Selenoorganic compound, ebselen, inhibits nitric oxide and tumor necrosis factor-alpha production by the modulation of jun-N-terminal kinase and the NF-kappab signaling pathway in rat Kupffer cells.
In response to the bacterial endotoxin, LPS, Kupffer cells are induced to express NO and TNF-alpha. 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 LPS-induced NO and TNF-alpha production by cultured rat liver Kupffer cells. LPS can activate both the NF-kappaB signaling pathway and MAPK signal transduction pathways such as JNK and p38 MAPK. We find that ebselen inhibits LPS-induced NF-kappaB 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-alpha 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.
Shimohashi
N
N
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Nakamuta
M
M
Uchimura
K
K
Sugimoto
R
R
Iwamoto
H
H
Enjoji
M
M
Nawata
H
H
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001393:Azoles / Q000494:pharmacology*; D015153:Blotting, Western; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005455:Fluorescent Antibody Technique; D007527:Isoenzymes / Q000378:metabolism; D054833:Isoindoles; D048031:JNK Mitogen-Activated Protein Kinases; D007728:Kupffer Cells / Q000201:enzymology*; D008070:Lipopolysaccharides / Q000378:metabolism; D008099:Liver / Q000293:injuries; D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000378:metabolism; D016566:Organoselenium Compounds / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011453:Prostaglandins / Q000096:biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012772:Shock, Septic / Q000517:prevention & control; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D048051:p38 Mitogen-Activated Protein Kinases
D000975:Antioxidants; D001393:Azoles; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D054833:Isoindoles; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D016328:NF-kappa B; D009573:Nitrites; D016566:Organoselenium Compounds; D011453:Prostaglandins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; C042986:ebselen; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases