRefGoogle Scholar
  32. 32.
    Coward WR, Okayama Y, Sagara H, et al.: NF-kappa B and TNF-alpha: a positive autocrine loop in human lung mast cells? J Immunol 2002, 169:5287–5293.PubMedGoogle Scholar
  33. 33.
    Berry MA, Hargadon B, Shelley M, et al.: Evidence of a role of tumor necrosis factor alpha in refractory asthma. N Engl J Med 2006, 354:697–708.PubMedCrossRefGoogle Scholar
  34. 34.
    Gordon JR, Galli SJ: Release of both preformed and newly synthesized tumor necrosis factor alpha (TNF-alpha)/cachectin by mouse mast cells stimulated via the Fc epsilon RI. A mechanism for the sustained action of mast cell-derived TNF-alpha during IgE-dependent biological responses. J Exp Med 1991, 174:103–107.PubMedCrossRefGoogle Scholar
  35. 35.
    Thomas PS, Yates DH, Barnes PJ: Tumor necrosis factor-alpha increases airway responsiveness and sputum neutrophilia in normal human subjects. Am J Respir Crit Care Med 1995, 152:76–80.PubMedGoogle Scholar
  36. 36.
    Lukacs NW, Strieter RM, Chensue SW, et al.: TNF-alpha mediates recruitment of neutrophils and eosinophils during airway inflammation. J Immunol 1995, 154:5411–5417.PubMedGoogle Scholar
  37. 37.
    Casale TB, Costa JJ, Galli SJ: TNF alpha is important in human lung allergic reactions. Am J Respir Cell Mol Biol 1996, 15:35–44.PubMedGoogle Scholar
  38. 38.
    Amrani Y, Chen H, Panettieri RA Jr: Activation of tumor necrosis factor receptor 1 in airway smooth muscle: a potential pathway that modulates bronchial hyper-responsiveness in asthma? Respir Res 2000, 1:49–53.PubMedCrossRefGoogle Scholar
  39. 39.
    Tosi MF, Stark JM, Smith CW, et al.: Induction of ICAM-1 expression on human airway epithelial cells by inflammatory cytokines: effects on neutrophil-epithelial cell adhesion. Am J Respir Cell Mol Biol 1992, 7:214–221.PubMedGoogle Scholar
  40. 40.
    Thornhill MH, Wellicome SM, Mahiouz DL, et al.: Tumor necrosis factor combines with IL-4 or IFN-gamma to selectively enhance endothelial cell adhesiveness for T cells. The contribution of vascular cell adhesion molecule-1-dependent and-independent binding mechanisms. J Immunol 1991, 146:592–598.PubMedGoogle Scholar
  41. 41.
    Busse PJ, Zhang TF, Srivastava K, et al.: Chronic exposure to TNF-alpha increases airway mucus gene expression in vivo. J Allergy Clin Immunol 2005, 116:1256–1263.PubMedCrossRefGoogle Scholar
  42. 42.
    Levine SJ, Larivee P, Logun C, et al.: Tumor necrosis factor-alpha induces mucin hypersecretion and MUC-2 gene expression by human airway epithelial cells. Am J Respir Cell Mol Biol 1995, 12:196–204.PubMedGoogle Scholar
  43. 43.
    Lora JM, Zhang DM, Liao SM, et al.: Tumor necrosis factor-alpha triggers mucus production in airway epithelium through an IkappaB kinase beta-dependent mechanism. J Biol Chem 2005, 280:36510–36517.PubMedCrossRefGoogle Scholar
  44. 44.
    Choi IW, Sun K, Kim YS, et al.: TNF-alpha induces the late-phase airway hyperresponsiveness and airway inflammation through cytosolic phospholipase A(2) activation. J Allergy Clin Immunol 2005, 116:537–543.PubMedCrossRefGoogle Scholar
  45. 45.
    Kips JC, Tavernier J, Pauwels RA: Tumor necrosis factor causes bronchial hyperresponsiveness in rats. Am Rev Respir Dis 1992, 145:332–336.PubMedGoogle Scholar
  46. 46.
    Holgate ST: Cytokine and anti-cytokine therapy for the treatment of asthma and allergic disease. Cytokine 2004, 28:152–157.PubMedCrossRefGoogle Scholar
  47. 47.
    Toussirot E, Wendling D: The use of TNF-alpha blocking agents in rheumatoid arthritis: an overview. Expert Opin Pharmacother 2004, 5:581–594.PubMedCrossRefGoogle Scholar
  48. 48.
    Bruce C, Thomas PS: The effect of marimastat, a metalloprotease inhibitor, on allergen-induced asthmatic hyper-reactivity. Toxicol Appl Pharmacol 2005, 205:126–132.PubMedCrossRefGoogle Scholar
  49. 49.
    van Deventer SJ: A place for TACE [comment]. Gut 2002, 51:5–6.PubMedCrossRefGoogle Scholar
  50. 50.
    Rudmann DG, Moore MW, Tepper JS, et al.: Modulation of allergic inflammation in mice deficient in TNF receptors. Am J Physiol Lung Cell Mol Physiol 2000, 279:L1047–L1057.PubMedGoogle Scholar
  51. 51.
    Zuany-Amorim C, Manlius C, Dalum I, et al.: Induction of TNF-alpha autoantibody production by AutoVac TNF106: a novel therapeutic approach for the treatment of allergic diseases. Int Arch Allergy Immunol 2004, 133:154–163.PubMedCrossRefGoogle Scholar
  52. 52.
    Bruce CT, Thomas PS: TNF-alpha as a target for anti-asthma therapy [letter]. Clin Sci (Lond) 2006, 110:265.CrossRefGoogle Scholar
  53. 53.
    Campbell IK, Roberts LJ, Wicks IP: Molecular targets in immune-mediated diseases: the case of tumour necrosis factor and rheumatoid arthritis. Immunol Cell Biol 2003, 81:354–366.PubMedCrossRefGoogle Scholar
  54. 54.
    Oliveri C, Polosa R: Etanercept in chronic severe asthma [comment]. Thorax 2006, 61:640; author reply 640.PubMedGoogle Scholar
  55. 55.
    Fleischmann RM, Iqbal I, Stern RL: Considerations with the use of biological therapy in the treatment of rheumatoid arthritis. Expert Opin Drug Saf 2004, 3:391–403.PubMedCrossRefGoogle Scholar
  56. 56.
    Fleischmann R, Iqbal I, Nandeshwar P, et al.: Safety and efficacy of disease-modifying anti-rheumatic agents: focus on the benefits and risks of etanercept. Drug Saf 2002, 25:173–197.PubMedCrossRefGoogle Scholar
  57. 57.
    Gomez-Reino JJ, Carmona L, Valverde VR, et al.: Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: a multicenter active-surveillance report. Arthritis Rheum 2003, 48:2122–2127.PubMedCrossRefGoogle Scholar
  58. 58.
    Wallis RS, Broder MS, Wong JY, et al.: Granulomatous infectious diseases associated with tumor necrosis factor antagonists. Clin Infect Dis 2004, 38:1261–1265.PubMedCrossRefGoogle Scholar
  59. 59.
    Mohan N, Edwards ET, Cupps TR, et al.: Demyelination occurring during anti-tumor necrosis factor alpha therapy for inflammatory arthritides. Arthritis Rheum 2001, 44:2862–2869.PubMedCrossRefGoogle Scholar
  60. 60.
    Robinson WH, Genovese MC, Moreland LW: Demyelinating and neurologic events reported in association with tumor necrosis factor alpha antagonism: by what mechanisms could tumor necrosis factor alpha antagonists improve rheumatoid arthritis but exacerbate multiple sclerosis? Arthritis Rheum 2001, 44:1977–1983.PubMedCrossRefGoogle Scholar
  61. 61.
    Davydov L: Omalizumab (Xolair) for treatment of asthma. Am Fam Physician 2005, 71:341–342.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.Department of SurgeryUniversity of Michigan School of MedicineAnn ArborUSA

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