Modulation of IgE-dependent COX-2 gene expression by reactive oxygen species in human neutrophils.
Cyclooxygenase (COX) is a key enzyme in prostaglandin (PG) synthesis. Up-regulation of its COX-2 isoform is responsible for the increased PG release, taking place under inflammatory conditions, and also, is thought to be involved in allergic and inflammatory diseases. In the present work, we demonstrate that COX-2 expression becomes highly induced by anti-immunoglobulin E (IgE) antibodies and by antigens in human neutrophils from allergic patients. This induction was detected at mRNA and protein levels and was accompanied by a concomitant PGE(2) and thromboxane A(2) release. We also show evidence that inhibitors of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, such as 4-(2-aminoethyl)benzenesulphonyl fluoride and 4-hydroxy-3-methoxyaceto-phenone, completely cancelled anti-IgE-induced COX-2 protein up-regulation, suggesting that this process is mediated by reactive oxygen species (ROS) derived from NADPH oxidase activity. Moreover, the mitogen-activated protein kinases (MAPKs), p38 and extracellular signal-regulated kinase, and also, the transcription factor, nuclear factor (NF)-kappaB, are involved in the up-regulation of COX-2 expression, as specific chemical inhibitors of these two kinases, such as SB203580 and PD098059, and of the NF-kappaB pathway, such as N(alpha)-benzyloxycarbonyl-l-leucyl-l-leucyl-l-leucinal, abolished IgE-dependent COX-2 induction. Evidence is also presented, using Fe(2)(+)/Cu(2)(+) ions, that hydroxyl radicals generated from hydrogen peroxide through Fenton reactions could constitute candidate modulators able to directly trigger anti-IgE-elicited COX-2 expression through MAPK and NF-kappaB pathways. Present results underscore a new role for ROS as second messengers in the modulation of COX-2 expression by human neutrophils in allergic conditions.
Vega
Antonio
A
Departamento de Bioquímica Médica y Biología, Universidad de Sevilla, E-41009 Sevilla, Spain.
Chacón
Pedro
P
Alba
Gonzalo
G
El Bekay
Rajaa
R
Martín-Nieto
José
J
Sobrino
Francisco
F
D051546:Cyclooxygenase 2 / Q000187:drug effects* / Q000235:genetics* / Q000276:immunology; D015232:Dinoprostone / Q000276:immunology; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism / Q000494:pharmacology; D007073:Immunoglobulin E / Q000187:drug effects* / Q000276:immunology; D007074:Immunoglobulin G / Q000494:pharmacology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000276:immunology; D019255:NADPH Oxidases / Q000276:immunology; D016328:NF-kappa B / Q000276:immunology; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013928:Thromboxane A2 / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
D007074:Immunoglobulin G; D016328:NF-kappa B; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D007073:Immunoglobulin E; D013928:Thromboxane A2; D006861:Hydrogen Peroxide; D051546:Cyclooxygenase 2; D019255:NADPH Oxidases; D020929:Mitogen-Activated Protein Kinase Kinases; D015232:Dinoprostone