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 LXRa signalling in human neutrophils. We found that PAF exerted an inhibitory effect on mRNA expression of TO901317-induced LXRa, 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 LXRa 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 LXRa and its related genes, which supports the notion that LXRa ligands exert a modulatory role in the neutrophil-mediated inflammatory response.

Grapefruit Flavonoid Naringenin Regulates the Expression of LXRα in THP-1 Macrophages by Modulating AMP-Activated Protein Kinase

“…39 The stimulation of LXRα by its synthetic agonist (TO901317) induces a decrease in ROS levels produced in human neutrophils. 12,40 The behavior of naringenin is different to that observed by us with other LXRα stimulators. We have reported previously that he status redox cellular is essential for the activity LXRα.…”

“…Pro-oxidant molecules inhibit LXRα production and antioxidant compound reverted this effect and even enhanced LXRα expression. 12,40 In this article we detected that a pro-oxidant stimuli, naringenin, induced a clear LXRα and target genes stimulation, this effect had been previously detected by us in neutrophils with other strong prooxidant agents at high concentrations, platelet-activating factor (PAF) and H 2 O 2 . 41 We concluded that a low ROS production inhibited LXRα expression but high ROS production induced LXRα and target genes mRNA expression.…”