Effect of the 21-aminosteroid on nuclear factor-κB activation of Kupffer cells in endotoxin shock

• Published in: Surgery 2000-01, Vol.127 (1), p.79-86
• Main Authors: Okada, Kazuro, Marubayashi, Seiji, Fukuma, Kazuyuki, Yamada, Kazuo, Dohi, Kiyohiko
• Format: Article
• Language: English
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Antioxidants - pharmacology; Biological and medical sciences; Cells, Cultured; Dose-Response Relationship, Drug; Emergency and intensive care: infection, septic shock; I-kappa B Proteins - antagonists & inhibitors; I-kappa B Proteins - metabolism; Intensive care medicine; Interleukin-6 - antagonists & inhibitors; Interleukin-6 - metabolism; Kupffer Cells - drug effects; Kupffer Cells - metabolism; Kupffer Cells - physiology; Lipopolysaccharides - pharmacology; Male; Medical sciences; NF-kappa B - antagonists & inhibitors; NF-kappa B - physiology; Pregnatrienes - pharmacology; Rats; Rats, Wistar; RNA, Messenger - antagonists & inhibitors; Shock, Septic - pathology; Shock, Septic - physiopathology; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0039-6060; 1532-7361
• DOI: 10.1067/msy.2000.102425

Background: 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-κB 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-κB 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-α, interleukin-6, tumor necrosis factor-α messenger RNA, nuclear factor-κB, and IκB proteins. Results: After the lipopolysaccharide addition, Kupffer cells released both tumor necrosis factor-α and interleukin-6. The 21-aminosteroid treatment suppressed the release of tumor necrosis factor-α in a dose-dependent manner. The 21-aminosteroid also inhibited the increase of tumor necrosis factor-α messenger RNA expression and nuclear factor-κB activation in Kupffer cells 1 hour and 30 minutes, respectively, after lipopolysaccharide addition. Furthermore, the 21-aminosteroid treatment suppressed the degradation of IκB proteins in lipopolysaccharide-stimulated Kupffer cells. Conclusions: These results suggest that the 21-aminosteroid inhibits release of the tumor necrosis factor-α and interleukin-6 from lipopolysaccharide-stimulated Kupffer cells by inhibiting nuclear factor-κB activation. This is accomplished by inhibiting IκB degradation in endotoxin shock and this may prove useful for the treatment of endotoxin shock. (Surgery 2000;127:79-86)