ETHANOL PROMOTES CELL-DEATH BY INHIBITION OF THE INSULIN-LIKE-GROWTH-FACTOR-I RECEPTOR

The mechanism by which chronic alcohol abuse induces widespread cell a nd tissue damage is unknown. Insulin-like growth factor I (IGF-I) is a n important inhibitor of apoptosis in many cell types, in addition to its ability to stimulate proliferation. We have demonstrated previousl y (J. Biol. Chem. 268:21777-21782, 1993; Lab. Invest. 71:657-662, 1994 ) that ethanol in low concentrations inhibits the tyrosine autophospho rylation of the IGF-I receptor (IGF-IR) and IGF-I-mediated cell prolif eration. We now demonstrate that ethanol reverses the antiapoptotic ac tion of the IGF-IR in a tumor necrosis factor-alpha (TNF-alpha) model of apoptosis. In serum-depleted medium, IGF-I markedly protected BALB/ c3T3 cells from TNF-alpha-induced apoptosis. Ethanol reversed the prot ective action of IGF-I, but did not enhance TNF-alpha killing in the a bsence of IGF-I. Half-maximal effective concentrations of ethanol were 5 to 10 mM. In the presence of 5 to 10% fetal bovine serum, TNF-alpha was cytotoxic for 3T3 cells only in the presence of ethanol. Mouse em bryo fibroblasts with targeted knockout of the IGF-IR were completely insensitive to ethanol, in contrast with the ethanol-induced potentiat ion of apoptosis in wild-type cells. These results indicate that ethan ol directly interacts with cellular factors that inhibit apoptosis and could provide a novel mechanism for ethanol-induced cytotoxicity in g eneral.