INDUCTION OF LIVER-ASSOCIATED TRANSFORMING-GROWTH-FACTOR BETA-1 (TGF-BETA-1) MESSENGER-RNA EXPRESSION BY CARBON-TETRACHLORIDE LEADS TO THE INHIBITION OF T-HELPER-2 CELL-ASSOCIATED LYMPHOKINES

Acute treatment of B6C3F1 mice with a hepatotoxic dose (500 mg/kg) of carbon tetrachloride (CCl4) produced a marked but transient increase i n transforming growth factor beta 1 (TGF-beta 1) mRNA expression in th e liver within 24 hr, We have previously shown that an identical dose of CCl4 also produces a marked increase in serum TGF-beta 1 concentrat ions which peak at 48 hr and produce a marked inhibition of the anti-s RBC IgM antibody forming cell (AFC) response, Similar increases in TGF -beta 1 transcripts in the liver were also induced by an acute hepatot oxic dose (600 mg/kg) of acetaminophen, No increase in TGF-beta 1 mRNA expression was detected in the spleen following treatment with either agent, Direct addition of TGF-beta 1 (0.05-1.0 ng/ml) to naive spleno cyte cultures produced a marked and dose-related inhibition of the ant i-sRBC IgM AFC response, Under the same conditions, TGF-beta 1 induced a marked decrease in IL-4 and IL-5 mRNA expression in sRBC-sensitized splenocytes. Concomitantly, TGF-beta 1 induced a rapid increase in NF -kappa B/Re1 trans-acting factor binding within the first 24 hr post-s RBC sensitization of splenocytes, Conversely, NF-kappa B/Re1 binding a ctivity was inhibited on Days 2 through 4 in sRBC-sensitized splenocyt es in the presence of TGF-beta 1 The increase in NF-kappa B/Re1 bindin g within 24 hr following sRBC sensitization is consistent with the pos itive influence TGF-beta 1 exerts on Th1 cytokines such as IL-2 and IF N-gamma. Conversely the decrease in NF-kappa B/Re1 binding at the late r time period during the AFC response (Days 2-4) coincides with the in hibitory effects TGF-beta 1 exerted on IgM productin by B cells. (C) 1 997 Academic Press.