Platelet-activating factor and hydrogen peroxide exert a dual modulatory effect on the transcription of LXRα and its target genes in human neutrophils

• Published in: International immunopharmacology 2016-09, Vol.38, p.357-366
• Main Authors: Reyes-Quiroz, María E., Alba, Gonzalo, Sáenz, Javier, Geniz, Isabel, Jiménez, Juan, Martín-Nieto, José, Santa-María, Consuelo, Sobrino, Francisco
• Format: Article
• Language: English
• Subjects: ATP Binding Cassette Transporter 1 - genetics; ATP Binding Cassette Transporter 1 - metabolism; Carrier Proteins - pharmacology; Cells, Cultured; DNA-Binding Proteins; ERK1 and 2; Extracellular Signal-Regulated MAP Kinases - metabolism; Human neutrophils, PAF; Humans; Hydrocarbons, Fluorinated - pharmacology; Hydrogen Peroxide - pharmacology; Immunity, Innate; Lipid Metabolism; Liver X receptor; Liver X Receptors - genetics; Liver X Receptors - metabolism; Neutrophils - drug effects; Neutrophils - immunology; NF-kappa B - metabolism; NF-κB; Phosphorylation - drug effects; Sterol Regulatory Element Binding Protein 1 - genetics; Sterol Regulatory Element Binding Protein 1 - metabolism; Sulfonamides - pharmacology; Transcriptional Activation - drug effects
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2016.05.001

Liver X receptors (LXRs) are ligand-activated nuclear receptors involved mainly in the regulation of cholesterol metabolism in many organs, including liver and intestine, as well as in macrophages and neutrophils. Besides, both anti-inflammatory and pro-inflammatory properties have been ascribed to LXRs. The effect of the inflammatory condition on the expression of LXRα and its target genes has not been previously addressed in human neutrophils. We have described that platelet-activating factor (PAF) and hydrogen peroxide (H2O2) are potent pro-inflammatory mediators that link the haemostatic and innate immune systems. In this work we report that H2O2 at low doses (1 pM-1μM) exerts an inhibitory effect on TO901317-induced mRNA expression of LXRα and of its target genes encoding the ATP-binding cassette (ABC) transporters ABCA1 and ABCG1, and the sterol regulatory element-binding protein 1c (SREBP1c). However, an opposite behaviour, i.e., a transcription-enhancing effect, was found at higher H2O2 doses (100–500μM) on most of these genes. A similar dual effect was observed when the pro-inflammatory molecule PAF was used. Interestingly, H2O2 production separately elicited by 10nM PAF or 1μM H2O2 was similarly low, and analogously, H2O2 production levels elicited by 5μM PAF or 100μM H2O2 were similarly high when they were compared. On the other hand, low doses of PAF or H2O2 induced phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK 1/2) and NF-κB activation, However, PAF or H2O2 at high doses did not produce changes in NF-κB activation levels. In summary, our results show that H2O2, either exogenous or PAF-induced, exerts a dual regulation on mRNA expression of LXRα and its target genes. •Dual effects of H2O2 and PAF on the LXRα pathway and its target genes•Low but not high doses of H2O2 and PAF induce phosphorylation of NF-κB.•PAF-induced H2O2 was concentration dependent.