© 2002 by European Society of Cardiology
Copyright © 2002, European Society of Cardiology
Oxidized phospholipids inhibit cyclooxygenase-2 in human macrophages via nuclear factor-
B/IB- and ERK2-dependent mechanisms
aE. Grossi Paoletti Center, Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy
bInstitut de Génétique et Biologie Moléculaire et Cellulaire (IGMBC), Illkirch, France
susanna.colli{at}unimi.it
* Corresponding author. Tel.: +39-2-5835-8291; fax: +39-2-5835-8250
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-
B binding to DNA. This effect was consequent to alterations of the degradation pattern of IB
. 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-B/IB and ERK2 pathways. An altered inflammatory response by macrophages within atheromata may contribute to the progression of atherosclerosis.
KEYWORDS Atherosclerosis; Infection/inflammation; Macrophages; Prostaglandins; Signal transduction
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