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Effect of the 21-aminosteroid on nuclear factor-kappa B activation of Kupffer cells in endotoxin shock.

AbstractBACKGROUND:
The 21-aminosteroid (U-74389G) is a nonglucocorticoid steroid that was synthesized to inhibit lipid peroxidation without the glucocorticoid activity. We recently demonstrated that the 21-aminosteroid administered to endotoxin shock mice reduces liver injury and improves the survival rate of mice through inhibition of nuclear factor-kappa B activation in the liver. The study was undertaken to determine whether the 21-aminosteroid could suppress pro-inflammatory gene up-regulation through inhibition of nuclear factor-kappa B activation in Kupffer cells.
METHODS:
Kupffer cells were isolated from rats by collagenase perfusion followed by pronase digestion. After a lipopolysaccharide addition, each assay was performed for tumor necrosis factor-alpha, interleukin-6, tumor necrosis factor-alpha messenger RNA, nuclear factor-kappa B, and I kappa B proteins.
RESULTS:
After the lipopolysaccharide addition, Kupffer cells released both tumor necrosis factor-alpha and interleukin-6. The 21-aminosteroid treatment suppressed the release of tumor necrosis factor-alpha in a dose-dependent manner. The 21-aminosteroid also inhibited the increase of tumor necrosis factor-alpha messenger RNA expression and nuclear factor-kappa B activation in Kupffer cells 1 hour and 30 minutes, respectively, after lipopolysaccharide addition. Furthermore, the 21-aminosteroid treatment suppressed the degradation of I kappa B proteins in lipopolysaccharide-stimulated Kupffer cells.
CONCLUSIONS:
These results suggest that the 21-aminosteroid inhibits release of the tumor necrosis factor-alpha and interleukin-6 from lipopolysaccharide-stimulated Kupffer cells by inhibiting nuclear factor-kappa B activation. This is accomplished by inhibiting I kappa B degradation in endotoxin shock and this may prove useful for the treatment of endotoxin shock.
AuthorsK Okada, S Marubayashi, K Fukuma, K Yamada, K Dohi
JournalSurgery (Surgery) Vol. 127 Issue 1 Pg. 79-86 (Jan 2000) ISSN: 0039-6060 [Print] United States
PMID10660762 (Publication Type: Journal Article)
Chemical References
  • Antioxidants
  • I-kappa B Proteins
  • Interleukin-6
  • Lipopolysaccharides
  • NF-kappa B
  • Pregnatrienes
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • U 74389F
Topics
  • Animals
  • Antioxidants (pharmacology)
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • I-kappa B Proteins (antagonists & inhibitors, metabolism)
  • Interleukin-6 (antagonists & inhibitors, metabolism)
  • Kupffer Cells (drug effects, metabolism, physiology)
  • Lipopolysaccharides (pharmacology)
  • Male
  • NF-kappa B (antagonists & inhibitors, physiology)
  • Pregnatrienes (pharmacology)
  • RNA, Messenger (antagonists & inhibitors)
  • Rats
  • Rats, Wistar
  • Shock, Septic (pathology, physiopathology)
  • Tumor Necrosis Factor-alpha (antagonists & inhibitors, genetics, metabolism)

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