Activation of nuclear factor kappa B and cytokine imbalance in experimental alcoholic liver disease in the rat

Inflammatory stimuli and lipid peroxidation activate nuclear factor kappa B (NF-kappa B) and upregulate proinflammatory cytokines and chemokines, The present study evaluated the relationship between pathological liver injury, endotoxemia, lipid peroxidation, and NF-kappa B activation and imbalance b etween pro- and anti-inflammatory cytokines. Rats (5 per group) were fed et hanol and a diet containing saturated fat, palm oil, corn oil, or fish oil by intragastric infusion. Dextrose isocalorically replaced ethanol in contr ol rats. Pathological analysis was performed and measurements of endotoxin were taken, lipid peroxidation, NF-kappa B, and messenger RNA (mRNA) levels of proinflammatory cytokines (tumor necrosis factor-alpha [TNF alpha], int erleukin-1 beta [IL-1 beta], interferon-gamma, [IFN-gamma], and IL-12), C-C chemokines (regulated upon activation, normal T cell expressed and secrete d [RANTES], monocyte chemotactic protein [MCP]-1, macrophage inflammatory p rotein [MIP]-1 alpha), C-X-C chemokines (cytokine induced neutrophil chemoa ttractant (CINC), MIP-2, IP-10, and epithelial neutrophil activating protei n [ENA]-78), and anti-inflammatory cytokines (IL-10, IL-4, and IL-13), Acti vation of NF-kappa B and increased expression of proinflammatory cytokines C-C and C-X-C chemokines was seen in the rats exhibiting necroinflammatory injury (fish oil-ethanol [FE] and corn oil-ethanol[CE]). These groups also had the highest levels of endotoxin and lipid peroxidation, Levels of IL-10 and IL-4 mRNA were lower in the group exhibiting inflammatory liver injury . Thus, activation of NF-kappa B occurs in the presence of proinflammatory stimuli and results in increased expression of proinflammatory cytokines an d chemokines, The Kupffer cell is probably the major cell type showing acti vation of NF-kappa B although the contribution of endothelial cells and hep atocytes cannot be excluded. Downregulation of antiinflammatory cytokines m ay additionally exacerbate liver injury.