title: Fluvastatin inhibits the induction of inducible nitric oxide synthase, an inflammatory biomarker, in hepatocytes.
abstract: OBJECTIVE
  Statins (3-hydroxy-3-methylglutaryl coenzyme A [HMG-CoA] reductase inhibitors), which were originally designed to lower plasma cholesterol levels, are increasingly recognized as anti-inflammatory agents. In the inflamed liver, pro-inflammatory cytokines stimulate the induction of inducible nitric oxide synthase (iNOS). Overproduction of NO by iNOS has been implicated as a factor in liver injury. We examined pro-inflammatory cytokine-stimulated hepatocytes as a simple in vitro injury model to determine liver-protective effects of statins. We hypothesized that statins are involved in the downregulation of iNOS, resulting in decreased hepatic inflammation.
  
  
  METHODS
  Hepatocytes were isolated from rats by collagenase perfusion and centrifugation. Primary cultured hepatocytes were treated with interleukin (IL)-1β in the presence or absence of fluvastatin. The induction of iNOS and its signaling pathway were analyzed.
  
  
  RESULTS
  IL-1β produced increased levels of NO. This effect was inhibited by fluvastatin, which exerted its maximal effects at 100 μM. Fluvastatin decreased the levels of iNOS protein and its mRNA expression. Fluvastatin had no effects on IκB degradation and nuclear factor-κB activation. However, fluvastatin inhibited the upregulation of type I IL-1 receptor mRNA and protein expression. Transfection experiments demonstrated that fluvastatin suppressed iNOS induction by the inhibition of promoter transactivation and mRNA stabilization. Fluvastatin reduced the expression of an iNOS gene antisense-transcript, which is involved in iNOS mRNA stability.
  
  
  CONCLUSIONS
  Results indicate that fluvastatin inhibits the induction of iNOS at both transcriptional and post-transcriptional steps, leading to the prevention of NO production. Fluvastatin may provide therapeutic potential in iNOS induction involved in various liver injuries.
authors.affiliation: Department of Surgery, Kansai Medical University, Moriguchi, Japan.
authors.forename: Katsuji
authors.initials: K
authors.lastname: Tokuhara
authors.forename: Kozo
authors.initials: K
authors.lastname: Habara
authors.forename: Masaharu
authors.initials: M
authors.lastname: Oishi
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Miki
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Masaki
authors.initials: M
authors.lastname: Kaibori
authors.forename: Mikio
authors.initials: M
authors.lastname: Nishizawa
authors.forename: Tadayoshi
authors.initials: T
authors.lastname: Okumura
authors.forename: A-Hon
authors.initials: AH
authors.lastname: Kwon