title: Induction of liver-associated transforming growth factor beta 1 (TGF-beta 1) mRNA expression by carbon tetrachloride leads to the inhibition of T helper 2 cell-associated lymphokines.
abstract: 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 beta 1 (TGF-beta 1) 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-beta 1 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-beta 1 transcripts scripts in the liver were also induced by an acute hepatotoxic 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 splenocyte cultures produced a marked and dose-related inhibition of the anti-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/Rel trans-acting factor binding within the first 24 hr post-sRBC sensitization of splenocytes. Conversely, NF-kappa B/Rel binding activity was inhibited on Days 2 through 4 in sRBC-sensitized splenocytes in the presence of TGF-beta 1. The increase in NF-kappa B/Rel binding within 24 hr following sRBC sensitization is consistent with the positive influence TGF-beta 1 exerts on Th1 cytokines such as IL-2 and IFN-gamma. Conversely the decrease in NF-kappa B/Rel binding at the later time period during the AFC response (Days 2-4) coincides with the inhibitory effects TGF-beta 1 exerted on IgM production by B cells.
authors.affiliation: Department of Pharmacology & Toxicology, Michigan State University, East Lansing, USA.
authors.forename: Y J
authors.initials: YJ
authors.lastname: Jeon
authors.forename: S H
authors.initials: SH
authors.lastname: Han
authors.forename: K H
authors.initials: KH
authors.lastname: Yang
authors.forename: N E
authors.initials: NE
authors.lastname: Kaminski
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology; D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D007075:Immunoglobulin M / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008222:Lymphokines / Q000037:antagonists & inhibitors*; D051379:Mice; D008815:Mice, Inbred Strains; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D011247:Pregnancy; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics*; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics*
chemical_list: D007075:Immunoglobulin M; D008222:Lymphokines; D016328:NF-kappa B; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D000082:Acetaminophen; D002251:Carbon Tetrachloride