Am. J. Respir. Crit. Care Med., Volume 158, Number 5, November 1998, 1585-1592

Activation and Localization of Transcription Factor, Nuclear Factor-B, in Asthma

LORRAINE A. HART, VIJAYA L. KRISHNAN, IAN M. ADCOCK, PETER J. BARNES, and K. FAN CHUNG

Department of Thoracic Medicine, National Heart and Lung Institute at the Imperial College School of Medicine; and Royal Brompton Hospital, London, United Kingdom

Asthma is associated with increased expression of inflammatory proteins including cytokines, enzymes, and adhesion molecules. Induction of many of the genes for these proteins is regulated by the transcription factor, nuclear factor-B (NF-B). We therefore examined whether airway cells from patients with asthma show increased activation of NF-B. Nuclear proteins were extracted from cells of induced sputum and from bronchial biopsies of normal subjects and patients with asthma. NF-B-binding to its consensus DNA binding site, as investigated with ³²P-labeled oligonucleotides and electrophoretic-mobility-shift assay, showed a 2.5-fold increase (p < 0.003) in NF-B-DNA binding in induced sputum of asthma patients. Nuclear staining, representing activated NF-B, was observed in macrophages of induced sputum. Immunohistochemical examination of bronchial biopsy specimens with an antibody to p65, a constituent of NF-B, showed more airway epithelial cells with nuclear staining in asthma patients (45.1 ± 7.2% versus 20.7 ± 3.9%; n = 9; p < 0.01), and a 2.5-fold greater number of cells with cytoplasmic staining in the mucosal region (p < 0.05). Pooled nuclear extracts of bronchial biopsy specimens from asthma patients showed a 44% greater level of NF-B-DNA binding. Activation of NF-B may be the basis for increased expression of many inflammatory genes and for the perpetuation of chronic airway inflammation in asthma.

This article has been cited by other articles:

				C. Pantano, J. L. Ather, J. F. Alcorn, M. E. Poynter, A. L. Brown, A. S. Guala, S. L. Beuschel, G. B. Allen, L. A. Whittaker, M. Bevelander, et al. Nuclear Factor-{kappa}B Activation in Airway Epithelium Induces Inflammation and Hyperresponsiveness Am. J. Respir. Crit. Care Med., May 1, 2008; 177(9): 959 - 969. [Abstract] [Full Text] [PDF]

				S. P. Chapoval, A. Al-Garawi, J. M. Lora, I. Strickland, B. Ma, P. J. Lee, R. J. Homer, S. Ghosh, A. J. Coyle, and J. A. Elias Inhibition of NF-{kappa}B Activation Reduces the Tissue Effects of Transgenic IL-13 J. Immunol., November 15, 2007; 179(10): 7030 - 7041. [Abstract] [Full Text] [PDF]

				Z. Bao, S. Lim, W. Liao, Y. Lin, C. Thiemermann, B. P. Leung, and W. S. F. Wong Glycogen Synthase Kinase-3beta Inhibition Attenuates Asthma in Mice Am. J. Respir. Crit. Care Med., September 1, 2007; 176(5): 431 - 438. [Abstract] [Full Text] [PDF]

				A. P Rogerio, C. R Cardoso, C. Fontanari, M. A Souza, S. R Afonso-Cardoso, E. V. Silva, N. S Koyama, F. L Basei, E. G Soares, J. B Calixto, et al. Anti-asthmatic potential of a D-galactose-binding lectin from Synadenium carinatum latex Glycobiology, August 1, 2007; 17(8): 795 - 804. [Abstract] [Full Text] [PDF]

				I. H. Heijink, P. M. Kies, H. F. Kauffman, D. S. Postma, A. J. M. van Oosterhout, and E. Vellenga Down-Regulation of E-Cadherin in Human Bronchial Epithelial Cells Leads to Epidermal Growth Factor Receptor-Dependent Th2 Cell-Promoting Activity J. Immunol., June 15, 2007; 178(12): 7678 - 7685. [Abstract] [Full Text] [PDF]

				A. Nadeem, M. Fan, H. R. Ansari, C. Ledent, and S. Jamal Mustafa Enhanced airway reactivity and inflammation in A2A adenosine receptor-deficient allergic mice Am J Physiol Lung Cell Mol Physiol, June 1, 2007; 292(6): L1335 - L1344. [Abstract] [Full Text] [PDF]

				R. Newton, N. S. Holden, M. C. Catley, W. Oyelusi, R. Leigh, D. Proud, and P. J. Barnes Repression of Inflammatory Gene Expression in Human Pulmonary Epithelial Cells by Small-Molecule I{kappa}B Kinase Inhibitors J. Pharmacol. Exp. Ther., May 1, 2007; 321(2): 734 - 742. [Abstract] [Full Text] [PDF]

				S. T. Holgate, D. E. Davies, R. M. Powell, P. H. Howarth, H. M. Haitchi, and J. W. Holloway Local genetic and environmental factors in asthma disease pathogenesis: chronicity and persistence mechanisms Eur. Respir. J., April 1, 2007; 29(4): 793 - 803. [Abstract] [Full Text] [PDF]

				R. B. Marienfeld, L. Palkowitsch, and S. Ghosh Dimerization of the I{kappa}B Kinase-Binding Domain of NEMO Is Required for Tumor Necrosis Factor Alpha-Induced NF-{kappa}B Activity Mol. Cell. Biol., December 15, 2006; 26(24): 9209 - 9219. [Abstract] [Full Text] [PDF]

				C. Thompson, A. Cloutier, Y. Bosse, M. Thivierge, C. L. Gouill, P. Larivee, P. P. McDonald, J. Stankova, and M. Rola-Pleszczynski CysLT1 Receptor Engagement Induces Activator Protein-1- and NF-{kappa}B-Dependent IL-8 Expression Am. J. Respir. Cell Mol. Biol., December 1, 2006; 35(6): 697 - 704. [Abstract] [Full Text] [PDF]

				I Strickland and S Ghosh Use of cell permeable NBD peptides for suppression of inflammation Ann Rheum Dis, November 1, 2006; 65(suppl_3): iii75 - iii82. [Abstract] [Full Text] [PDF]

				K. S. Lee, S. J. Park, S. R. Kim, K. H. Min, S. M. Jin, H. K. Lee, and Y. C. Lee Modulation of Airway Remodeling and Airway Inflammation by Peroxisome Proliferator-Activated Receptor {gamma} in a Murine Model of Toluene Diisocyanate-Induced Asthma J. Immunol., October 15, 2006; 177(8): 5248 - 5257. [Abstract] [Full Text] [PDF]

				P. J. Barnes Corticosteroid effects on cell signalling Eur. Respir. J., February 1, 2006; 27(2): 413 - 426. [Abstract] [Full Text] [PDF]

				A Bourbia, M A Cruz, and H J Rozycki NF-{kappa}B in tracheal lavage fluid from intubated premature infants: association with inflammation, oxygen, and outcome Arch. Dis. Child. Fetal Neonatal Ed., January 1, 2006; 91(1): F36 - F39. [Abstract] [Full Text] [PDF]

				D. H. Broide, T. Lawrence, T. Doherty, J. Y. Cho, M. Miller, K. McElwain, S. McElwain, and M. Karin Allergen-induced peribronchial fibrosis and mucus production mediated by I{kappa}B kinase {beta}-dependent genes in airway epithelium PNAS, December 6, 2005; 102(49): 17723 - 17728. [Abstract] [Full Text] [PDF]

				M. A. Birrell, E. Hardaker, S. Wong, K. McCluskie, M. Catley, J. De Alba, R. Newton, S. Haj-Yahia, K. T. Pun, C. J. Watts, et al. I{kappa}-B Kinase-2 Inhibitor Blocks Inflammation in Human Airway Smooth Muscle and a Rat Model of Asthma Am. J. Respir. Crit. Care Med., October 15, 2005; 172(8): 962 - 971. [Abstract] [Full Text] [PDF]

				J. Moorman, M. Saad, S. Kosseifi, and G. Krishnaswamy Hepatitis C Virus and the Lung: Implications for Therapy Chest, October 1, 2005; 128(4): 2882 - 2892. [Abstract] [Full Text] [PDF]

				L. M. Hamilton, S. M. Puddicombe, R. J. Dearman, I. Kimber, T. Sandstrom, A. Wallin, P. H. Howarth, S. T. Holgate, S. J. Wilson, and D. E. Davies Altered protein tyrosine phosphorylation in asthmatic bronchial epithelium Eur. Respir. J., June 1, 2005; 25(6): 978 - 985. [Abstract] [Full Text] [PDF]

				M. E. Poynter, R. Cloots, T. van Woerkom, K. J. Butnor, P. Vacek, D. J. Taatjes, C. G. Irvin, and Y. M. W. Janssen-Heininger NF-{kappa}B Activation in Airways Modulates Allergic Inflammation but Not Hyperresponsiveness J. Immunol., December 1, 2004; 173(11): 7003 - 7009. [Abstract] [Full Text] [PDF]

				P. K. Jeffery Remodeling and Inflammation of Bronchi in Asthma and Chronic Obstructive Pulmonary Disease Proceedings of the ATS, November 1, 2004; 1(3): 176 - 183. [Abstract] [Full Text] [PDF]

				I. M. Adcock, K. Ito, and P. J. Barnes Glucocorticoids: Effects on Gene Transcription Proceedings of the ATS, November 1, 2004; 1(3): 247 - 254. [Abstract] [Full Text] [PDF]

				C. Desmet, P. Gosset, B. Pajak, D. Cataldo, M. Bentires-Alj, P. Lekeux, and F. Bureau Selective Blockade of NF-{kappa}B Activity in Airway Immune Cells Inhibits the Effector Phase of Experimental Asthma J. Immunol., November 1, 2004; 173(9): 5766 - 5775. [Abstract] [Full Text] [PDF]

				J. A. Long, M. Fogel-Petrovic, D. A. Knight, P. J. Thompson, and J. W. Upham Higher Prostaglandin E2 Production by Dendritic Cells from Subjects with Asthma Compared with Normal Subjects Am. J. Respir. Crit. Care Med., September 1, 2004; 170(5): 485 - 491. [Abstract] [Full Text] [PDF]

				A Agusti, M Morla, J Sauleda, C Saus, and X Busquets NF-{kappa}B activation and iNOS upregulation in skeletal muscle of patients with COPD and low body weight Thorax, June 1, 2004; 59(6): 483 - 487. [Abstract] [Full Text] [PDF]

				R. Gagliardo, P. Chanez, M. Mathieu, A. Bruno, G. Costanzo, C. Gougat, I. Vachier, J. Bousquet, G. Bonsignore, and A. M. Vignola Persistent Activation of Nuclear Factor-{kappa}B Signaling Pathway in Severe Uncontrolled Asthma Am. J. Respir. Crit. Care Med., November 15, 2003; 168(10): 1190 - 1198. [Abstract] [Full Text] [PDF]

				A. KUMAR, S. LNU, R. MALYA, D. BARRON, J. MOORE, D. B. CORRY, and A. M. BORIEK Mechanical stretch activates nuclear factor-kappaB, activator protein-1, and mitogen-activated protein kinases in lung parenchyma: implications in asthma FASEB J, October 1, 2003; 17(13): 1800 - 1811. [Abstract] [Full Text] [PDF]

				S.T. Holgate, D. E. Davies, S. Puddicombe, A. Richter, P. Lackie, J. Lordan, and P. Howarth Mechanisms of airway epithelial damage: epithelial-mesenchymal interactions in the pathogenesis of asthma Eur. Respir. J., September 20, 2003; 22(44_suppl): 24S - 29s. [Full Text] [PDF]

				P. J. Barnes and I. M. Adcock How Do Corticosteroids Work in Asthma? Ann Intern Med, September 2, 2003; 139(5_Part_1): 359 - 370. [Full Text] [PDF]

				M. E. Poynter, C. G. Irvin, and Y. M. W. Janssen-Heininger A Prominent Role for Airway Epithelial NF-{kappa}B Activation in Lipopolysaccharide-Induced Airway Inflammation J. Immunol., June 15, 2003; 170(12): 6257 - 6265. [Abstract] [Full Text] [PDF]

				K. Page, J. Li, L. Zhou, S. Iasvoyskaia, K. C. Corbit, J.-W. Soh, I. B. Weinstein, A. R. Brasier, A. Lin, and M. B. Hershenson Regulation of Airway Epithelial Cell NF-{kappa}B-Dependent Gene Expression by Protein Kinase C{delta} J. Immunol., June 1, 2003; 170(11): 5681 - 5689. [Abstract] [Full Text] [PDF]

				S. La Grutta, R. Gagliardo, F. Mirabella, G. B. Pajno, G. Bonsignore, J. Bousquet, V. Bellia, and A. M. Vignola Clinical and Biological Heterogeneity in Children with Moderate Asthma Am. J. Respir. Crit. Care Med., June 1, 2003; 167(11): 1490 - 1495. [Abstract] [Full Text] [PDF]

				M.C. Monici, M. Aguennouz, A. Mazzeo, C. Messina, and G. Vita Activation of nuclear factor-{kappa}B in inflammatory myopathies and Duchenne muscular dystrophy Neurology, March 25, 2003; 60(6): 993 - 997. [Abstract] [Full Text] [PDF]

				P. J. Barnes Theophylline: New Perspectives for an Old Drug Am. J. Respir. Crit. Care Med., March 15, 2003; 167(6): 813 - 818. [Full Text] [PDF]

				I. Jibiki, S. Hashimoto, S. Maruoka, Y. Gon, A. Matsuzawa, H. Nishitoh, H. Ichijo, and T. Horie Apoptosis Signal-Regulating Kinase 1-Mediated Signaling Pathway Regulates Nitric Oxide-Induced Activator Protein-1 Activation in Human Bronchial Epithelial Cells Am. J. Respir. Crit. Care Med., March 15, 2003; 167(6): 856 - 861. [Abstract] [Full Text] [PDF]

				S. Blesa, J. Cortijo, M. Mata, A. Serrano, D. Closa, F. Santangelo, J.M. Estrela, J. Suchankova, and E.J. Morcillo Oral N-acetylcysteine attenuates the rat pulmonary inflammatory response to antigen Eur. Respir. J., March 1, 2003; 21(3): 394 - 400. [Abstract] [Full Text] [PDF]

				A. H. Boulares, A. J. Zoltoski, Z. A. Sherif, P. Jolly, D. Massaro, and M. E. Smulson Gene Knockout or Pharmacological Inhibition of Poly(ADP-Ribose) Polymerase-1 Prevents Lung Inflammation in a Murine Model of Asthma Am. J. Respir. Cell Mol. Biol., March 1, 2003; 28(3): 322 - 329. [Abstract] [Full Text] [PDF]

				W. R. Henderson Jr., E. Y. Chi, J.-L. Teo, C. Nguyen, and M. Kahn A Small Molecule Inhibitor of Redox-Regulated NF-{kappa}B and Activator Protein-1 Transcription Blocks Allergic Airway Inflammation in a Mouse Asthma Model J. Immunol., November 1, 2002; 169(9): 5294 - 5299. [Abstract] [Full Text] [PDF]

				J. Li, S. Kartha, S. Iasvovskaia, A. Tan, R. K. Bhat, J. M. Manaligod, K. Page, A. R. Brasier, and M. B. Hershenson Regulation of human airway epithelial cell IL-8 expression by MAP kinases Am J Physiol Lung Cell Mol Physiol, October 1, 2002; 283(4): L690 - L699. [Abstract] [Full Text] [PDF]

				A. Di Stefano, G. Caramori, T. Oates, A. Capelli, M. Lusuardi, I. Gnemmi, F. Ioli, K.F. Chung, C.F. Donner, P.J. Barnes, et al. Increased expression of nuclear factor-{kappa}B in bronchial biopsies from smokers and patients with COPD Eur. Respir. J., September 1, 2002; 20(3): 556 - 563. [Abstract] [Full Text] [PDF]

				M. E. Poynter, C. G. Irvin, and Y. M. W. Janssen-Heininger Rapid Activation of Nuclear Factor-{kappa}B in Airway Epithelium in a Murine Model of Allergic Airway Inflammation Am. J. Pathol., April 1, 2002; 160(4): 1325 - 1334. [Abstract] [Full Text] [PDF]

				A. Hozumi, Y. Nishimura, T. Nishiuma, Y. Kotani, and M. Yokoyama Induction of MMP-9 in normal human bronchial epithelial cells by TNF-alpha via NF-kappa B-mediated pathway Am J Physiol Lung Cell Mol Physiol, December 1, 2001; 281(6): L1444 - L1452. [Abstract] [Full Text] [PDF]

				R. A. Bakker, S. B. J. Schoonus, M. J. Smit, H. Timmerman, and R. Leurs Histamine H1-Receptor Activation of Nuclear Factor-kappa B: Roles for Gbeta gamma - and Galpha q/11-Subunits in Constitutive and Agonist-Mediated Signaling Mol. Pharmacol., November 1, 2001; 60(5): 1133 - 1142. [Abstract] [Full Text] [PDF]

				M. O. Aksoy, W. Bin, Y. Yang, D. Yun-You, and S. G. Kelsen Nuclear factor-kappa B augments beta 2-adrenergic receptor expression in human airway epithelial cells Am J Physiol Lung Cell Mol Physiol, November 1, 2001; 281(5): L1271 - L1278. [Abstract] [Full Text] [PDF]

				S. J. WILSON, A. WALLIN, G. DELLA-CIOPPA, T. SANDSTROM, and S. T. HOLGATE Effects of Budesonide and Formoterol on NF-kappa B, Adhesion Molecules, and Cytokines in Asthma Am. J. Respir. Crit. Care Med., September 15, 2001; 164(6): 1047 - 1052. [Abstract] [Full Text] [PDF]

				G. Caramori, S. Lim, K. Ito, K. Tomita, T. Oates, E. Jazrawi, K.F. Chung, P.J. Barnes, and I.M. Adcock Expression of GATA family of transcription factors in T-cells, monocytes and bronchial biopsies Eur. Respir. J., September 1, 2001; 18(3): 466 - 473. [Abstract] [Full Text] [PDF]

				C. M. Fleming, H. He, A. Ciota, D. Perkins, and P. W. Finn Administration of Pentoxifylline During Allergen Sensitization Dissociates Pulmonary Allergic Inflammation from Airway Hyperresponsiveness J. Immunol., August 1, 2001; 167(3): 1703 - 1711. [Abstract] [Full Text] [PDF]

				K.F. Chung Cytokines in chronic obstructive pulmonary disease Eur. Respir. J., July 2, 2001; 18(34_suppl): 50S - 59s. [Abstract] [Full Text] [PDF]

				F. Bureau, S. Delhalle, G. Bonizzi, L. Fievez, S. Dogne, N. Kirschvink, A. Vanderplasschen, M.-P. Merville, V. Bours, and P. Lekeux Mechanisms of Persistent NF-{kappa}B Activity in the Bronchi of an Animal Model of Asthma J. Immunol., November 15, 2000; 165(10): 5822 - 5830. [Abstract] [Full Text] [PDF]

				S. LIM, D. GRONEBERG, A. FISCHER, T. OATES, G. CARAMORI, W. MATTOS, I. ADCOCK, P. J. BARNES, and K. F. CHUNG Expression of Heme Oxygenase Isoenzymes 1 and 2 in Normal and Asthmatic Airways . Effect of Inhaled Corticosteroids Am. J. Respir. Crit. Care Med., November 1, 2000; 162(5): 1912 - 1918. [Abstract] [Full Text]

				A. Shukla, C. Timblin, K. BeruBe, T. Gordon, W. McKinney, K. Driscoll, P. Vacek, and B. T. Mossman Inhaled Particulate Matter Causes Expression of Nuclear Factor (NF)-kappa B-Related Genes and Oxidant-Dependent NF-kappa B Activation In Vitro Am. J. Respir. Cell Mol. Biol., August 1, 2000; 23(2): 182 - 187. [Abstract] [Full Text]

				D. JAFFUEL, P. DEMOLY, C. GOUGAT, P. BALAGUER, G. MAUTINO, P. GODARD, J. BOUSQUET, and M. MATHIEU Transcriptional Potencies of Inhaled Glucocorticoids Am. J. Respir. Crit. Care Med., July 1, 2000; 162(1): 57 - 63. [Abstract] [Full Text]

				F. H. Guo, S. A. A. Comhair, S. Zheng, R. A. Dweik, N. T. Eissa, M. J. Thomassen, W. Calhoun, and S. C. Erzurum Molecular Mechanisms of Increased Nitric Oxide (NO) in Asthma: Evidence for Transcriptional and Post-Translational Regulation of NO Synthesis J. Immunol., June 1, 2000; 164(11): 5970 - 5980. [Abstract] [Full Text] [PDF]

				J. W. Christman, R. T. Sadikot, and T. S. Blackwell The Role of Nuclear Factor-{kappa} B in Pulmonary Diseases Chest, May 1, 2000; 117(5): 1482 - 1487. [Abstract] [Full Text] [PDF]

				F. BUREAU, G. BONIZZI, N. KIRSCHVINK, S. DELHALLE, D. DESMECHT, M.-P. MERVILLE, V. BOURS, and P. LEKEUX Correlation between Nuclear Factor-kappa B Activity in Bronchial Brushing Samples and Lung Dysfunction in an Animal Model of Asthma Am. J. Respir. Crit. Care Med., April 1, 2000; 161(4): 1314 - 1321. [Abstract] [Full Text]

				L. HART, S. LIM, I. ADCOCK, P. J. BARNES, and K. FAN CHUNG Effects of Inhaled Corticosteroid Therapy on Expression and DNA-Binding Activity of Nuclear Factor kappa B in Asthma Am. J. Respir. Crit. Care Med., January 1, 2000; 161(1): 224 - 231. [Abstract] [Full Text]

				P. R. MILLS, R. J. DAVIES, and J. L. DEVALIA Airway Epithelial Cells, Cytokines, and Pollutants Am. J. Respir. Crit. Care Med., November 1, 1999; 160(5): S38 - 43. [Abstract] [Full Text] [PDF]

				L. J. Egan, D. C. Mays, C. J. Huntoon, M. P. Bell, M. G. Pike, W. J. Sandborn, J. J. Lipsky, and D. J. McKean Inhibition of Interleukin-1-stimulated NF-kappa B RelA/p65 Phosphorylation by Mesalamine Is Accompanied by Decreased Transcriptional Activity J. Biol. Chem., September 10, 1999; 274(37): 26448 - 26453. [Abstract] [Full Text] [PDF]

				Y. Amrani, A. L. Lazaar, and R. A. Panettieri Jr. Up-Regulation of ICAM-1 by Cytokines in Human Tracheal Smooth Muscle Cells Involves an NF-{kappa}B-Dependent Signaling Pathway That Is Only Partially Sensitive to Dexamethasone J. Immunol., August 15, 1999; 163(4): 2128 - 2134. [Abstract] [Full Text] [PDF]

				Y. Nasuhara, I. M. Adcock, M. Catley, P. J. Barnes, and R. Newton Differential Ikappa B Kinase Activation and Ikappa Balpha Degradation by Interleukin-1beta and Tumor Necrosis Factor-alpha in Human U937 Monocytic Cells. EVIDENCE FOR ADDITIONAL REGULATORY STEPS IN kappa B-DEPENDENT TRANSCRIPTION J. Biol. Chem., July 9, 1999; 274(28): 19965 - 19972. [Abstract] [Full Text] [PDF]

				S. S. Brar, T. P. Kennedy, A. B. Sturrock, T. P. Huecksteadt, M. T. Quinn, T. M. Murphy, P. Chitano, and J. R. Hoidal NADPH oxidase promotes NF-kappa B activation and proliferation in human airway smooth muscle Am J Physiol Lung Cell Mol Physiol, April 1, 2002; 282(4): L782 - L795. [Abstract] [Full Text] [PDF]