Publications
268 results found
Ueda K, Nishimoto Y, Kimura G, et al., 2016, Repeated lipopolysaccharide exposure causes corticosteroid insensitive airway inflammation via activation of phosphoinositide-3-kinase δ pathway, Biochemistry and Biophysics Reports, Vol: 7, Pages: 367-373, ISSN: 2405-5808
Corticosteroid resistance is one of major barriers to effective management of chronic inflammatory respiratory diseases, such as chronic obstructive pulmonary disease (COPD) and severe asthma. These patients often experience exacerbations with viral and/or bacterial infection, which may cause continuous corticosteroid insensitive inflammation. In this study, we observed that repeated exposure of lipopolysaccharide (LPS) intranasally attenuated the anti-inflammatory effects of the corticosteroid fluticasone propionate (FP) on neutrophils and CXCL1 levels in bronchoalveolar lavage (BAL) fluid in an in vivo murine model. Histone deacetylase-2 (HDAC2) and NF-E2 related factor 2 (Nrf2) levels in lungs after LPS administration for 3 consecutive days were significantly decreased to 38.9±6.3% (mean±SEM) and 77.5±2.7% of the levels seen after only one day of LPS exposure, respectively. In addition, 3 days LPS exposure resulted in an increase of Akt phosphorylation, indicating activation of the phosphoinositide-3-kinase (PI3K) pathway by 4-fold in lungs compared with 1 day of exposure. Furthermore, combination treatment with theophylline and FP significantly decreased the neutrophil accumulation and CXCL1 concentrations in BAL fluid from 22.5±1.8×10 4 cells/mL and 214.6±20.6 pg/mL to 7.9±0.5×10 4 cells/mL and 61.9±13.3 pg/mL, respectively. Combination treatment with IC87114, a selective PI3Kδ inhibitor, and FP also significantly decreased neutrophils and CXCL1 levels from 16.8±0.7×10 4 cells/mL and 182.4±4.6 pg/mL to 5.9±0.3×10 4 cells/mL and 71.4±2.7 pg/mL, respectively. Taken together, repeated exposure of LPS causes corticosteroid-insensitive airway inflammation in vivo, and the corticosteroid-resistance induced by LPS is at least partly mediated through the activation of PI3Kδ, resulting in decreased levels of HDAC2 and Nrf2. These findi
Brookes D, Coates M, Allen H, et al., 2016, LATE-BREAKING ABSTRACT: Effects of a single treatment with PC786, a novel inhibitor of respiratory syncytial virus replication, on viral load and biomarkers in fully differentiated human bronchial epithelial cells, European Respiratory Society, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Alzoubi S, Brody L, Rahman S, et al., 2016, Synergy between histone deacetylase inhibitors and DNA-damaging agents is mediated by histone deacetylase 2 in colorectal cancer, Oncotarget, Vol: 7, Pages: 44505-44521, ISSN: 1949-2553
Previous studies have associated the overexpression of histone deacetylase 2 (HDAC2) and the presence of TP53 mutations with the progression to advanced stage drug resistant colorectal cancer (CRC). However, the mechanistic link between HDAC2 expression and the TP53 mutational status has remained unexplored. Here, we investigated the function of HDAC2 in drug resistance by assessing the synergistic effects of DNA-targeted chemotherapeutic agents and HDAC inhibitors (HDACis) on two TP53-mutated colorectal adenocarcinoma CRC cell lines (SW480 and HT-29) and on the TP53-wild type carcinoma cell line (HCT116 p53+/+) and its TP53 deficient sub-line (HCT116 p53-/-). We showed that in the untreated SW480 and HT-29 cells the steady-state level of HDAC2 was low compared to a TP53-wild type carcinoma cell line (HCT116 p53+/+). Increased expression of HDAC2 correlated with drug resistance, and depletion by shRNA sensitised the multi-drug resistance cell line HT-29 to CRC chemotherapeutic drugs such as 5-fluorouracil (5-FU) and oxaliplatin (Oxa). Combined treatment with the HDACi suberoylanilide hydroxamic acid plus 5-FU or Oxa reduced the level of HDAC2 expression, modified chromatin structure and induced mitotic cell death in HT-29 cells. Non-invasive bioluminescence imaging revealed significant reductions in xenograft tumour growth with HDAC2 expression level reduced to <50% in treated animals. Elevated levels of histone acetylation on residues H3K9, H4K12 and H4K16 were also found to be associated with resistance to VPA/Dox or SAHA/Dox treatment. Our results suggest that HDAC2 expression rather than the p53 mutation status influences the outcome of combined treatment with a HDACi and DNA-damaging agents in CRC.
Kobayashi Y, Ito K, Kanda A, et al., 2016, Protein tyrosine phosphatase PTP-RR regulates corticosteroid sensitivity., Respiratory Research, Vol: 17, ISSN: 1465-993X
BACKGROUND: We have recently reported that protein phosphate 2A (PP2A) inactivation resulted in increased phosphorylation of the mitogen-activated protein kinase (MAPK) c-Jun N-terminal kinase 1 (JNK1) and glucocorticoid receptors (GR) at Ser(226), thereby reducing GR nuclear translocation and causing corticosteroid insensitivity in severe asthmatics. Protein tyrosine phosphatases (PTPs) are also known to be critically involved in the regulation of MAPKs, such as JNK and therefore potentially associated with GR function. The aim of study was to elucidate the involvement of MAPK-PTPs (PTP-RR, PTP-N5 and PTP-N7), which can dephosphorylate MAPKs, in the regulation of corticosteroid sensitivity. METHODS: Corticosteroid sensitivity, GR nuclear translocation, phosphorylation levels of GR-Ser(226), JNK1 and PP2A catalytic subunit (PP2AC)-Tyr(307) and protein expression levels and activities of PTP-RR and PP2AC were evaluated in U937 cells and/or peripheral blood mononuclear cells (PBMCs). Knock-down effects of MAPK-PTPs using siRNA were also evaluated. RESULTS: Knock-down of PTP-RR, but not of PTP-N5 or PTP-N7 impaired corticosteroid sensitivity, induced GR-Ser(226) phosphorylation and reduced GR nuclear translocation. Under IL-2/IL-4-induced corticosteroid insensitivity, PTP-RR expression, activity and associations with JNK1 and GR were reduced but PTP-RR activity was restored by formoterol. Also in PBMCs from severe asthmatic patients, PTP-RR and JNK1 expression were reduced and GR-Ser(226) phosphorylation increased. Furthermore, PTP-RR was associated with PP2A. PTP-RR reduction enhanced PP2AC-Tyr(307) phosphorylation leading to impairment of PP2A expression and activity. CONCLUSIONS: We demonstrated that with corticosteroid insensitivity PTP-RR fails to reduce phosphorylation of JNK1 and GR-Ser(226), resulting in down-regulation of GR nuclear translocation. Reduced PTP-RR may represent a novel cause of corticosteroid insensitivity in severe asthmatics.
Onions ST, Ito K, Charron CE, et al., 2016, Discovery of Narrow Spectrum Kinase Inhibitors: New Therapeutic Agents for the Treatment of COPD and Steroid-Resistant Asthma, JOURNAL OF MEDICINAL CHEMISTRY, Vol: 59, Pages: 1727-1746, ISSN: 0022-2623
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- Citations: 18
Mitani A, Ito K, Vuppusetty C, et al., 2016, Restoration of corticosteroid sensitivity in chronic obstructive pulmonary disease by inhibition of mammalian target of rapamycin, American Journal of Respiratory and Critical Care Medicine, Vol: 193, Pages: 143-153, ISSN: 1073-449X
Rationale: Corticosteroid resistance is a major barrier to the effective treatment of chronic obstructive pulmonary disease (COPD). Several molecular mechanisms have been proposed, such as activations of the phosphoinositide-3-kinase/Akt pathway and p38 mitogen-activated protein kinase. However, the mechanism for corticosteroid resistance is still not fully elucidated.Objectives: To investigate the role of mammalian target of rapamycin (mTOR) in corticosteroid sensitivity in COPD.Methods: The corticosteroid sensitivity of peripheral blood mononuclear cells collected from patients with COPD, smokers, and nonsmoking control subjects, or of human monocytic U937 cells exposed to cigarette smoke extract (CSE), was quantified as the dexamethasone concentration required to achieve 30% inhibition of tumor necrosis factor-α–induced CXCL8 production in the presence or absence of the mTOR inhibitor rapamycin. mTOR activity was determined as the phosphorylation of p70 S6 kinase, using Western blotting.Measurements and Main Results: mTOR activity was increased in peripheral blood mononuclear cells from patients with COPD, and treatment with rapamycin inhibited this as well as restoring corticosteroid sensitivity. In U937 cells, CSE stimulated mTOR activity and c-Jun expression, but pretreatment with rapamycin inhibited both and also reversed CSE-induced corticosteroid insensitivity.Conclusions: mTOR inhibition by rapamycin restores corticosteroid sensitivity via inhibition of c-Jun expression, and thus mTOR is a potential novel therapeutic target for COPD.
Footitt J, Mallia P, Durham AL, et al., 2016, Oxidative and Nitrosative Stress and Histone Deacetylase-2 Activity in Exacerbations of COPD., Chest, Vol: 149, Pages: 62-73, ISSN: 1931-3543
BACKGROUND: Respiratory virus infections are commonly associated with COPD exacerbations, but little is known about the mechanisms linking virus infection to exacerbations. Pathogenic mechanisms in stable COPD include oxidative and nitrosative stress and reduced activity of histone deacetylase-2 (HDAC2), but their roles in COPD exacerbations is unknown. We investigated oxidative and nitrosative stress (O&NS) and HDAC2 in COPD exacerbations using experimental rhinovirus infection. METHODS: Nine subjects with COPD (Global Initiative for Chronic Obstructive Lung Disease stage II), 10 smokers, and 11 nonsmokers were successfully infected with rhinovirus. Markers of O&NS-associated cellular damage, and inflammatory mediators and proteases were measured in sputum, and HDAC2 activity was measured in sputum and bronchoalveolar macrophages. In an in vitro model, monocyte-derived THP-1 cells were infected with rhinovirus and nitrosylation and activity of HDAC2 was measured. RESULTS: Rhinovirus infection induced significant increases in airways inflammation and markers of O&NS in subjects with COPD. O&NS markers correlated with virus load and inflammatory markers. Macrophage HDAC2 activity was reduced during exacerbation and correlated inversely with virus load, inflammatory markers, and nitrosative stress. Sputum macrophage HDAC2 activity pre-infection was inversely associated with sputum virus load and inflammatory markers during exacerbation. Rhinovirus infection of monocytes induced nitrosylation of HDAC2 and reduced HDAC2 activity; inhibition of O&NS inhibited rhinovirus-induced inflammatory cytokines. CONCLUSIONS: O&NS, airways inflammation, and impaired HDAC2 may be important mechanisms of virus-induced COPD exacerbations. Therapies targeting these mechanisms offer potential new treatments for COPD exacerbations.
Lee K-Y, Ito K, Maneechotesuwan K, 2016, Inflammation to Pulmonary Diseases, MEDIATORS OF INFLAMMATION, Vol: 2016, ISSN: 0962-9351
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- Citations: 6
Mitani A, Mercado N, Vuppusetty C, et al., 2015, INHIBITION OF MTOR RESTORES CORTICOSTEROID SENSITIVITY IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE, RESPIROLOGY, Vol: 20, Pages: 44-44, ISSN: 1323-7799
Higaki M, Wada H, Mikura S, et al., 2015, Interleukin-10 modulates pulmonary neutrophilic inflammation induced by cigarette smoke exposure, EXPERIMENTAL LUNG RESEARCH, Vol: 41, Pages: 525-534, ISSN: 0190-2148
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- Citations: 13
Colley T, Mercado N, Kunori Y, et al., 2015, Defective sirtuin-1 increases IL-4 expression through acetylation of GATA-3 in patients with severe asthma., Journal of Allergy and Clinical Immunology, Vol: 137, Pages: 1595-1597.e7, ISSN: 1097-6825
Coates M, Brookes D, Ito K, et al., 2015, RESPIRATORY SYNCYTIAL VIRUS LEADS TO MORE RAPID CELL DEATH IN PHE508DEL BRONCHIAL EPITHELIAL CELLS, PEDIATRIC PULMONOLOGY, Vol: 50, Pages: 314-315, ISSN: 8755-6863
Charron C, Chaudhuri R, Spears M, et al., 2015, Atorvastatin lowers inflammatory sputum mediators in smokers with asthma, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Durham AL, Footitt J, Essilfie-Quaye S, et al., 2015, LSC Abstract - Rhinovirus infection induces NRF2 in monocytes but not in epithelial cells, via distinct intracellular pathways, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
To WS, Aungier SR, Cartwright AJ, et al., 2015, Potent anti-inflammatory effects of the narrow spectrum kinase inhibitor RV1088 on rheumatoid arthritis synovial membrane cells, BRITISH JOURNAL OF PHARMACOLOGY, Vol: 172, Pages: 3805-3816, ISSN: 0007-1188
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- Citations: 10
Kimura G, Ueda K, Kusama T, et al., 2015, Repeated LPS exposure induces corticosteroid insensitive airway inflammation in mice mediated by PI3K δ pathway, Publisher: JAPANESE PHARMACOLOGICAL SOC, Pages: S241-S241, ISSN: 1347-8613
Mercado N, Ito K, Barnes PJ, 2015, Accelerated ageing of the lung in COPD: new concepts, THORAX, Vol: 70, Pages: 482-489, ISSN: 0040-6376
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- Citations: 209
Contoli M, Ito K, Padovani A, et al., 2015, Th2 cytokines impair innate immune responses to rhinovirus in respiratory epithelial cells, Allergy, Vol: 70, Pages: 910-920, ISSN: 0105-4538
BackgroundAsthma and other Th2 inflammatory conditions have been associated with increased susceptibility to viral infections. The mechanisms by which Th2 cytokines can influence immune responses to infections are largely unknown.MethodsWe measured the effects of Th2 cytokines (IL-4 and IL-13) on bronchial epithelial cell innate immune antiviral responses by assessing interferon (IFN-β and IFN-λ1) induction following rhinovirus (RV)-16 infection. We also investigated the modulatory effects of Th2 cytokines on Toll-like receptor 3 (TLR3), interferon-responsive factor 3 (IRF3) and nuclear factor (NF)-kB, that is key molecules and transcription factors involved in the rhinovirus-induced interferon production and inflammatory cascade. Pharmacological and redox modulation of these pathways was also assessed.ResultsTh2 cytokines impaired RV-16-induced interferon production, increased rhinovirus replication and impaired TLR3 expression in bronchial epithelial cells. These results were replicated in vivo: we found increased IL-4 mRNA levels in nasal epithelial cells from nasal brushing of atopic rhinitis patients and a parallel reduction in TLR3 expression and increased RV-16 replication compared to nonatopic subjects. Mechanistically, Th2 cytokines impaired RV-16-induced activation of IRF3, but had no effects on RV-16-induced NF-kB activation in bronchial epithelial cell cultures. N-acetylcysteine and phosphoinositide 3-kinase (PI3K) inhibitor restored the inhibitory effects of Th2 cytokines over RV-16-induced activation of IRF3.ConclusionsIL-4 and IL-13, through inhibition of TLR3 expression and signalling (IRF3), impair immune response to RV-16 infection. These data suggest that Th2 conditions increase susceptibility to infections and identify pharmacological approaches with potential to restore impaired immune response in these conditions.
Thomson NC, Charron CE, Chaudhuri R, et al., 2015, Atorvastatin in combination with inhaled beclometasone modulates inflammatory sputum mediators in smokers with asthma, PULMONARY PHARMACOLOGY & THERAPEUTICS, Vol: 31, Pages: 1-8, ISSN: 1094-5539
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- Citations: 26
To M, Honda N, Hitani A, et al., 2015, Oxidative Stress Increased Nontypable Haemophilus Influenzae Invasion To Airway Epithelial Cells Via Platelet-Activating Factor Receptor Upregulation, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Malhotra D, Thimmulappa RK, Mercado N, et al., 2014, Retraction: Denitrosylation of HDAC2 by targeting Nrf2 restores glucocorticosteroid sensitivity in macrophages from COPD patients., J Clin Invest, Vol: 124
Ito K, Mercado N, 2014, STOP accelerating lung aging for the treatment of COPD, EXPERIMENTAL GERONTOLOGY, Vol: 59, Pages: 21-27, ISSN: 0531-5565
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- Citations: 25
Ito K, 2014, Oxidative stress pathways as new therapeutic opportunities: from infection to lung ageing, Publisher: WILEY-BLACKWELL, Pages: 30-30, ISSN: 1748-1708
Mercado N, Kizawa Y, Ueda K, et al., 2014, Activation of Transcription Factor Nrf2 Signalling by the Sphingosine Kinase Inhibitor SKI-II Is Mediated by the Formation of Keap1 Dimers, PLOS ONE, Vol: 9, ISSN: 1932-6203
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- Citations: 18
Koziol-White C, Strong P, Ito K, et al., 2014, Rhinovirus 16 (rv16) Induced Mediator Release, But Not Airway Hyper-Responsiveness, From Human Small Airways Is Modulated By The Narrow Spectrum Kinase Inhibitor Rv1088, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Kimura G, Ueda K, Masuko T, et al., 2014, Effects of BIRB796 on LPS-induced airway inflammation in cigarette smoke-exposed mice, 87th Annual Meeting of the Japanese-Pharmacological-Society, Publisher: JAPANESE PHARMACOLOGICAL SOC, Pages: 227P-227P, ISSN: 1347-8613
Footitt J, Mallia P, Durham A, et al., 2013, HDAC ACTIVITY IN MACROPHAGES IN EXPERIMENTAL RHINOVIRUS INFECTION IN COPD, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A58-A59, ISSN: 0040-6376
Papi A, Contoli M, Adcock IM, et al., 2013, Rhinovirus infection causes steroid resistance in airway epithelium through nuclear factor κB and c-Jun N-terminal kinase activation, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 132, Pages: 1075-+, ISSN: 0091-6749
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- Citations: 71
Kobayashi Y, Bossley C, Gupta A, et al., 2013, Passive smoking impairs histone deacetylase-2 in children with severe asthma, CHEST Journal, ISSN: 0012-3692
To M, Hitani A, Kano I, et al., 2013, Defect of HDAC7 causes impaired VEGF expression in response to hypoxia in COPD, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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