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B Inhibition1
* Department of Physiology and
Laboratory of Fundamental Virology and Immunology, Molecular and Cellular Therapy Center, and
Department of Immunology-Vaccinology, Faculty of Veterinary Medicine, University of Liège, Liège, Belgium
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-
B, a critical activator of inflammatory gene expression. However,
exogenous cyPGs inhibit NF-B 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-B inhibition
(viz, low micromolar concentrations), significantly potentiate the
inflammatory response to TNF-
. At these concentrations, cyPGs induce
production of reactive oxygen species, thereby synergizing with TNF-
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
study 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.
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