American Journal of Respiratory Medicine

, Volume 2, Issue 3, pp 211–219 | Cite as

The Role of Nuclear Factor Kappa B in the Pathogenesis of Pulmonary Diseases: Implications for Therapy

Leading Article

Abstract

The nuclear factor kappa B (NF-κB) transcription factor plays a key role in the induction of pro-inflammatory gene expression, leading to the synthesis of cytokines, adhesion molecules, chemokines, growth factors and enzymes. Results of studies in in vitro and in vivo models of inflammation and malignancy have also suggested central roles for NF-κB in programmed cell death, or apoptosis.

NF-κB plays a central role in a variety of acute and chronic inflammatory diseases. In the common lung diseases associated with a significant inflammatory component such as severe sepsis, acute lung injury, acute respiratory distress syndrome, cystic fibrosis and asthma, the pathogenic roles of NF-κB have been extensively investigated. In COPD, activation of NF-κB has been implicated in disease pathogenesis but its exact role is less clearly demonstrable in this heterogeneous patient population. However, the principal risk factor for COPD, cigarette smoking, is strongly associated with NF-κB activation.

Activation of NF-κB has been demonstrated in mineral dust diseases and probably plays a role in the pathogenesis of these chronic illnesses. NF-kB also plays a variety of roles in lung cancer including resistance to chemotherapy, inhibition of tumorigenesis and inducing expression of antiapoptotic genes. The complex NF-κB pathway offers a variety of potential molecular targets for chemotherapeutic intervention. A variety of agents aimed at modulating NF-κB activity are in various stages of investigation.

References

  1. 1.
    Sen R, Baltimore D. Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell 1986; 46: 705–16PubMedCrossRefGoogle Scholar
  2. 2.
    Schwartz MD, Moore EE, Moore FA, et al. Nuclear factor-kappaB is activated in alveolar macrophages from patients with acute respiratory distress syndrome. Crit Care Med 1996; 24: 1285–92PubMedCrossRefGoogle Scholar
  3. 3.
    Blackwell TS, Holden EP, Blackwell TR, et al. Activation of NF-kappaB in rat lung by treatment with endotoxin: modulation with N-acetyalcysteine. J Immunol 1996; 157: 1630–7PubMedGoogle Scholar
  4. 4.
    Ghosh S, May MJ, Kopp EB. NF-kappaB and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol 1998; 16: 225–60PubMedCrossRefGoogle Scholar
  5. 5.
    Henkel T, Machleidt T, Alkalay I, et al. Rapid proteolysis of I kappa B-alpha is necessary for activation of transcription factor NF-kappaB. Nature 1993; 365: 182–5PubMedCrossRefGoogle Scholar
  6. 6.
    Sizemore N, Leung S, Stark GR. Activation of phosphatidylinositol 3-kinase in response to Interleukin-1 leads to phosphorylation and activation of the NF-kappaB p65/RelA subunit. Mol Cell Biol 1999; 19: 4798–805PubMedGoogle Scholar
  7. 7.
    Zhong H, SuYang H, Erdjument-Bromage H, et al. The transcriptional activity of NF-kappaB is regulated by the IkappaB-associated PKAc subunit through a cyclic AMP-independent mechanism. Cell 1997; 89: 413–24PubMedCrossRefGoogle Scholar
  8. 8.
    Arenzana-Seisdedos F, Thompson J, Rodriguez MS, et al. Inducible nuclear expression of newly synthesized I kappa B alpha negatively regulates DNA-binding and transcriptional activities of NF-kappa B. Mol Cell Biol 1995; 15: 2689–96PubMedGoogle Scholar
  9. 9.
    Chen L-F, Fischle W, Verdin E, et al. Duration of nuclear NF-kappaB action regulated by reversible acetylation. Science 2001; 293: 1653–7CrossRefGoogle Scholar
  10. 10.
    Mercurio F, Manning AM. Multiple signals converging on NF-kappaB. Curr Opin Cell Biol 1999; 11: 226–32PubMedCrossRefGoogle Scholar
  11. 11.
    Opal SM, Huber CE. Bench-to-bedside review: toll-like receptors and their role in septic shock. Crit Care 2002; 6(2): 125–36PubMedCrossRefGoogle Scholar
  12. 12.
    Barnes PJ, Karin M. Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med 1997; 336(15): 1066–71PubMedCrossRefGoogle Scholar
  13. 13.
    Moine P, McIntyre R, Schwartz MD, et al. NF-kappaB regulatory mechanisms in alveolar macrophages from patients with acute respiratory distress syndrome. Shock 2000; 13(2): 85–91PubMedCrossRefGoogle Scholar
  14. 14.
    Shenkar R, Yum HK, Arcaroli J, et al. Interactions between CBP, NF-kappaB, and CREB in the lungs after hemorrhage and endotoxemia. Am J Physiol Lung Cell Mol Physiol 2001; 281(2): L418–26PubMedGoogle Scholar
  15. 15.
    Pepperl S, Dorger M, Ringel F, et al. Hyperoxia upregulates the NO pathway in alveolar macrophages in vitro: role of AP-1 and NF-kappaB. Am J Physiol Lung Cell Mol Physiol 2001; 280(5): L905–13PubMedGoogle Scholar
  16. 16.
    Pugin J, Dunn I, Jolliet P, et al. Activation of human macrophages by mechanical ventilation in vitro. Am J Physiol 1998; 275 (6 Pt 1): L1040–50PubMedGoogle Scholar
  17. 17.
    Leeper-Woodford SK, Detmer K. Acute hypoxia increases alveolar macrophage tumor necrosis factor activity and alters NF-kappaB expression. Am J Physiol 1999; 276 (6 Pt 1): L909–16PubMedGoogle Scholar
  18. 18.
    Janssen-Heininger YM, Macara I, Mossman BT. Cooperativity between oxidants and tumor necrosis factor in the activation of nuclear factor (NF)-kappaB: requirement of Ras/mitogen-activated protein kinases in the activation of NF-kappaB by oxidants. Am J Respir Cell Mol Biol 1999; 20(5): 942–52PubMedGoogle Scholar
  19. 19.
    Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344(10): 699–709PubMedCrossRefGoogle Scholar
  20. 20.
    Esmon CT. Protein C anticoagulant pathway and its role in controlling microvascular thrombosis and inflammation. Crit Care Med 2001; 29 (7 Suppl.): S48–51PubMedCrossRefGoogle Scholar
  21. 21.
    Joyce DE, Grinnell BW. Recombinant human activated protein C attenuates the inflammatory response in endothelium and monocytes by modulating nuclear factor-kappaB. Crit Care Med 2002; 30 (5 Suppl.): S288–93PubMedCrossRefGoogle Scholar
  22. 22.
    Zhao S, Qi Y, Liu X, et al. Activation of NF-kappa B in bronchial epithelial cells from children with asthma. Chin Med J (Engl) 2001; 114(9): 909–11Google Scholar
  23. 23.
    Wilson SJ, Wallin A, Della-Cioppa G, et al. Effects of budesonide and formoterol on NF-kappaB, adhesion molecules, and cytokines in asthma. Am J Respir Crit Care Med 2001; 164(6): 1047–52PubMedGoogle Scholar
  24. 24.
    Shukla A, Timblin C, BeruBe K, et al. Inhaled particulate matter causes expression of nuclear factor (NF)-kappaB-related genes and oxidant-dependent NF-kappaB activation in vitro. Am J Respir Cell Mol Biol 2000; 23(2): 182–7PubMedGoogle Scholar
  25. 25.
    Hamid Q, Springall DR, Riveros-Moreno V, et al. Induction of nitric oxide synthase in asthma. Lancet 1993; 342: 1510–3PubMedCrossRefGoogle Scholar
  26. 26.
    Kim I, Moon S, Kim S, et al. Vascular endothelial growth factor expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin through nuclear factor-kappa B activation in endothelial cells. J Biol Chem 2001; 276(10): 7614–20PubMedCrossRefGoogle Scholar
  27. 27.
    Dikov M, Oyama T, Cheng P, et al. Vascular endothelial growth factor effects on nuclear factor-kappaB activation in hematopoietic progenitor cells. Cancer Res 2001; 61(5): 2015–21PubMedGoogle Scholar
  28. 28.
    Kasahara Y, Tuder R, Taraseviciene-Stewart L, et al. Inhibition of VEGF receptors causes lung cell apoptosis and emphysema. J Clin Invest 2000; 106(11): 1311–9PubMedCrossRefGoogle Scholar
  29. 29.
    Baldwin Jr AS. The NF-kappaB and IkappaB proteins: new discoveries and insights. Annu Rev Immunol 1996; 14: 649–81PubMedCrossRefGoogle Scholar
  30. 30.
    Nishikawa M, Kakemizu N, Ito T, et al. Superoxide mediates cigarette smoke-induced infiltration of neutrophils into the airways through nuclear factor-kappaB activation and IL-8 mRNA expression in guinea pigs in vivo. Am J Respir Cell Mol Biol 1999; 20: 189–98PubMedGoogle Scholar
  31. 31.
    Christman JW, Sadikot RT, Blackwell TS. The role of nuclear factor kappaB in pulmonary diseases. Chest 2000; 117: 1482–7PubMedCrossRefGoogle Scholar
  32. 32.
    Teramoto S, Kume H. The role of nuclear factor-kappaB activation in airway inflammation following adenovirus infection and COPD. Chest 2000; 119(4): 1294–5CrossRefGoogle Scholar
  33. 33.
    Cafferata EGA, Guerrico AMG, Pivetta OH, et al. NF-kappaB activation is involved in regulation of cystic fibrosis transmembrane conductance regulator (CFTR) by interleukin-1beta. J Biol Chem 2001; 276(18): 15441–4PubMedCrossRefGoogle Scholar
  34. 34.
    Brouillard F, Bouthier M, Leclerc T, et al. NF-kappa B mediates up-regulation of CFTR gene expression in Calu-3 cells by interleukin-1beta. J Biol Chem 2001; 276(12): 9486–91PubMedCrossRefGoogle Scholar
  35. 35.
    Venkatakrishnan A, Stecenko AA, King G, et al. Exaggerated activation of nuclear factor-kappaB and altered IkappaB-beta processing in cystic fibrosis bronchial epithelial cells. Am J Respir Cell Mol Biol 2000; 23(3): 396–403PubMedGoogle Scholar
  36. 36.
    Weber AJ, Soong G, Bryan R, et al. Activation of NF-kappaB in airway epithelial cells is dependent on CFTR trafficking and Cl-channel function. Am J Physiol Lung Cell Mol Physiol 2001; 281(1): L71–8PubMedGoogle Scholar
  37. 37.
    Scheid P, Kempster L, Griesenbach U, et al. Inflammation in cystic fibrosis airways: relationship to increased bacterial adherence. Eur Respir J 2001; 17(1): 27–35PubMedCrossRefGoogle Scholar
  38. 38.
    DiMango E, Ratner AJ, Bryan R, et al. Activation of NF-kappaB by adherent Pseudomonas aeruginosa in normal and cystic fibrosis respiratory epithelial cells. J Clin Invest 1998; 101(11): 2598–605PubMedCrossRefGoogle Scholar
  39. 39.
    Ghio AJ, Marshall BC, Diaz JL, et al. Tyloxapol inhibits NF-kappa B and cytokine release, scavenges HOCI, and reduces viscosity of cystic fibrosis sputum. Am J Respir Crit Care Med 1996; 154 (3 Pt 1): 783–8PubMedGoogle Scholar
  40. 40.
    Drent M, van den Berg R, Haenen GR, et al. NF-kappaB activation in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2001; 18(1): 50–6PubMedGoogle Scholar
  41. 41.
    Kreipe H, Radzun HJ, Heidorn K, et al. Proliferation, macrophage colony-stimulating factor, and macrophage colony-stimulating factor-receptor expression of alveolar macrophages in active sarcoidosis. Lab Invest 1990; 62(6): 697–703PubMedGoogle Scholar
  42. 42.
    Conron M, Bondeson J, Pantelidis P, et al. Alveolar macrophages and T cells from sarcoid, but not normal lung, are permissive to adenovirus infection and allow analysis of NF-kappa b-dependent signaling pathways. Am J Respir Cell Mol Biol 2001; 25(2): 141–9PubMedGoogle Scholar
  43. 43.
    Baldwin Jr AS. Control of oncogenesis and cancer therapy resistance by the transcription factor NF-kappaB. J Clin Invest 2001; 107(3): 241–6PubMedCrossRefGoogle Scholar
  44. 44.
    Karin M, Lin A. NF-kappaB at the crossroads of life and death. Nat Immunol 2002; 3(3): 221–7PubMedCrossRefGoogle Scholar
  45. 45.
    Rosell R, Taron M, O’Brate A. Predictive molecular markers in non-small cell lung cancer. Curr Opin Oncol 2001; 13(2): 101–9PubMedCrossRefGoogle Scholar
  46. 46.
    Jones DR, Broad RM, Madrid LV, et al. Inhibition of NF-kappaB sensitizes non-small cell lung cancer cells to chemotherapy-induced apoptosis. Ann Thorac Cardiovasc Surg 2000; 70(3): 930–6Google Scholar
  47. 47.
    Cusack JJ, Liu R, Baldwin Jr AS. Inducible chemoresistance to 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin (CPT-11) in colorectal cancer cells and xenograft models is overcome by inhibition of nuclear factorkappa activation. Cancer Res 2000; 60: 2323–30PubMedGoogle Scholar
  48. 48.
    Haley KJ, Patidar K, Zhang F, et al. Tumor necrosis factor induces neuroendocrine differentiation in small cell lung cancer cell lines. Am J Physiol 1998; 275 (2 Pt 1): L311–21PubMedGoogle Scholar
  49. 49.
    Batra RK, Guttridge DC, Brenner DA, et al. IkappaBalpha gene transfer is cytotoxic to squamous-cell lung cancer cells and sensitizes them to tumor necrosis factor-alpha-mediated cell death. Am J Respir Cell Mol Biol 1999; 21(2): 238–45PubMedGoogle Scholar
  50. 50.
    Milligan SA, Nopajaroonsri C. Inhibition of NF-kappa B with proteasome inhibitors enhances apoptosis in human lung adenocarcinoma cells in vitro. Anticancer Res 2001; 21(1A): 39–44PubMedGoogle Scholar
  51. 51.
    Ding M, Shi X, Castranova V, et al. Predisposing factors in occupational lung cancer: inorganic minerals and chromium. J Environ Pathol Toxicol Oncol 2000; 19(1-2): 129–38PubMedGoogle Scholar
  52. 52.
    Sacks M, Gordon J, Bylander J. Silica-induced pulmonary inflammation in rats: activation of NF-kappaB and its suppression by dexamethasone. Biochem Biophys Res Commun 1998; 253: 181–4PubMedCrossRefGoogle Scholar
  53. 53.
    Kennedy T, Ghio AJ, Reed W, et al. Copper dependent inflammation and nuclear factor kappa B activation by particulate air pollution. Am J Respir Cell Mol Biol 1998; 19: 366–78PubMedGoogle Scholar
  54. 54.
    Takizawa H, Ohtoshi T, Kawasaki S, et al. Diesel exhaust particles induce NF-kB activity in human bronchial epithelial cells in vitro: importance in cytokine transcription. J Immunol 1999; 162: 4705–11PubMedGoogle Scholar
  55. 55.
    Quay JL, Reed W, Samet J, et al. Air pollution particles induce IL-6 gene expression in human airway epithelial cells via NF-kappaB activation. Am J Respir Cell Mol Biol 1998; 19: 98–106PubMedGoogle Scholar
  56. 56.
    Kawasaki S, Takizawa H, Takami K, et al. Benzene-extracted components are important for the major activity of diesel exhaust particles: effect on interleukin-8 gene expression in human bronchial epithelial cells. Am J Respir Cell Mol Biol 2001; 24(4): 419–26PubMedGoogle Scholar
  57. 57.
    Bonvallot V, Baeza-Squiban A, Baulig A, et al. Organic compounds from diesel exhaust particles elicit a proinflammatory response in human airway epithelial cells and induce cytochrome p450 1A1 expression. Am J Respir Cell Mol Biol 2001; 25(4): 515–21PubMedGoogle Scholar
  58. 58.
    Dai J, Churg A. Relationship of fiber surface iron and active oxygen species to expression of procollagen, PDGF-A, and TGF-beta(1) in tracheal explants exposed to amosite asbestos. Am J Respir Cell Mol Biol 2001; 24(4): 427–35PubMedGoogle Scholar
  59. 59.
    Gilmour PS, Beswick PH, Brown DM, et al. Detection of surface free radical activity of respirable industrial fibres using supercoiled phi X174 RF1 plasmid DNA. Carcinogenesis 1995; 16: 2973–9PubMedCrossRefGoogle Scholar
  60. 60.
    Janssen YM, Driscoll KE, Howard B, et al. Asbestos causes translocation of p65 protein and increases NF-kappa B DNA binding activity in rat lung epithelial and pleural mesothelial cells. Am J Pathol 1997; 151(2): 389–401PubMedGoogle Scholar
  61. 61.
    Janssen YM, Barchowsky A, Treadwell M, et al. Asbestos induces nuclear factor kappa B (NF-kappa B) DNA-binding activity and NF-kappa B-dependent gene expression in tracheal epithelial cells. Proc Natl Acad Sci U S A 1995; 92(18): 8458–62PubMedCrossRefGoogle Scholar
  62. 62.
    Cheng N, Shi X, Ye J, et al. Role of transcription factor NF-kappaB in asbestos-induced TNFalpha response from macrophages. Exp Mol Pathol 1999; 66(3): 201–10PubMedCrossRefGoogle Scholar
  63. 63.
    Brown DM, Beswick PH, Donaldson K. Induction of nuclear translocation of NF-kappaB in epithelial cells by respirable mineral fibres. J Pathol 1999; 189(2): 258–64PubMedCrossRefGoogle Scholar
  64. 64.
    Robledo R, Mossman BT. Cellular and molecular mechanisms of asbestos-induced fibrosis. J Cell Physiol 1999; 180(2): 158–66PubMedCrossRefGoogle Scholar
  65. 65.
    Bremner P, Heinrich M. Natural products as targeted modulators of the nuclear factor-kappaB pathway. J Pharm Pharmcol 2002; 54(4): 453–72CrossRefGoogle Scholar
  66. 66.
    Sheehan M, Wong HR, Hake PW, et al. Parthenolide, an inhibitor of the nuclear factor-kappaB pathway, ameliorates cardiovascular derangement and outcome in endotoxic shock in rodents. Mol Pharmacol 2002; 61(5): 953–63PubMedCrossRefGoogle Scholar
  67. 67.
    Adams J, Palombella VJ, Sausville EA, et al. Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res 1999; 59: 2615–22PubMedGoogle Scholar
  68. 68.
    Javelaud D, Poupon MF, Wietzerbin J, et al. Inhibition of constitutive NF-kappa B activity suppresses tumorigenicity of Ewing sarcoma EW7 cells. Int J Cancer 2002; 98(2): 193–8PubMedCrossRefGoogle Scholar
  69. 69.
    Romanelli A, Pedone C, Saviano M, et al. Molecular interactions with nuclear factor kappaB (NF-kappaB) transcription factors of a PNA-DNA chimera mimicking NF-kappaB binding sites. Eur J Biochem 2001; 268(23): 6066–75PubMedCrossRefGoogle Scholar
  70. 70.
    Ueno T, Sawa Y, Kitagawa-Sakakida S, et al. Nuclear factor-kappa B decoy attenuates neuronal damage after global brain ischemia: a future strategy for brain protection during circulatory arrest. J Thorac Cardiovasc Surg 2001; 122(4): 720–7PubMedCrossRefGoogle Scholar
  71. 71.
    Sakaue G, Shimaoka M, Fukuoka T, et al. NF-kappa B decoy suppresses cytokine expression and thermal hyperalgesia in a rat neuropathic pain model. Neuroreport 2001; 12(10): 2079–84PubMedCrossRefGoogle Scholar
  72. 72.
    Tonita T, Takeuchi E, Tonita N, et al. Suppressed severity of collagen-induced arthritis by in vivo transfection of nuclear factor kappaB decoy oligo-nucleotides as a gene therapy. Arthritis Rheum 1999; 42(12): 2532–42CrossRefGoogle Scholar
  73. 73.
    Almawi WY, Melemedjian O. Negative regulation of nuclear factor-kappaB activation and function by glucocorticoids. J Mol Endocrinol 2002; 28(2): 69–78PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2003

Authors and Affiliations

  1. 1.Division of Allergy, Pulmonary, and Critical Care Medicine, Department of MedicineVanderbilt University School of MedicineUSA
  2. 2.Department of Veterans AffairsNashvilleUSA
  3. 3.Pulmonary and Critical Care MedicineVanderbilt University School of MedicineNashvilleUSA

Personalised recommendations