A proinflammatory role for the cyclopentenone prostaglandins at low micromolar concentrations: Oxidative stress-induced extracellular signal-regulated kinase activation without NF-kappa B inhibition
[en] An anti-inflammatory role and therapeutic potential for cyclopentenone PGs (cyPGs) has been suggested, based on observations that levels of cyPGs in exudates increase during the resolution phase of inflammation, and that exogenous cyPGs may attenuate the inflammatory response in vivo and in vitro mainly through inhibition of NF-kappaB, a critical activator of inflammatory gene expression. However, exogenous cyPGs inhibit NF-kappaB only at concentrations substantially higher than those of endogenous cyPGs present in inflammatory fluids, thus challenging the hypothesis that cyPGs are naturally occurring inhibitors of inflammation and suggesting that cyPGs at low concentrations might have previously unappreciated effects. In this study, using various cell types, we report that cyPGs, when used at concentrations substantially lower than required for NF-kappaB inhibition (viz, low micromolar concentrations), significantly potentiate the inflammatory response to TNF-alpha. At these concentrations, cyPGs induce production of reactive oxygen species, thereby synergizing with TNF-alpha to activate the extracellular signal-regulated kinase 1/2, an activation which in turn potentiates proinflammatory cytokine expression at both transcriptional and posttranscriptional levels. Our studs establishes a proinflammatory role for cyPGs at low micromolar concentrations, raises the possibility that cyPGs do not act as physiologic anti-inflammatory mediators, and questions the therapeutic potential of these compounds.
Disciplines :
Anatomy (cytology, histology, embryology...) & physiology Veterinary medicine & animal health Biochemistry, biophysics & molecular biology
Author, co-author :
Bureau, Fabrice ✱; Université de Liège - ULiège > Département de sciences fonctionnelles > Biochimie et biologie moléculaire
Desmet, Christophe ✱; Université de Liège - ULiège > Biochimie et biologie moléculaire
Pastoret, Paul-Pierre ; Université de Liège - ULiège > Département des maladies infectieuses et parasitaires > Département des maladies infectieuses et parasitaires
PiettE, J.
Lekeux, Pierre ; Université de Liège - ULiège > Département de sciences fonctionnelles > Physiologie
✱ These authors have contributed equally to this work.
Language :
English
Title :
A proinflammatory role for the cyclopentenone prostaglandins at low micromolar concentrations: Oxidative stress-induced extracellular signal-regulated kinase activation without NF-kappa B inhibition
Publication date :
May 2002
Journal title :
Journal of Immunology
ISSN :
0022-1767
eISSN :
1550-6606
Publisher :
American Association of Immunologists, Baltimore, United States - Maryland
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