Acute treatment of B6C3F1 mice with a hepatotoxic dose (500 mg/kg) of carbon tetrachloride (CCl4) produced a marked but transient increase in transforming growth factor β1 (TGF-β1) mRNA expression in the liver within 24 hr. We have previously shown that an identical dose of CCl4 also produces a marked increase in serum TGF-β1 concentrations which peak at 48 hr and produce a marked inhibition of the anti-sRBC IgM antibody forming cell (AFC) response. Similar increases in TGF-β1 transcripts in the liver were also induced by an acute hepatotoxic dose (600 mg/kg) of acetaminophen. No increase in TGF-β1 mRNA expression was detected in the spleen following treatment with either agent. Direct addition of TGF-β1 (0.05-1.0 ng/ml) to naive splenocyte cultures produced a marked and dose-related inhibition of the anti-sRBC IgM AFC response. Under the same conditions, TGF-β1 induced a marked decrease in IL-4 and IL-5 mRNA expression in sRBC-sensitized splenocytes. Concomitantly, TGF-β1 induced a rapid increase in NF-κB/Rel trans-acting factor binding within the first 24 hr post-sRBC sensitization of splenocytes. Conversely, NF-κB/Rel binding activity was inhibited on Days 2 through 4 in sRBC-sensitized splenocytes in the presence of TGF-β1. The increase in NF-κB/Rel binding within 24 hr following sRBC sensitization is consistent with the positive influence TGF-β1 exerts on Th1 cytokines such as IL-2 and IFN-γ. Conversely the decrease in NF-κB/Rel binding at the later time period during the AFC response (Days 2-4) coincides with the inhibitory effects TGF-β1 exerted on IgM production by B cells.
Bibliographical noteFunding Information:
1This work was supported by funds from NIEHS Grant PO1-94-007. 2Present address: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Taejon, Korea.