ToxSci Advance Access originally published online on November 22, 2006
Toxicological Sciences 2007 96(1):2-15; doi:10.1093/toxsci/kfl173
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Role of the Kupffer Cell in Mediating Hepatic Toxicity and Carcinogenesis
* AstraZeneca, Safety Assessment Alderley Park, Macclesfield, Cheshire, SK10 4TG United Kingdom
Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan MI 48824
Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, Denver, Colorado CO 80262
Department of Environmental Sciences and Engineering, University of North Carolina School of Public Health, Chapel Hill, North Carolina IN 46202
¶ Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana NC 27599-7431
1 To whom correspondence should be addressed. Fax: +44 (0) 1625 516031. E-mail: ruth.roberts{at}astrazeneca.com.
Received September 7, 2006; accepted November 12, 2006
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Abstract |
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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.
Key Words: Kupffer cell; hepatocarcinogenesis; liver; hepatotoxicity; mode of action; adverse drug reactions.
Symposium held at the 40th Annual Meeting of the Society of Toxicology (SOT), San Diego, California. Sponsored by the Carcinogenesis Speciality Section.
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