title: Very low density lipoprotein potentiates tumor necrosis factor-alpha expression in macrophages.
abstract: High levels of the triacylglycerol-rich lipoproteins, very low density lipoprotein (VLDL) and intermediate density lipoprotein (IDL) have been identified as independent risk factors for coronary heart disease, and inflammation is thought to contribute to atherosclerosis and its complications. To understand how dyslipidemia promotes inflammation, we have characterised the effects of VLDL treatment on production of tumor necrosis factor-alpha (TNF) by human monocyte-derived macrophages. VLDL strongly potentiated lipopolysaccharide (LPS)-induced expression of TNF mRNA and secretion of TNF protein. VLDL activated mitogen-activated protein kinase-ERK kinase 1/2 (MEK1/2), and potentiated LPS-induced MEK1/2 activation. The MEK1/2 inhibitor U0126 strongly diminished TNF expression, indicating that MEK1/2 plays a central role in the regulation of TNF expression. VLDL did not activate transcription factors NF-kappaB and PPAR-gamma, but it activated AP-1 at least as potently as LPS, and potentiated LPS-induced activation of AP-1. The inhibitor U0126 completely prevented this potentiation. Inhibition of AP-1 by decoy oligonucleotides abolished potentiation of TNF secretion by VLDL. In conclusion, VLDL treatment potentiates TNF expression in macrophages by activation of MEK1/2 and AP-1. These findings suggest that triacylglycerol-rich lipoproteins are involved in inflammatory processes associated with atherosclerosis.
authors.affiliation: Department of Medicine, Lund University, Wallenberg Laboratory, Malmö University Hospital, SE-20502 Malmö, Sweden. maria.stollenwerk@medforsk.mas.lu.se
authors.forename: Maria M
authors.initials: MM
authors.lastname: Stollenwerk
authors.forename: Alexandru
authors.initials: A
authors.lastname: Schiopu
authors.forename: Gunilla Nordin
authors.initials: GN
authors.lastname: Fredrikson
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Dichtl
authors.forename: Jan
authors.initials: J
authors.lastname: Nilsson
authors.forename: Mikko P S
authors.initials: MP
authors.lastname: Ares
mesh_terms: D001161:Arteriosclerosis / Q000276:immunology* / Q000503:physiopathology*; D018929:Cell Culture Techniques; D006801:Humans; D007249:Inflammation; D008079:Lipoproteins, VLDL / Q000494:pharmacology*; D048728:MAP Kinase Kinase Kinase 1 / Q000494:pharmacology; D048730:MAP Kinase Kinase Kinase 2 / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology* / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D012307:Risk Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
chemical_list: D008079:Lipoproteins, VLDL; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D048728:MAP Kinase Kinase Kinase 1; D048730:MAP Kinase Kinase Kinase 2