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Am J Physiol Gastrointest Liver Physiol (May 14, 2003). doi:10.1152/ajpgi.00442.2002
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Submitted on October 15, 2002
Accepted on May 14, 2003

TNF{alpha} induced cell killing in ethanol-exposed cells is dependent on p38 MAPK signaling but independent of Bid and caspase-8

John G. Pastorino1*, Nataly Shulga1, and Jan B. Hoek1

1 Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA

* To whom correspondence should be addressed. E-mail: John.Pastorino{at}jefferson.edu.

Alcoholic liver disease is associated with an increase in the number of necrotic and apoptotic liver parenchymal cells. Part of this injury is mediated by TNF{alpha}. Ethanol exposure sensitizes cells to the cytotoxic effects of TNF{alpha}. This may be due in part to the increased propensity of the mitochondria in ethanol-exposed cells to induction of the mitochondrial permeability transition (MPT) by various agents including the proapoptotic protein, Bax. This idea is supported by the observation that the increased cell death induced by TNF{alpha} in ethanol-exposed cells was dependent on development of the MPT. In the present study we elucidate the pathways through which ethanol exposure enhances TNF{alpha} induction of the MPT and the resulting cytotoxicity. Specifically, ethanol exposed cells display caspase-8 and Bid independent cell killing during TNF{alpha} treatment. Moreover, the ethanol-enhanced pathway is dependent on p38 MAPK signaling, which brings about caspase-3 activation, mitochondrial depolarization, accumulation of cytochrome c in the cytosol and the translocation of Bax to the mitochondria. Additionally, ethanol-exposed cells display a blunting of TNF{alpha} induced Akt activation and BAD phosphorylation that may account in part for the increased sensitivity of the mitochondria to Bax mediated damage.




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