Role of the Kupffer cell in mediating hepatic toxicity and carcinogenesis

Toxicol Sci. 2007 Mar;96(1):2-15. doi: 10.1093/toxsci/kfl173. Epub 2006 Nov 22.


Kupffer cells are resident macrophages of the liver and play an important role in its normal physiology and homeostasis as well as participating in the acute and chronic responses of the liver to toxic compounds. Activation of Kupffer cells directly or indirectly by toxic agents results in the release of an array of inflammatory mediators, growth factors, and reactive oxygen species. This activation appears to modulate acute hepatocyte injury as well as chronic liver responses including hepatic cancer. Understanding the role Kupffer cells play in these diverse responses is key to understanding mechanisms of liver injury. Idiosyncratic drug-induced liver disease results in morbidity and mortality, impacting severely on the development of new pharmacological agents. Modulation of the response of Kupffer cells by drugs has been suggested as a cause for the idiosyncratic response. Similarly, liver damage seen in chronic ethanol consumption appears to be modulated by Kupffer cell activation. More recent evidence has noted a contributory role of Kupffer cell activation in the process of hepatic carcinogenesis. Several nongenotoxic carcinogens, for example, activate Kupffer cells resulting in the release of cytokines and/or reactive oxygen species that induce hepatocyte cell proliferation and may enhance clonal expansion of preneoplastic cells leading to neoplasia. Kupffer cells therefore appear to play a central role in the hepatic response to toxic and carcinogenic agents. Taken together, the data presented in this symposium illustrate to the toxicologist the central role played by Kupffer cells in mediating hepatotoxicity.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Acute Disease
  • Animals
  • Carcinogens / toxicity
  • Cell Proliferation
  • Cell Transformation, Neoplastic / metabolism
  • Chemical and Drug Induced Liver Injury / metabolism
  • Cytokines / metabolism
  • Drug Hypersensitivity / metabolism
  • Hepatitis, Alcoholic / metabolism
  • Hepatocytes / metabolism
  • Humans
  • Kupffer Cells / drug effects
  • Kupffer Cells / metabolism*
  • Kupffer Cells / pathology
  • Liver / drug effects
  • Liver / metabolism*
  • Liver / pathology
  • Liver Diseases / metabolism*
  • Liver Diseases / pathology
  • Liver Neoplasms / chemically induced
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / pathology
  • PPAR alpha / agonists
  • Peroxisome Proliferators / toxicity
  • Precancerous Conditions / chemically induced
  • Precancerous Conditions / metabolism*
  • Precancerous Conditions / pathology
  • Reactive Oxygen Species / metabolism


  • Carcinogens
  • Cytokines
  • PPAR alpha
  • Peroxisome Proliferators
  • Reactive Oxygen Species