Selenoorganic compound, ebselen, inhibits nitric oxide and tumor necrosis factor-α production by the modulation of Jun-N-terminal kinase and the NF-κb signaling pathway in rat Kupffer cells
✍ Scribed by Naoya Shimohashi; Makoto Nakamuta; Koutaro Uchimura; Rie Sugimoto; Hiroaki Iwamoto; Munechika Enjoji; Hajime Nawata
- Publisher
- John Wiley and Sons
- Year
- 2000
- Tongue
- English
- Weight
- 267 KB
- Volume
- 78
- Category
- Article
- ISSN
- 0730-2312
No coin nor oath required. For personal study only.
✦ Synopsis
In response to the bacterial endotoxin, LPS, Kupffer cells are induced to express NO and TNF-␣. These compounds are involved in hepatic inflammation/injury, especially that associated with endotoxic shock. In this study, we demonstrate that ebselen (2-phenyl-1,2-benzisoselenazol-3[2H]one), a selenoorganic compound, blocks LPSinduced NO and TNF-␣ production by cultured rat liver Kupffer cells. LPS can activate both the NF-B signaling pathway and MAPK signal transduction pathways such as JNK and p38 MAPK. We find that ebselen inhibits LPS-induced NF-B nuclear translocalization, and also suppresses the LPS-induced phosphorylation of JNK, but not the phosphorylation of p38 MAPK. This inhibition of signal transduction leads to a decrease in the transcription of TNF-␣ and the inducible isoform of NO. Furthermore, ebselen inhibits LPS-induced COX-2 expression, which is responsible for proinflammatory prostaglandin production, without affecting constitutive COX-1 expression. These data suggest the mechanism by which ebselen acts as an antiinflammatory agent, and also suggest that ebselen may be potent in preventing hepatic injury such as endotoxic shock, in which Kupffer cell activation has been implicated.