THE ROLE OF TNF IN HEPATOTOXICITY

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Tumor necrosis factor alpha (TNFalpha) has been demonstrated to be a primary mediator of endotoxin shock. One mechanism of TNF-induced injury is via the activation of NF-kB and the generation of reactive oxygen species. We have hypothesized that 2,3,7,8- tetrachlorodibenzodioxin (TCDD) -induced endotoxin hypersensitivity and subsequent induction of apoptosis may occur through modulation of TNFalpha signaling pathways. Recent efforts in our laboratory have focused on in vivo models of endotoxin hypersensitivity and the relationship between TNFalpha signaling and oxidative stress. We have characterized the kinetics of TCDD-induced hepatic damage in the liver by evaluating serum enzyme levels and quantitating apoptotic cells, and have evaluated alterations in gene expression at critical time points. We have shown that when rodents are treated with TCDD prior to endotoxin exposure a significant increase in toxicity occurs, and that inhibition of protein synthesis with cycloheximide blocks the TCDD- induced sensitivity to TNFalpha in this model. Expression of mRNA for genes associated with the TNF and Fas apoptotic pathways have been quantitated in liver tissue from control and treated animals using RT- PCR. TCDD modulated endotoxin-regulated early expression of Fas and altered the expression of TNFalpha and nuclear factor kappa B (NFKB). TCDD alone stimulated the expression NFKB gene expression but did not affect DNA binding. Expression of IKB-alpha and -beta was not affected by TCDD treatment. Additional studies have examined the effects of TCDD and correlation between TNF induction and nitric oxide production (as measured by detection of the 5 coordinate nitrosyl heme complexes) in F344 rats. Doses below 5 mg/kg TCDD did not increase nitric oxide levels in endotoxin-treated rats. However, at 50 mg/kg TCDD there was a significant elevation in nitrosyl hemoglobin detected in venous blood by electron paramagnetic resonance spectroscopy. The concentration profile of ferrous nitrosyl hemoproteins detected in both livers and kidneys were similar to that detected in blood. This project was previously reported as part of Z01 ES 30106 23 LT - tumor necrosis factor alpha, tetrachlorodibenzodioxin, endotoxin, apoptosis, Kupffer cells, hepatotoxicity, B6C3F1 mice