IL-6, IFN-gamma and TNF-alpha production by liver-associated T cells and acute liver injury in rats administered concanavalin A

The relationship between the development of acute hepatitis and the product ion of TNF-alpha IFN-gamma and IL-6 by liver-associated T lymphocytes follo wing intravenous injection of concanavalin A (Con A) was studied in rats. F ollowing a single injection of Con A, there was a dose and time-dependent c orrelation in the serum levels of serum alanine aminotransferase (ALT), IL- 6, IFN-gamma and TNF-alpha. These increases correlated with an increase in the numbers of CD4(+), CD8(+) and CD25(+) T cells in blood and CD4(+) and C D25(+) T cells in the liver perfusate, but not with CD8(+) T cells in liver perfusate. Increased levels of IL-6, IFN-gamma and TNF-alpha were constitu tively produced by liver-associated CD4(+) T cells when cultured. In Con A- stimulated cultures, liver-associated CD4(+) T cells secreted increasing le vels of TNF-alpha in a time-dependent manner following Con A injection, but TNF-alpha production by peripheral blood lymphocytes was transient with pe ak levels detected at I h which then declined over 24 h. Histological exami nation of the liver revealed fatty change, hepatocyte degeneration and necr osis, with an associated cell infiltrate of neutrophils and CD4(+) T cells both in the portal areas and around the central veins. These results suppor t the hypothesis that Con A-induced liver damage is mediated by CD4(+) T ce lls acting within the liver, at least in part through the secretion of TNF- alpha, IFN-gamma and IL-6.