Induction of Early-Immediate Genes by Tumer Necrosis Factor Alpha Contribute to Liver Repair Following Chemical-Induced Hepatotoxicity

Details

• Personal Author:
  Blackshear P ; Bruccoleri A ; Gallucci R ; Germolec DR ; Luster MI ; Simeonova P ; Thurman RG
• Description:
  We and others have shown that tumor necrosis factor alpha (TNF-alpha) expression is increased in the livers of experimental animals following exposure to the chemical hepatotoxin, carbon tetrachloride (CCl4). Because TNF-alpha is involved in mediating inflammatory responses, its elevated expression is presumed to be associated with potentiating hepatotoxicity and/or aiding in liver repair processes. To study the role of TNF-alphachemical-induced hepatotoxicity, mice were administered neutralizing antibodies to TNF-alpha before administration of low, but hepatotoxic, doses of CCl4. Antibody treatment prevented CCl4-mediated increases in early-immediate gene expression associated with liver regeneration, including expression of c-jun and c-fos proto- oncogenes, as well as DNA binding of the activator protein-1 (AP-1) nuclear transcription factor. Hepatocyte proliferation following CCl4 treatment was also reduced in anti-TNF-alpha antibody-treated mice, as evidenced by a lack of proliferating cell nuclear antigen (PCNA) staining. Antibody treatment slightly delayed liver repair processes, as evidenced by extending the period in which plasma liver enzyme levels were increased and hepatocellular necrosis could be observed. Consistent with the above observations, injection of recombinant TNF-alpha into control mice induced rapid expression of c-jun and c-fos proto-oncogenes. Taken together, these results indicate that TNF-alpha positively modulates liver recovery following CCl4 exposure presumably by stimulating early-immediate genes involved in hepatic mitogenesis, a phenomenon also observed following partial hepatectomy. [Description provided by NIOSH]
• Subjects:
  Animals Carcinogens Digestive System Digestive System Diseases Laboratories Liver Occupational Health Safety
• Keywords:
  Animal-studies Cell-damage Cell-growth Cellular-function Free-radical-generation Gene-mutation Genotoxic-effects Hepatotoxicity Laboratory-animals Liver-cells Liver-damage Liver-disorders Tumorigens

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• ISSN:
  0270-9139
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  North Carolina ; OSHA Region 3 ; OSHA Region 4 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  133-141
• Volume:
  25
• Issue:
  1
• NIOSHTIC Number:
  nn:20033961
• Citation:
  Hepatology 1997 Jan; 25(1):133-141
• Contact Point Address:
  M. Luster, Ph.D., Toxicology and Molecular Microbiology Branch, National Institute for Occupational Safety and Health, 1095 Willowdale Rd., MS-3014, Morgantown, WV, 26505-2888
• CAS Registry Number:
  Carbon tetrachloride (CAS RN 56-23-5)
• Federal Fiscal Year:
  1997
• Peer Reviewed:
  True
• Source Full Name:
  Hepatology
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:dfad433903cf31e615ddc9d6ec6ff7dbd011c07476d046668c7e9163a309dac8f86077dcee724609f75cad1654754e9273cc120ac4ff15d710d04691abb428b5
• Download URL:
  https://stacks.cdc.gov/view/cdc/189357/cdc_189357_DS1.pdf
• File Type:
  [PDF - 2.22 MB ]