Publications
268 results found
Lee KY, Ito K, Hayashi R, et al., 2006, NF-κB and activator protein 1 response elements and the role of histone modifications in IL-1-β-induced TGF-β1 gene transcription, JOURNAL OF IMMUNOLOGY, Vol: 176, Pages: 603-615, ISSN: 0022-1767
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- Citations: 135
Adcock IM, Hayashi R, Ito K, et al., 2006, Corticosteroids: Glucocorticoid Receptors, Encyclopedia of Respiratory Medicine, Four-Volume Set, Pages: 568-576, ISBN: 9780123708793
Corticosteroids bind to and activate a cytoplasmic glucocorticoid receptor (GR) which exists as several isoforms derived from a single gene product by alternative splicing. The activated glucocorticoid receptor translocates into the nucleus and binds to specific response elements in the promoter regions of anti-inflammatory genes such as lipocortin-1 and secretory leukocyte protease inhibitor. However, the major anti-inflammatory effects of glucocorticoids appear to be due largely to interaction between the activated glucocorticoid receptor and transcription factors, notably nuclear factor kappa B (NF-κB) and activator protein-1, that mediate the expression of inflammatory genes. NF-κB switches on inflammatory genes via a process involving recruitment of transcriptional coactivator proteins and changes in chromatin modifications such as histone acetylation. The interactions between NF-κB and the glucocorticoid receptor result in differing effects on histone modifications and subsequent chromatin remodeling. GR is subjected to posttranslational modifications and these may influence hormone binding and nuclear translocation, alter glucocorticoid receptor interactions and protein half-life. Therapeutically, drugs that enhance glucocorticoid receptor nuclear translocation (long-acting β-agonists) and GR-associated histone deacetylase activity (theophylline) have been shown to be effective add-on therapies. In addition, dissociated glucocorticoids that target NF-κB preferentially have also been successful in the treatment of allergic disease in the skin.
Adcock IM, Ito K, Caramori G, 2006, Transcription Factors: Overview, Encyclopedia of Respiratory Medicine, Four-Volume Set, Pages: 243-251, ISBN: 9780123708793
The term 'transcription factor' refers to a large family of proteins, which exert transcriptional control via specific interactions with regulatory gene sequences. Here, we provide a summary of the different classes of the transcription factor divided according to their DNA-binding motifs. The modular structure of transcription factors and the presence of distinct interacting domains determine the ability of these factors to associate with each other and with coactivating/repressing proteins. By recruiting transcriptional coactivators, transcription factors can induce changes in chromatin structure enabling gene expression to occur. We use the activation of the Rel transcription factor NF-B and the nuclear receptor GR as examples to indicate some of the intricacies and subtleties of DNA binding, chromatin remodeling, and transcription factor cross-talk. Finally, we review the evidence for the involvement of select transcription factors in allergic and inflammatory diseases of the lung, and how changes in the expression and/or activity of these factors may vary in disease and provide important targets for future drug development.
Ito K, Getting SJ, Charron CE, 2006, Mode of glucocorticoid actions in airway disease, THESCIENTIFICWORLDJOURNAL, Vol: 6, Pages: 1750-1769, ISSN: 1537-744X
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- Citations: 35
Caramori G, Ito K, Contoli M, et al., 2006, Molecular mechanisms of respiratory virus-induced asthma and COPD exacerbations and pneumonia, CURRENT MEDICINAL CHEMISTRY, Vol: 13, Pages: 2267-2290, ISSN: 0929-8673
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- Citations: 21
Adcock IM, Ito K, Barnes PJ, 2005, Histone deacetylation: an important mechanism in inflammatory lung diseases., COPD, Vol: 2, Pages: 445-455, ISSN: 1541-2555
Inflammatory lung diseases are characterised by increased expression of multiple inflammatory genes that are regulated by proinflammatory transcription factors, such as NF-kappaB. Gene expression is regulated by modifications such as acetylation of core histones through the concerted action of coactivators such as CBP (cAMP-response element binding protein (CREB)-binding protein) which have intrinsic histone acetyltransferase (HAT) activity and are able to recruit other HAT enzymes. Conversely gene repression is mediated via histone deacetylases (HDAC) and other corepressors. In biopsies from asthmatic subjects there is an increase in HAT activity and some reduction in HDAC activity. Both of these changes are partially reversed by corticosteroid therapy. Corticosteroids switch off inflammatory genes in asthma through a combination of a direct inhibition of HAT activity and by the recruitment of HDAC2 to the activated NF-kappaB-stimulated inflammatory gene complex. In chronic obstructive pulmonary disease (COPD), a corticosteroid insensitive disease, there is a reduction in HDAC activity and HDAC2 expression, which may account for the amplified inflammation and resistance to the actions of corticosteroids. The reduction in HDAC2 may be secondary to oxidative and nitrative stress as a result of cigarette smoking and severe inflammation. This may also occur to differing degrees in severe asthma, smoking asthmatic patients and cystic fibrosis. Similar mechanisms may also account for the steroid resistance seen within latent adenovirus infections. The reduction in HDAC activity induced by oxidative stress can be restored by theophylline, acting through specific kinases, which may be able to reverse steroid resistance in COPD and other inflammatory lung diseases. The modulation of HAT/HDAC activity may lead to the development of novel anti-inflammatory approaches to inflammatory lung diseases that are currently difficult to treat.
Walters MJ, Paul-Clark MJ, McMaster SK, et al., 2005, Cigarette smoke activates human monocytes by an oxidant-AP-1 signaling pathway: Implications for steroid resistance, MOLECULAR PHARMACOLOGY, Vol: 68, Pages: 1343-1353, ISSN: 0026-895X
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- Citations: 73
Ricciardolo FLM, Caramori G, Ito K, et al., 2005, Nitrosative stress in the bronchial mucosa of severe chronic obstructive pulmonary disease, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 116, Pages: 1028-1035, ISSN: 0091-6749
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- Citations: 112
Usmani OS, Ito K, Maneechotesuwan K, et al., 2005, Glucocorticoid receptor nuclear translocation in airway cells after inhaled combination therapy, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 172, Pages: 704-712, ISSN: 1073-449X
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- Citations: 166
Barnes PJ, Adcock IM, Ito K, 2005, Histone deacetylase activity and COPD - Reply, NEW ENGLAND JOURNAL OF MEDICINE, Vol: 353, Pages: 528-529, ISSN: 0028-4793
Brindicci C, Ito K, Resta O, et al., 2005, Exhaled nitric oxide from lung periphery is increased in COPD, EUROPEAN RESPIRATORY JOURNAL, Vol: 26, Pages: 52-59, ISSN: 0903-1936
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- Citations: 162
Wada H, Kagoshima M, Ito K, et al., 2005, 5-Azacytidine suppresses RNA polymerase II recruitment to the SLPI gene, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, Vol: 331, Pages: 93-99, ISSN: 0006-291X
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- Citations: 15
Ito K, Ito M, Elliott WM, et al., 2005, Decreased histone deacetylase activity in chronic obstructive pulmonary disease, NEW ENGLAND JOURNAL OF MEDICINE, Vol: 352, Pages: 1967-1976, ISSN: 0028-4793
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- Citations: 722
Barnes PJ, Adcock IM, Ito K, 2005, Histone acetylation and deacetylation: importance in inflammatory lung diseases, EUROPEAN RESPIRATORY JOURNAL, Vol: 25, Pages: 552-563, ISSN: 0903-1936
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- Citations: 153
Adcock IM, Cosio B, Tsaprouni L, et al., 2005, Redox regulation of histone deacetylases and glucocorticoid-mediated inhibition of the inflammatory response, ANTIOXIDANTS & REDOX SIGNALING, Vol: 7, Pages: 144-152, ISSN: 1523-0864
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- Citations: 58
Adcock IM, Ito K, 2005, Glucocorticoid pathways in chronic obstructive pulmonary disease therapy., Proc Am Thorac Soc, Vol: 2, Pages: 313-319, ISSN: 1546-3222
Lung function measures in patients with chronic obstructive pulmonary disease remain insensitive to corticosteroid actions, in contrast to the clinical improvements observed in most patients with asthma. By uncovering the reason for this paradox, physicians should be able to implement treatment regimens that restore corticosteroid sensitivity. Corticosteroids exert their effects by binding to a cytoplasmic glucocorticoid receptor, which is subjected to post-translational modification by phosphorylation. Receptor phosphorylation may influence hormone binding and nuclear translocation, as well as alter other glucocorticoid receptor interactions, its protein half-life, and downregulation processes. This suggests that a "phosphorylation code" may exist for glucocorticoid receptor function. Oxidative stress due to cigarette smoke may also be a mechanism for the corticosteroid resistance observed in chronic obstructive pulmonary disease, as it enhances proinflammatory transcription. Reduced glucocorticoid nuclear translocation along with attenuated histone deacetylase activity may be partially responsible for this effect. Therapies targeting these aspects of the glucocorticoid receptor activation pathway may reverse steroid resistance in patients with chronic obstructive pulmonary disease.
Caramori G, Adcock IM, Ito K, 2004, Anti-inflammatory inhibitors of IkappaB kinase in asthma and COPD., Curr Opin Investig Drugs, Vol: 5, Pages: 1141-1147, ISSN: 1472-4472
Nuclear factor-kappaB (NFkappaB) is an inducible transcription factor that plays a central role in the regulation of many immune and inflammatory responses. While NFkappaB is required for cell survival and immunity, abnormal expression and/or activation of NFkappaB leads to the development of many pathological states, especially those involved in chronic and acute inflammation. Many different signal transduction pathways, originating from a wide variety of cellular stresses and stimuli, converge on a single target; the NFkappaB/IkappaB complex and its activating kinase (inhibitor of kappaB kinase, IKK). Here, we review some of the major NFkappaB activating pathways, their role in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD), and their potential as targets in the treatment of asthma and COPD.
Hayashi R, Wada H, Ito K, et al., 2004, Effects of glucocorticoids on gene transcription, EUROPEAN JOURNAL OF PHARMACOLOGY, Vol: 500, Pages: 51-62, ISSN: 0014-2999
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- Citations: 199
Donnelly LE, Newton R, Kennedy GE, et al., 2004, Anti-inflammatory effects of resveratrol in lung epithelial cells: molecular mechanisms, AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, Vol: 287, Pages: L774-L783, ISSN: 1040-0605
Cosio BG, Tsaprouni L, Ito K, et al., 2004, Theophylline restores histone deacetylase activity and steroid responses in COPD macrophages, Journal of Experimental Medicine, Vol: 200, Pages: 689-695, ISSN: 1540-9538
Caramori G, Ito K, Adcock IM, 2004, Targeting Th2 cells in asthmatic airways., Curr Drug Targets Inflamm Allergy, Vol: 3, Pages: 243-255, ISSN: 1568-010X
The most effective anti-asthmatic drugs currently available include inhaled beta2-agonists and glucocorticoids and control asthma in about 95% of patients. The current asthma therapies are not cures and symptoms return soon after the treatment is stopped even after long-term therapy. In addition, severe glucocorticoid-dependent and -resistant asthma still represents a great clinical burden accounting for approximately 50% of the health care costs of asthma and reducing the side-effects of glucocorticoids using novel dissociated steroids, soft steroids or with steroid-sparing agents will prove beneficial. Furthermore, the mechanisms involved in the persistence of inflammation are poorly understood and the reasons why some patients have severe life threatening asthma and others have very mild disease are still unknown. Hopefully, it will soon be possible to identify and manipulate the molecular switches that result in asthmatic inflammation. This may lead to the treatment of susceptible individuals at birth or in the early years and thus prevent the disease from becoming established. Drug development for asthma has been directed at improving currently available drugs and finding new compounds that usually target the Th2-driven airway inflammatory response. Several new drugs have been developed to target specific components of the Th2-driven inflammatory process in asthma (e.g. IgE antibodies, cytokines and/or chemokines, immunomodulators, antagonists of adhesion molecules), although they have not yet been proven to be particularly effective. Some of these new Th2-oriented strategies may in the future not only control symptoms, but also potentially prevent or cure the disease.
Caramori G, Ito K, Adcock IM, 2004, Transcription factors in asthma and COPD, IDRUGS, Vol: 7, Pages: 764-770, ISSN: 1369-7056
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- Citations: 13
CosÃo BG, Mann B, Ito K, et al., 2004, Histone acetylase and deacetylase activity in alveolar macrophages and blood mononocytes in asthma, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 170, Pages: 141-147, ISSN: 1073-449X
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- Citations: 198
Adcock IM, Ito K, 2004, Steroid resistance in asthma: a major problem requiring novel solutions or a non-issue?, CURRENT OPINION IN PHARMACOLOGY, Vol: 4, Pages: 257-262, ISSN: 1471-4892
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- Citations: 57
Matthews JG, Ito K, Barnes PJ, et al., 2004, Defective glucocorticoid receptor nuclear translocation and altered histone acetylation patterns in glucocorticoid-resistant patients, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 113, Pages: 1100-1108, ISSN: 0091-6749
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- Citations: 159
Catley MC, Cambridge LM, Nasuhara Y, et al., 2004, Inhibitors of protein kinase C (PKC) prevent activated transcription -: Role of events downstream of NF-κB DNA binding, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 279, Pages: 18457-18466, ISSN: 0021-9258
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- Citations: 68
Koch A, Giembycz M, Ito K, et al., 2004, Mitogen-activated protein kinase modulation of nuclear factor-KB-induced granulocyte macrophage-colony-stimulating factor release from human alveolar macrophages, AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, Vol: 30, Pages: 342-349, ISSN: 1044-1549
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- Citations: 46
Barnes PJ, Ito K, Adcock IM, 2004, Corticosteroid resistance in chronic obstructive pulmonary disease: inactivation of histone deacetylase, LANCET, Vol: 363, Pages: 731-733, ISSN: 0140-6736
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- Citations: 280
Ito K, Hanazawa T, Tomita K, et al., 2004, Oxidative stress reduces histone deacetylase 2 activity and enhances IL-8 gene expression: role of tyrosine nitration, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, Vol: 315, Pages: 240-245, ISSN: 0006-291X
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- Citations: 278
Adcock IM, Ito K, Barnes PJ, 2004, Glucocorticoids: effects on gene transcription., Proc Am Thorac Soc, Vol: 1, Pages: 247-254, ISSN: 1546-3222
The major antiinflammatory effects of glucocorticoids appear to be due largely to interaction between the activated glucocorticoid receptor and transcription factors, notably nuclear factor-kappaB (NF-kappaB) and activator protein-1, that mediate the expression of inflammatory genes. NF-kappaB switches on inflammatory genes via a process involving recruitment of transcriptional coactivator proteins and changes in chromatin modifications such as histone acetylation. This process must occur in the correct temporal manner to allow for effective inflammatory gene expression to occur. Glucocorticoids, using a similar mechanism, are also able to switch on a number of antiinflammatory genes. An important question is why glucocorticoids switch off only inflammatory genes, as they clearly do not suppress all activated genes and are well tolerated as long-term treatments. The interactions between NF-kappaB and the glucocorticoid receptor result in differing effects on histone acetylation and deacetylation. Oxidative stress due to cigarette smoke may be an important factor in inducing glucocorticoid resistance in chronic obstructive pulmonary disease and may involve changes in histone acetylation/deacetylation balance.
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