Ascorbic acid ameliorates T cell-mediated acute liver injury in gulo-/- mice (173.41)

Abstract

Abstract Deficiency of ascorbic acid (vitamin C) is thought to be contributed to the pathogenesis of liver diseases. To clarify the role of vitamin C in protection from liver injury, we induced concanavalin A (Con A)-mediated hepatitis in vitamin C-insufficient gulo-/- mice, which cannot synthesize vitamin C like humans. In Con A-treated vitamin C-insufficient gulo-/- mice, the extensive production of pro-inflammatory cytokines, such as IFN-gamma and TNF-alpha was observed in plasma and liver. Moreover, extensive liver damage and apoptosis of hepatocytes were also found. Increased numbers of liver-infiltrating T cells in vitamin C-insufficient gulo-/- mice correlated with increase of hepatic levels of IFN-inducible factor (IP-10). Even though IL-22, a hepato-protective cytokine, was highly increased in vitamin C-insufficient gulo-/- mice, IL-22R alpha expression and STAT3 activation followed by IL-22 were not induced in hepatocyte. Finally, we confirmed that vitamin C-insufficient T cells has hyper-proliferating activity and extensive inflammatory cytokine production to Con A. Taken together, vitamin C-insufficiency in vivo causes uncontrolled production of pro-inflammatory cytokines by liver-infiltrating T cells and severe defects on STAT3 activation at the down-stream of IL-22R alpha on hepatocytes and hepatic inflammation deteriorated. It suggests that severe hepatic damages by autoimmune or chronic inflammation could be prevented by the sufficient vitamin C supplementation.