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Tumor necrosis factor alpha modulates transforming growth factor alpha espression following chemically-induced hepatoxicity.
Gallucci RM; Toriumi W; Simeonova PP; Luster MI
Toxicologist 1998 Mar; 42(1-S):272
Previous studies have shown that Tumor Necrosis Factor-a (TNF-a) expression is increased in the livers of experimental animals following exposure to the hepatotoxin carbon tetrachloride (CCl4). In addition, administering neutralizing antibodies to TNF-a (anti- TNF-a) prior to exposure to CCI4 delays the regenerative process of the liver. We hypothesized that TNF-a may influence liver regenerative processes through modulation of liver derived growth factors. Mice were administered anti-TNF-a prior to CCI4 treatment. Antibody treatment did not affect the mRNA expression, as assessed by RT-PCR, of hepatocyte growth factor, its receptor c-met, epidermal growth factor, epidermal growth factor receptor (EGFR), or acidic fibroblast growth factor. Anti- TNF-a also did not affect liver EGFR number or binding. However, anti- TNF-a decreased the expression of transforming growth factor alpha (TGF-a) approximately 2.5 fold 12 and 24 hours post CC14, administration. To confirm this finding ribonuclease protection assays were performed and similar results to that shown with RT- PCR were found. lnterleukin-6 (IL6) has been shown to be necessary for liver regeneration following partial hepatectomy, and TNF-a can induce the expression of IL6 in liver. To assess whether TNF-a directly modulates TGF- a expression in the murine liver, recombinant murine TNF-a or recombinant murine IL6 was administered. TNF-a upregulated TGF-a expression approximately four fold above control levels, whereas IL6 did not affect TGF-a mRNA expression 90 minutes post injection. Taken together, these data indicate that TNF-a modulates the expression of TGF-a in the liver following hepatotoxic injury with CCI4, and that this modulation is independent of IL6 induction.
Tumors; Liver-function; Liver-disorders; Liver-damage; Liver-tissue; Animal-studies; Animals; Laboratory-animals; Hepatotoxicity; Hepatotoxins
The Toxicologist. Society of Toxicology 37th Annual Meeting, March 1-5,1998, Seattle, Washington
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