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ToxSci Advance Access published online on April 15, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg047
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received November 22, 2002; accepted January 23, 2003
© 2003 Society of Toxicology

Immunotoxicology

Alcohol Consumption Decreases IL-2 Induced NF-{kappa}B Activity in Enriched NK Cells from C57BL/6 Mice

J. Zhou 1 G.G. Meadows 1*

1 Cancer Prevention & Research Center and the Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Pullman, WA 99164-6510

* To whom correspondence should be addressed. E-mail: meadows{at}wsu.edu.


  Abstract

Previously we showed that ethanol (EtOH) consumption suppressed IL2-induced cytolytic activity of murine splenic natural killer (NK) cells. Although IL2 receptor signaling is involved in activation of NK cells, neither the mechanism for this activation nor the role of EtOH consumption in modulating activation are completely understood. In this study we show by EMSA that enriched splenic NK cells from EtOH-consuming C57BL/6 mice exhibit reduced NF-{kappa}B and AP1 binding activity in response to IL2 stimulation as compared to the water-drinking mice. Semi-quantitative RT-PCR and real time PCR analyses indicated that EtOH consumption inhibits the induction of perforin, granzyme A, and granzyme B in response to IL2. PDTC and TPCK blocked NF{kappa}B and AP-1 binding activity in nuclear extracts of IL2-stimulated NK cells in an EMSA and also inhibited the IL2-induced expression of perforin, granzyme A, and granzyme B gene expression in enriched NK cells. These inhibitors dramatically suppressed IL2 stimulated NK cytolytic activity against YAC-1 lymphoma target cells. Taken together these results suggest that NF{kappa}B and AP-1 are important regulators of NK cell cytolytic function through regulation of perforin, granzyme A and granzyme B gene expression. The findings further suggest that the decreased cytolytic activity of IL2-stimulated NK cytolytic activity in EtOH-consuming mice is due at least in part to impaired transactivation of the these and possibly other genes involved in control of NK cell target lysis.

NF{kappa}B, AP1, NK cells, IL2, Ethanol, Perforin, Granzyme A, Granzyme B .


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