OBJECTIVE: Oxidized low-density lipoproteins (ox-LDL) or their components suppress macrophage inflammatory response by down-regulating cytokine synthesis, nitric oxide synthase and inducible cyclooxygenase (Cox-2). This event is crucial for the pathophysiological process leading to the formation of atherosclerotic plaque. Our present study focused on the mechanisms through which oxidized phospholipids inhibit LPS-induced Cox-2 expression in human macrophages. METHODS: Macrophages were incubated with a mixture of oxidized fragmented phospholipids (ox-PAPC), present in modified LDL, and then exposed to LPS. Cox-2 was evaluated in terms of protein levels, mRNA and activity. RESULTS: Ox-PAPC dose-dependently inhibited Cox-2 protein, mRNA and activity by preventing NF-kappaB binding to DNA. This effect was consequent to alterations of the degradation pattern of IkappaBalpha. Moreover, ox-PAPC markedly prevented extracellular signal-regulated kinase (ERK2) activation, leading to Cox-2 expression, whereas activation of the transcription factor peroxisome proliferator-activated receptors (PPARs) was not influenced. CONCLUSION: ox-PAPC down-regulates LPS-induced Cox-2 expression in human macrophages by targeting both NF-kappaB/IkappaB and ERK2 pathways. An altered inflammatory response by macrophages within atheromata may contribute to the progression of atherosclerosis.
|Titolo:||Oxidized phospholipids inhibit cyclooxygenase-2 in human macrophages via nuclear factor-kappaB/IkappaB- and ERK2-dependent mechanisms|
|Parole Chiave:||Macrophages; NF-kappa B; Cyclooxygenase 2; Prostaglandin-Endoperoxide Synthases; Dose-Response Relationship, Drug; Humans; Cyclooxygenase Inhibitors; Cell Culture Techniques; Cyclooxygenase 2 Inhibitors; Membrane Proteins; RNA, Messenger; Down-Regulation; I-kappa B Proteins; Isoenzymes; Lipopolysaccharides; Mitogen-Activated Protein Kinases; Lipoproteins, LDL|
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
|Data di pubblicazione:||1-ago-2002|
|Digital Object Identifier (DOI):||10.1016/S0008-6363(02)00437-6|
|Appare nelle tipologie:||01 - Articolo su periodico|