title: Platelet-activating factor downregulates the expression of liver X receptor-α and its target genes in human neutrophils.
abstract: Liver X receptors (LXRs) are ligand-activated members of the nuclear receptor superfamily that regulate the expression of genes involved in lipid metabolism and inflammation, although their role in inflammation and immunity is less well known. It has been reported that oxysterols/LXRs may act as anti-inflammatory molecules, although opposite actions have also been reported. In this study, we investigated the effect of platelet-activating factor (PAF), a proinflammatory molecule, on LXRα signalling in human neutrophils. We found that PAF exerted an inhibitory effect on mRNA expression of TO901317-induced LXRα, ATP-binding cassette transporter A1, ATP-binding cassette transporter G1, and sterol response element binding protein 1c. This negative action was mediated by the PAF receptor, and was dependent on the release of reactive oxygen species elicited by PAF, as it was enhanced by pro-oxidant treatment and reversed by antioxidants. Current data also support the idea that PAF induces phosphorylation of the LXRα molecule in an extracellular signal-regulated kinase 1/2-mediated fashion. These results suggest that a possible mechanism by which PAF exerts its proinflammatory effect is through the downregulation of LXRα and its related genes, which supports the notion that LXRα ligands exert a modulatory role in the neutrophil-mediated inflammatory response.
authors.affiliation: Departamento de Bioquímica Médica y Biología Molecular, Universidad de Sevilla, Spain.
authors.forename: María E
authors.initials: ME
authors.lastname: Reyes-Quiroz
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Alba
authors.forename: Consuelo
authors.initials: C
authors.lastname: Santa-María
authors.forename: Javier
authors.initials: J
authors.lastname: Saenz
authors.forename: Isabel
authors.initials: I
authors.lastname: Geniz
authors.forename: Juan
authors.initials: J
authors.lastname: Jiménez
authors.forename: Remedios
authors.initials: R
authors.lastname: Ramírez
authors.forename: José
authors.initials: J
authors.lastname: Martín-Nieto
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Pintado
authors.forename: Francisco
authors.initials: F
authors.lastname: Sobrino
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000924:Anticholesteremic Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D000071518:Liver X Receptors; D008214:Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018375:Neutrophil Activation / Q000187:drug effects; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D010972:Platelet Activating Factor / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010980:Platelet Membrane Glycoproteins / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051780:Sterol Regulatory Element Binding Protein 1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: C577836:ABCA1 protein, human; C419353:ABCG1 protein, human; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D000924:Anticholesteremic Agents; D000975:Antioxidants; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D016877:Oxidants; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D020033:Protein Isoforms; D043562:Receptors, G-Protein-Coupled; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; C039351:platelet activating factor receptor
keywords: extracellular signal-related kinase (ERK)1/2; human leukocytes; inflammation; liver X receptor α; platelet-activating factor