title: 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.affiliation: Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, 98125 Messina, Italy.
authors.forename: Concetta
authors.initials: C
authors.lastname: Crisafulli
authors.forename: Stefano
authors.initials: S
authors.lastname: Bruscoli
authors.forename: Emanuela
authors.initials: E
authors.lastname: Esposito
authors.forename: Emanuela
authors.initials: E
authors.lastname: Mazzon
authors.forename: Rosanna
authors.initials: R
authors.lastname: Di Paola
authors.forename: Tiziana
authors.initials: T
authors.lastname: Genovese
authors.forename: Placido
authors.initials: P
authors.lastname: Bramanti
authors.forename: Graziella
authors.initials: G
authors.lastname: Migliorati
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cuzzocrea
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D015153:Blotting, Western; D002478:Cells, Cultured; D002994:Clofibrate / Q000494:pharmacology; D004958:Estradiol / Q000008:administration & dosage / Q000502:physiology / Q000627:therapeutic use*; D020287:In Situ Nick-End Labeling; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010052:Ovariectomy; D047493:PPAR alpha / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D011014:Pneumonia / Q000188:drug therapy* / Q000378:metabolism; D011960:Receptors, Estrogen / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000893:Anti-Inflammatory Agents; D016328:NF-kappa B; D047493:PPAR alpha; D011960:Receptors, Estrogen; D014409:Tumor Necrosis Factor-alpha; D004958:Estradiol; D052247:Nitric Oxide Synthase Type II; D002994:Clofibrate