Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 280, Issue 42, Pages 35562-35570Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M504785200
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- NIDDK NIH HHS [DK48831] Funding Source: Medline
- NIGMS NIH HHS [GM15431] Funding Source: Medline
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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 PGA(2) and PGJ(2), are formed non-enzymatically as products of oxidative stress in vivo. We have, for the first time, examined the effects of synthetic 15-A(2)- and 15-J(2)-IsoPs, two groups of endogenous cyclopentenone IsoPs, on the inflammatory response in RAW264.7 and primary murine macrophages. Cyclopentenone IsoPs potently inhibited lipopolysaccharide-stimulated I kappa B alpha degradation and subsequent NF-kappa B 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 similar to 360 and 210 nM, respectively). 15-J(2)-IsoPs potently activated peroxisome proliferator-activated receptor gamma (PPAR gamma) nuclear receptors, whereas 15-A(2)-IsoP did not, although the anti-inflammatory effects of both molecules were PPAR gamma-independent. Interestingly 15-A(2)-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-A(2)-IsoPs on lipopolysaccharide- induced kappa F-kappa B activation, inducible nitric-oxide synthase expression, and nitrite production, suggesting that 15-A(2)-IsoPs inhibit the NF-kappa B pathway at least partially via a redox-dependent mechanism. 15-J(2)-IsoP, but not 15-A(2)-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.
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