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ToxSci Advance Access published online on November 22, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfl173
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received September 7, 2006
Accepted November 12, 2006

Review

Role of the Kupffer Cell in Mediating Hepatic Toxicity and Carcinogenesis

Ruth A. Roberts 1 *, Patricia E Ganey 2, Cynthia Ju 3, Lisa M. Kamendulis 4, Ivan Rusyn 5, and James E. Klaunig 4

1 AstraZeneca, Safety Assessment Alderley Park, Macclesfield, Cheshire, United Kingdom
2 Michigan State University, Department of Pharmacology and Toxicology, East Lansing, MI, USA
3 University of Colorado Health Sciences Center, Department of Pharmaceutical Sciences, Denver, CO, USA
4 University of North Carolina School of Public Health, Department of Environmental Sciences and Engineering, Chapel Hill, NC, USA
5 Indiana University School of Medicine, Department of Pharmacology and Toxicology, Indianapolis, IN, USA

* To whom correspondence should be addressed.
Ruth A. Roberts, E-mail: ruth.roberts{at}astrazeneca.com


  Abstract

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.


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