title: Oxidants induce a corticosteroid-insensitive phosphorylation of histone 3 at serine 10 in monocytes.
abstract: Oxidative stress enhances inflammation and reduces the effectiveness of corticosteroids, but the inflammatory signalling pathways induced by oxidants remain ill-defined. Phosphorylation of histone 3 at serine 10 (H3-Pser10) marks out a subset of inflammatory genes for transcription, several of which are induced in oxidant-associated inflammation. However, the influence of oxidants or of corticosteroids on this modification remains unknown. We assessed the regulation of H3-Pser10 by oxidants and lipopolysaccharide (LPS) in human blood monocytes and lung macrophages and the effectiveness of its abolition in controlling inflammatory gene expression in cells from asthmatic subjects compared to corticosteroids alone. Both oxidants and LPS promoted the induction of H3-Pser10 which was unaffected by corticosteroids. The induction of H3-Pser10 was mediated through p38α mitogen-activated protein kinase (MAPK) and IκB kinase 2 (IKK-2) signalling. Consequently, inhibitors of p38α MAPK or IKK-2 used in combination with dexamethasone were more effective at controlling inflammatory gene expression from monocytes and lung macrophages from asthmatic patients than the corticosteroid alone. Therefore, reduction of H3-Pser10 by inhibition of p38α MAPK or of IKK-2 may provide greater anti-inflammatory control than corticosteroids alone in oxidant-associated inflammation such as severe asthma.
authors.affiliation: Section of Airways Disease, National Heart & Lung Institute, Imperial College, London, United Kingdom; MRC Centre for Inflammation Research, Queens Medical Research Institute, University of Edinburgh Medical School, Edinburgh, United Kingdom.
authors.forename: John A
authors.initials: JA
authors.lastname: Marwick
authors.affiliation: Section of Airways Disease, National Heart & Lung Institute, Imperial College, London, United Kingdom.
authors.forename: Corina
authors.initials: C
authors.lastname: Tudor
authors.affiliation: Section of Airways Disease, National Heart & Lung Institute, Imperial College, London, United Kingdom.
authors.forename: Nadia
authors.initials: N
authors.lastname: Khorasani
authors.affiliation: Section of Airways Disease, National Heart & Lung Institute, Imperial College, London, United Kingdom.
authors.forename: Charalambos
authors.initials: C
authors.lastname: Michaeloudes
authors.affiliation: Section of Airways Disease, National Heart & Lung Institute, Imperial College, London, United Kingdom.
authors.forename: Pankaj K
authors.initials: PK
authors.lastname: Bhavsar
authors.affiliation: Section of Airways Disease, National Heart & Lung Institute, Imperial College, London, United Kingdom; NIHR Biomedical Research Unit, Royal Brompton Hospital, London, United Kingdom.
authors.forename: Kian F
authors.initials: KF
authors.lastname: Chung
mesh_terms: D000305:Adrenal Cortex Hormones / Q000494:pharmacology*; D000328:Adult; D005260:Female; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects*; D016877:Oxidants / Q000494:pharmacology*; D018384:Oxidative Stress; D010766:Phosphorylation; D012694:Serine / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000305:Adrenal Cortex Hormones; D006657:Histones; D016877:Oxidants; D012694:Serine; D048051:p38 Mitogen-Activated Protein Kinases