title: Geranylgeranylacetone ameliorates inflammatory response to lipopolysaccharide (LPS) in murine macrophages: inhibition of LPS binding to the cell surface.
abstract: We investigated whether pretreatment with geranylgeranylacetone (GGA), a potent heat shock protein (HSP) inducer, could inhibit proinflammatory cytokine liberation and nitric oxide (NO) production in lipopolysaccharide (LPS)-treated murine macrophages. The levels of NO and tumor necrosis factor-alpha (TNF-alpha) released from murine macrophage RAW 264 cells were increased dose- and time-dependently following treatment with LPS (1 microg/ml). GGA (80 microM) treatment 2 h before LPS addition significantly suppressed TNF-alpha and NO productions at 12 h and 24 h after LPS, respectively, indicating that GGA inhibits activation of macrophages. However, replacement by fresh culture medium before LPS treatment abolished the inhibitory effect of GGA on NO production in LPS-treated cells. Furthermore, GGA inhibited both HSP70 and inducible NO synthase expressions induced by LPS treatment despite an HSP inducer. When it was examined whether GGA interacts with LPS and/or affects expression of Toll-like receptor 4 (TLR4) and CD14 on the cell surface, GGA inhibited the binding of LPS to the cell surface, while GGA did not affect TLR4 and CD14 expressions. These results indicate that GGA suppresses the binding of LPS to the cell surface of macrophages, resulting in inhibiting signal transduction downstream of TLR4.
authors.affiliation: Division of Medical Biochemistry, Department of Pathophysiological and Therapeutic Science, Tottori University Faculty of Medicine, 86 Nishi-cho, Yonago 683-8503, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Mochida
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Matsura
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yamashita
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Horie
authors.forename: Shuzo
authors.initials: S
authors.lastname: Ohata
authors.forename: Chiaki
authors.initials: C
authors.lastname: Kusumoto
authors.forename: Tadashi
authors.initials: T
authors.lastname: Nishida
authors.forename: Yukari
authors.initials: Y
authors.lastname: Minami
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Inagaki
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Ishibe
authors.forename: Junya
authors.initials: J
authors.lastname: Nakada
authors.forename: Yoshiji
authors.initials: Y
authors.lastname: Ohta
authors.forename: Kazuo
authors.initials: K
authors.lastname: Yamada