A proinflammatory role for the cyclopentenone prostaglandins at low micromolar concentrations: oxidative stress-induced extracellular signal-regulated kinase activation without NF-kappa B inhibition.
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 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.
Bureau
Fabrice
F
Department of Physiology and Laboratory of Fundamental Virology and Immunology, Molecular and Cellular Therapy Center, University of Liège, Boulevard de Colonster, Bâtiment B42, Sart-Tilman, B-4000 Liège, Belgium. fabrice.bureau@ulg.ac.be
Desmet
Christophe
C
Mélotte
Dorothée
D
Jaspar
Fabrice
F
Volanti
Cédric
C
Vanderplasschen
Alain
A
Pastoret
Paul-Pierre
PP
Piette
Jacques
J
Lekeux
Pierre
P
D000276:Adjuvants, Immunologic / Q000378:metabolism / Q000502:physiology; D002478:Cells, Cultured; D003517:Cyclopentanes / Q000378:metabolism / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis; D004306:Dose-Response Relationship, Immunologic; D004789:Enzyme Activation / Q000276:immunology; D006367:HeLa Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism* / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism* / Q000502:physiology; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018384:Oxidative Stress / Q000276:immunology*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000378:metabolism / Q000502:physiology; D011453:Prostaglandins / Q000378:metabolism / Q000502:physiology*; D011454:Prostaglandins A / Q000378:metabolism / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000276:immunology; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism; D014158:Transcription, Genetic / Q000276:immunology; D014407:Tumor Cells, Cultured / Q000201:enzymology / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D020298:U937 Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D000276:Adjuvants, Immunologic; D003517:Cyclopentanes; D016207:Cytokines; D018836:Inflammation Mediators; D016328:NF-kappa B; D011453:Prostaglandins; D011454:Prostaglandins A; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; C013905:cyclopentenone; D015230:Prostaglandin D2; C100573:prostaglandin A1