Oxidative modulation of NF-kappaB signaling by oxidized low-density lipoprotein.
Oxidized low-density lipoprotein (oxLDL) modifies macrophage inflammatory responses in the pathogenesis of atherosclerosis. In the present study, we focused on gamma-glutamylcysteine synthetase (gamma-GCS), a rate limiting enzyme of glutathione synthesis, and examined whether inflammatory stimulation of gamma-GCS gene in macrophages by lipopolysaccharide (LPS) is modified when the cells were exposed to oxLDL. We found that the nuclear factor-kappaB (NF-kappaB)-mediated induction of gamma-GCS by LPS (100 ng/ml) was suppressed by a 48-h pre-treatment with oxLDL (50 micro/ml), and this was due to a decrease in the DNA-binding activity of NF-kappaB. Furthermore, pre-treatment with oxLDL caused a carbonylation of NF-kappaB subunit p65. With alpha-tocopherol, the oxLDL-induced carbonylation of proteins decreased with a restoration of DNA-binding activity of NF-kappaB. Together, these indicate that oxidative modification of NF-kappaB suppresses LPS-induced expression of gamma-GCS gene in ox-LDL-treated cells, suggesting an implication of oxLDL-induced modulation of NF-kappaB signaling with atherosclerosis.
D000818:Animals; D002460:Cell Line; D024202:Electrophoretic Mobility Shift Assay; D005721:Glutamate-Cysteine Ligase / Q000235:genetics; D005978:Glutathione / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000096:biosynthesis; D015398:Signal Transduction; D024502:alpha-Tocopherol / Q000494:pharmacology
D008070:Lipopolysaccharides; D008077:Lipoproteins, LDL; D016328:NF-kappa B; D012333:RNA, Messenger; C099252:oxidized low density lipoprotein; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D024502:alpha-Tocopherol