PPAR-alpha contributes to the anti-inflammatory activity of 17beta-estradiol.

Abstract

Because studies have shown that 17beta-estradiol (E2) produces anti-inflammatory effects after various adverse circulatory conditions, we have recently demonstrated that E2 significantly reduced the acute lung injury. Moreover, previous results suggest that peroxisome proliferator-activated receptor-alpha (PPAR-alpha), an intracellular transcription factor activated by fatty acids, plays a role in the control of inflammation. With the aim to characterize the role of PPAR-alpha in estrogen-mediated anti-inflammatory activity, we tested the efficacy of E2 in an experimental model of lung inflammation, carrageenan-induced pleurisy, comparing ovariectomized wild-type (WT) and PPAR-alpha lacking (PPAR-alphaKO) mice. Results indicate that E2-mediated anti-inflammatory activity is weakened in PPAR-alphaKO mice, compared with WT control groups. In particular, E2 was less effective in PPAR-alphaKO, compared with WT mice, in inhibition of cell migration as well as lung injury, NF-kB activation, TNF-alpha production, and inducible nitric-oxide synthase (iNOS) activation. Moreover, macrophages from PPAR-alphaKO were less susceptible to E2-induced iNOS inhibition in vitro compared with macrophages from WT mice. Moreover, the results indicate that PPAR-alpha was required for estrogen receptor up-regulation, following E2 treatment. These results show for the first time that PPAR-alpha contributes to the anti-inflammatory activity of E2.

• Authors: Concetta Crisafulli, Stefano Bruscoli, Emanuela Esposito, Emanuela Mazzon, Rosanna Di Paola, Tiziana Genovese, Placido Bramanti, Graziella Migliorati, Salvatore Cuzzocrea
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 331 Issue 3 Pg. 796-807 (Dec 2009) ISSN: 1521-0103 [Electronic] United States
• PMID: 19755663 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• NF-kappa B
• PPAR alpha
• Receptors, Estrogen
• Tumor Necrosis Factor-alpha
• Estradiol
• Nitric Oxide Synthase Type II
• Clofibrate

Topics

• Animals
• Anti-Inflammatory Agents (administration & dosage, therapeutic use)
• Blotting, Western
• Cells, Cultured
• Clofibrate (pharmacology)
• Estradiol (administration & dosage, physiology, therapeutic use)
• In Situ Nick-End Labeling
• Macrophages, Peritoneal (drug effects, metabolism)
• Mice
• Mice, Knockout
• NF-kappa B (metabolism)
• Nitric Oxide Synthase Type II (metabolism)
• Ovariectomy
• PPAR alpha (agonists, genetics, physiology)
• Pneumonia (drug therapy, metabolism)
• Receptors, Estrogen (biosynthesis)
• Tumor Necrosis Factor-alpha (metabolism)
• Up-Regulation