title: Valproic acid increases susceptibility to endotoxin shock through enhanced release of high-mobility group box 1.
abstract: High-mobility group box 1 (HMGB1) is a nuclear factor and a secreted protein. During inflammation, HMGB1 is secreted into the extracellular space where it can interact with the receptor for advanced glycation end products and trigger proinflammatory signals. Extracellular HMGB1 plays a critical role in several inflammatory diseases such as sepsis and rheumatoid arthritis. Valproic acid (VPA) is one of the most frequently prescribed antiepileptic drugs. The present study was undertaken to investigate the effect of VPA on secretion of HMGB1 in systemic inflammatory responses induced by lipopolysaccharide. Pretreatment with VPA increased the susceptibility of mice to lipopolysaccharide in endotoxemia. Valproic acid induced HMGB1 release and nuclear factor κB activation in RAW-blue cells. Valproic acid promoted the phosphorylation of ERK1/2 but not that of p38 or JNK. The MEK1/2 inhibitor PD98059 also suppressed HMGB1 release and activation of nuclear factor κB induced by VPA. Valproic acid induced expression of γ-aminobutyric acid receptors in macrophages, and picrotoxin, a γ-aminobutyric acid A receptor antagonist, inhibited the VPA-activated phosphorylation of ERK and VPA-induced HMGB1 release. These results suggest that VPA may exacerbate innate immune responses to endotoxin through enhanced release of HMGB1.
authors: Department of Oral Disease Research, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan.
authors: Shinsuke
authors: S
authors: Sugiura
authors: Yuichi
authors: Y
authors: Ishihara
authors: Toshinori
authors: T
authors: Komatsu
authors: Makoto
authors: M
authors: Hagiwara
authors: Naomi
authors: N
authors: Tanigawa
authors: Yoshiko
authors: Y
authors: Kato
authors: Hiroki
authors: H
authors: Mizutani
authors: Ko-ichi
authors: K
authors: Kawahara
authors: Ikuro
authors: I
authors: Maruyama
authors: Toshihide
authors: T
authors: Noguchi
authors: Kenji
authors: K
authors: Matsushita
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D019446:Endotoxemia / Q000139:chemically induced* / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014635:Valproic Acid / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D005419:Flavonoids; D024243:HMGB1 Protein; D008070:Lipopolysaccharides; D016328:NF-kappa B; D014635:Valproic Acid; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one