A proinflammatory role for the cyclopentenone prostaglandins at low micromolar concentrations:: Oxidative stress-induced extracellular signal-regulated kinase activation without NF-κB inhibition

被引:30
作者
Bureau, F
Desmet, C
Mélotte, D
Jaspar, F
Volanti, C
Vanderplasschen, A
Pastoret, PP
Piette, J
Lekeux, P
机构
[1] Univ Liege, Dept Physiol, Mol & Cellular Therapy Ctr, B-4000 Liege, Belgium
[2] Univ Liege, Lab Fundamental Virol & Immunol, Mol & Cellular Therapy Ctr, B-4000 Liege, Belgium
[3] Univ Liege, Fac Vet Med, Dept Immunol Vaccinol, B-4000 Liege, Belgium
关键词
D O I
10.4049/jimmunol.168.10.5318
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
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页码:5318 / 5325
页数:8
相关论文
共 51 条
[1]   Oxidative stress activates extracellular signal-regulated kinases through Src and ras in cultured cardiac myocytes of neonatal rats [J].
Aikawa, R ;
Komuro, I ;
Yamazaki, T ;
Zou, YZ ;
Kudoh, S ;
Tanaka, M ;
Shiojima, I ;
Hiroi, Y ;
Yazaki, Y .
JOURNAL OF CLINICAL INVESTIGATION, 1997, 100 (07) :1813-1821
[2]   NEUTROPHIL-ACTIVATING PEPTIDE-1 INTERLEUKIN-8, A NOVEL CYTOKINE THAT ACTIVATES NEUTROPHILS [J].
BAGGIOLINI, M ;
WALZ, A ;
KUNKEL, SL .
JOURNAL OF CLINICAL INVESTIGATION, 1989, 84 (04) :1045-1049
[3]   Mechanisms of persistent NF-κB activity in the bronchi of an animal model of asthma [J].
Bureau, F ;
Delhalle, S ;
Bonizzi, G ;
Fiévez, L ;
Dogné, S ;
Kirschvink, N ;
Vanderplasschen, A ;
Merville, MP ;
Bours, V ;
Lekeux, P .
JOURNAL OF IMMUNOLOGY, 2000, 165 (10) :5822-5830
[4]   Inhibition of IκB kinase and IκB phosphorylation by 15-deoxy-Δ12,14-prostaglandin J2 in activated murine macrophages [J].
Castrillo, A ;
Díaz-Guerra, MJM ;
Hortelano, S ;
Martín-Sanz, P ;
Boscá, L .
MOLECULAR AND CELLULAR BIOLOGY, 2000, 20 (05) :1692-1698
[5]   15-deoxy-Δ 12,14-prostaglandin J2 inhibition of NF-κB-DNA binding through covalent modification of the p50 subunit [J].
Cernuda-Morollón, E ;
Pineda-Molina, E ;
Cañada, FJ ;
Pérez-Sala, D .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (38) :35530-35536
[6]   REGULATION OF INTERLEUKIN-5 AND GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR EXPRESSION [J].
COUSINS, DJ ;
STAYNOV, DZ ;
LEE, TH .
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 1994, 150 (05) :S50-S53
[7]   Cytokine-activated endothelial cells delay neutrophil apoptosis in vitro and in vivo: a role for granulocyte/macrophage colony-stimulating factor [J].
Coxon, A ;
Tang, T ;
Mayadas, TN .
JOURNAL OF EXPERIMENTAL MEDICINE, 1999, 190 (07) :923-933
[8]   Multiple epithelial cell-derived factors enhance neutrophil survival -: Regulation by glucocorticoids and tumor necrosis factor-α [J].
Daffern, PJ ;
Jagels, RA ;
Hugli, TE .
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, 1999, 21 (02) :259-267
[9]  
DAHINDEN CA, 1984, J IMMUNOL, V133, P1477
[10]   Positive and negative regulation of IκB kinase activity through IKKβ subunit phosphorylation [J].
Delhase, M ;
Hayakawa, M ;
Chen, Y ;
Karin, M .
SCIENCE, 1999, 284 (5412) :309-313