Differential effects of lipoprotein lipase on tumor necrosis factor-alpha and interferon-gamma-mediated gene expression in human endothelial cells.
Lipoprotein lipase (LPL) is a key enzyme in the hydrolysis of triglyceride-rich lipoproteins. In vascular diseases, such as atherosclerosis, inflammation plays an important role in the pathogenesis of the disease. We examined the role of LPL in modulating tumor necrosis factor-alpha (TNF-alpha)- and interferon-gamma (IFN-gamma)-mediated inflammatory cytokine signal transduction pathways in human aortic endothelial cells (HAECs). LPL significantly suppressed TNF-alpha-induced gene expression, and this suppression was reversed by tetrahydrolipstatin and heparinase. In contrast, LPL synergistically enhanced IFN-gamma-induced gene expression in HAECs. To elucidate the molecular mechanisms of LPL action, we investigated the role of transcription factors nuclear factor kappa B (NF-kappaB) and signal transducer and activator of transcription factor 1 (Stat1). The anti-inflammatory response of LPL in suppressing TNF-alpha-induced gene expression was a result of its inhibition of NF-kappaB activity by the abrogation of IkappaB-alpha degradation and phosphorylation of the p65 subunit. Although LPL alone had no effect on Stat1 activation, LPL enhanced IFN-gamma-induced phosphorylation of Stat1 on tyrosine 701 and serine 727, as well as Stat1-mediated transactivation. The synergistic effect of LPL on IFN-gamma-induced Stat1 activation was mediated by enhanced activation of the tyrosine kinase JAK2 and was abrogated by LY294002, a specific inhibitor of the phosphatidylinositol 3'-kinase pathway. Our studies indicate that LPL has differential effects on several inflammatory pathways known to be important in atherosclerosis.
Kota
Rama S
RS
Department of Internal Medicine, Division of Endocrinology, Clinical Nutrition and Vascular Medicine, School of Medicine, University of California, Davis, California 95616, USA. rskota@ucdavis.edu
Ramana
Chilakamarti V
CV
Tenorio
Fatima A
FA
Enelow
Richard I
RI
Rutledge
John C
JC
D001011:Aorta / Q000166:cytology; D015243:Cholesterol, VLDL / Q000378:metabolism; D016895:Culture Media, Serum-Free; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D019040:E-Selectin / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000378:metabolism; D005786:Gene Expression Regulation; D019763:Heparin Lyase / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism*; D007783:Lactones / Q000378:metabolism; D008071:Lipoprotein Lipase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D000077403:Orlistat; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D015243:Cholesterol, VLDL; D016895:Culture Media, Serum-Free; D016207:Cytokines; D004268:DNA-Binding Proteins; D019040:E-Selectin; D004791:Enzyme Inhibitors; D007783:Lactones; D016328:NF-kappa B; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma; D000077403:Orlistat; D019869:Phosphatidylinositol 3-Kinases; D008071:Lipoprotein Lipase; D019763:Heparin Lyase