title: Edaravone prevents iNOS expression by inhibiting its promoter transactivation and mRNA stability in cytokine-stimulated hepatocytes.
abstract: Edaravone has an anti-inflammatory effect in experimental models of various organ injuries. We reported that edaravone reduces the induction of inducible nitric oxide synthase (iNOS) as well as pro-inflammatory cytokines in endotoxin-treated rats with partial hepatectomy, leading to the prevention of liver injury. Studies were performed to investigate the mechanisms involved in the inhibition of iNOS expression by edaravone in hepatocytes. Primary cultured rat hepatocytes were treated with interleukin (IL)-1beta in the presence or absence of edaravone, and iNOS and its signal were analyzed. Edaravone decreased the expression of iNOS mRNA and its protein stimulated by IL-1beta, resulting in the reduction of NO production. Edaravone inhibited the activation of transcription factor NF-kappaB through IkappaB degradation and the up-regulation of type I IL-1 receptor through PI3K/Akt activation, which are essential signals for iNOS induction. Further transfection experiments with iNOS promoter-luciferase construct having iNOS 3'-UTR revealed that edaravone decreased the stability of iNOS mRNA. In support of this observation, edaravone decreased the expression of iNOS antisense-transcript, which stabilizes iNOS mRNA by interacting with its 3'-UTR and RNA-binding protein. Edaravone may inhibit the induction of iNOS gene expression at steps of promoter transactivation and mRNA stabilization in cytokine-stimulated hepatocytes.
authors: Department of Surgery, Kansai Medical University, Osaka 570-8506, Japan.
authors: Hideyuki
authors: H
authors: Yoshida
authors: A-Hon
authors: AH
authors: Kwon
authors: Masaki
authors: M
authors: Kaibori
authors: Katsushige
authors: K
authors: Tsuji
authors: Kozo
authors: K
authors: Habara
authors: Masanori
authors: M
authors: Yamada
authors: Yasuo
authors: Y
authors: Kamiyama
authors: Mikio
authors: M
authors: Nishizawa
authors: Seiji
authors: S
authors: Ito
authors: Tadayoshi
authors: T
authors: Okumura
mesh_terms: D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002478:Cells, Cultured; D000077553:Edaravone; D016166:Free Radical Scavengers / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D053583:Interleukin-1beta / Q000494:pharmacology*; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics*; D051381:Rats; D017208:Rats, Wistar; D015533:Transcriptional Activation
chemical_list: D016166:Free Radical Scavengers; D053583:Interleukin-1beta; D012333:RNA, Messenger; D052247:Nitric Oxide Synthase Type II; D000077553:Edaravone; D000983:Antipyrine