LPS induces ALOX5 promoter activation and 5-lipoxygenase expression in human monocytic cells. (March 2020)

• Record Type: Journal Article
• Authors: Poirier, Samuel J; Boudreau, Luc H; Flamand, Nicolas; Surette, Marc E
• Is Part Of: Prostaglandins, leukotrienes, and essential fatty acids. Volume 154(2020)
• Publication Date: 2020-03
• Subjects: Leukotrienes -- TGF-β -- THP-1 -- Mono Mac 1 -- Reporter gene assays -- Inflammation; Abbreviations: 5-HETE 5-hydroxyeicosatetraenoic acid -- 5-LO 5-lipoxygenase -- CML Chronic myeloid leukemia -- cysLT Cysteinyl-leukotriene -- gDNA Genomic DNA -- LT Leukotrienes -- LPS Lipopolysaccharide -- MM1 Mono Mac 1; Lipids -- Periodicals; Unsaturated fatty acids -- Periodicals; Prostaglandins -- Periodicals; Leukotrienes -- Periodicals; Fatty Acids, Unsaturated -- Periodicals; Acides gras insaturés -- Périodiques; Prostaglandines -- Périodiques; Leucotriènes -- Périodiques; Lipides -- Périodiques; 612.01577
• DOI: 10.1016/j.plefa.2020.102078
• Languages: English
• ISSNs: 0952-3278

Abstract

Highlights: LPS induces human monocytic cell maturation and increased leukotriene biosynthesis. Leukotriene biosynthesis is associated with increased 5-lipoxygenase expression. The first report of agonist-induced ALOX5 promoter activation in human leukocytes. New insight on mechanisms of 5-lipoxygenase regulation in immature leukocytes. Abstract: 5-lipoxygenase (5-LO), coded by the ALOX5 gene, is expressed in leukocytes and catalyzes the formation of leukotrienes, pro-inflammatory lipid mediators. Leukotrienes are central to immune responses, but are also involved in inflammatory disorders and 5-LO expression is associated with leukemia stem cell survival. It is therefore important to understand mechanisms that control 5-LO expression. This study investigated the control of 5-LO expression and leukotriene biosynthesis following the maturation of human monocytic cells. MonoMac-1 (MM1) and THP-1 cells were incubated for up to 72 h with or without LPS and TGF-β. LPS, but not TGF-β, increased CD14 expression in both MM1 and THP-1 cells. Incubation with LPS (100 ng/ml) and TGF-β (1 ng/ml) synergistically increased the capacity of MM1 cells to produce 5-LO products from undetectable levels to 40±5 pmol/10 6 cells. 5-LO product biosynthesis in THP-1 cells increased 25-fold. A synergistic effect of LPS and TGF-β was measured with increases in 5-LO mRNA of 54- and 13-fold in MM1 and THP-1 cells, respectively. 5-LO protein expression increased significantly in both MM1 and THP-1 cells. ALOX5 promoter activity was significantly elevated >2-fold in both cell lines following LPS treatment, but TGF-β was without effect. The main 5-LO products were cysteinyl-leukotrienes, however LPS and TGF-β did not impact on the capacity of the cells to metabolize leukotriene A4 . Overall, this study demonstrates that receptor-mediated stimulation of MM1 and THP-1 cells by LPS is associated with increased 5-LO expression. This represents a new mechanism by which leukotriene biosynthesis can be modulated by pathological agents.