Cyclopentenone isoprostanes inhibit the inflammatory response in macrophages.

Musiek ES, Gao L, Milne GL, Han W, Everhart MB, Wang D, Backlund MG, DuBois RN, Zanoni G, Vidari G, Blackwell TS, Morrow JD
J Biol Chem. 2005 280 (42): 35562-70

PMID: 16100121 · DOI:10.1074/jbc.M504785200

Although both inflammation and oxidative stress contribute to the pathogenesis of many disease states, the interaction between the two is poorly understood. Cyclopentenone isoprostanes (IsoPs), highly reactive structural isomers of the bioactive cyclopentenone prostaglandins PGA2 and PGJ2, are formed non-enzymatically as products of oxidative stress in vivo. We have, for the first time, examined the effects of synthetic 15-A2- and 15-J2-IsoPs, two groups of endogenous cyclopentenone IsoPs, on the inflammatory response in RAW264.7 and primary murine macrophages. Cyclopentenone IsoPs potently inhibited lipopolysaccharide-stimulated IkappaB alpha degradation and subsequent NF-kappaB nuclear translocation and transcriptional activity. Expression of inducible nitric-oxide synthase and cyclooxygenase-2 were also inhibited by cyclopentenone IsoPs as was nitrite and prostaglandin production (IC50 approximately 360 and 210 nM, respectively). 15-J2-IsoPs potently activated peroxisome proliferator-activated receptor gamma (PPARgamma) nuclear receptors, whereas 15-A2-IsoP did not, although the anti-inflammatory effects of both molecules were PPARgamma-independent. Interestingly 15-A2-IsoPs induced oxidative stress in RAW cells that was blocked by the antioxidant 4-hydroxy-TEMPO (TEMPOL) or the mitochondrial uncoupler carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone. TEMPOL also abrogated the inhibitory effect of 15-A2-IsoPs on lipopolysaccharide-induced NF-kappaB activation, inducible nitricoxide synthase expression, and nitrite production, suggesting that 15-A2-IsoPs inhibit the NF-kappaB pathway at least partially via a redox-dependent mechanism. 15-J2-IsoP, but not 15-A2-IsoP, also potently induced RAW cell apoptosis again via a PPAR gamma-independent mechanism. These findings suggest that cyclopentenone IsoPs may serve as negative feedback regulators of inflammation and have important implications for defining the role of oxidative stress in the inflammatory response.

MeSH Terms (40)

Active Transport, Cell Nucleus Animals Anti-Inflammatory Agents Antioxidants Apoptosis Arachidonic Acid Arachidonic Acids Blotting, Northern Blotting, Western Bone Marrow Cells Carbonyl Cyanide m-Chlorophenyl Hydrazone Cell Line Cell Nucleus Cyclic N-Oxides Cyclooxygenase 2 Cyclopentanes F2-Isoprostanes Genes, Reporter Hydroxylamine I-kappa B Proteins Inflammation Inhibitory Concentration 50 Isoprostanes Lipopolysaccharides Macrophages Mice Microscopy, Fluorescence Models, Chemical NF-kappa B NF-KappaB Inhibitor alpha Nitric Oxide Synthase Type II Nitrites Oxidative Stress PPAR gamma Prostaglandins Protein Biosynthesis Tetrazolium Salts Thiazoles Transcription, Genetic Tumor Necrosis Factor-alpha

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