RT Journal Article SR Electronic T1 Antisense Oligonucleotide Inhibition of Bcl-xL and Bid Expression in Liver Regulates Responses in a Mouse Model of Fas-Induced Fulminant Hepatitis JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 24 OP 33 DO 10.1124/jpet.103.050435 VO 307 IS 1 A1 Hong Zhang A1 Jennifer Taylor A1 Doreen Luther A1 Joe Johnston A1 Susan Murray A1 Jacqueline R. Wyatt A1 Andrew T. Watt A1 Seongjoon Koo A1 Cathie York-DeFalco A1 Kimberly Stecker A1 Nicholas M. Dean YR 2003 UL http://jpet.aspetjournals.org/content/307/1/24.abstract AB Activation of the cell-surface receptor Fas can lead to apoptosis in parenchymal cells in the liver, and if severe enough, result in fulminant hepatic failure and animal death. In the present study, we have examined the roles played by the Bcl-2 family members Bcl-xL and Bid in regulating this response. To do this, we have developed chemically modified 2′-O-(2-methoxy) ethyl antisense inhibitors of both Bid and Bcl-xL expression. In Balb/c mice, dosing with these antisense oligonucleotides reduced expression of the targeted mRNA by greater than 80% in the liver. This reduction was highly dependent upon oligonucleotide sequence and oligonucleotide dose. Reduction of Bcl-xL expression resulted in a potentiation of Fas-mediated apoptosis in liver and significant increase of the lethality of Fas-mediated fulminant hepatitis (p < 0.0001). In contrast, reduction of Bid expression protected the animals against Fas-mediated fulminant hepatitis and death (p < 0.0001). Simultaneous dosing of mice with Bcl-xL and Bid-targeting antisense oligonucleotides resulted in an inhibition of expression of both targeted proteins and protection of the animals from Fas-mediated apoptosis. These results demonstrate, for the first time, the role of Bcl-xL in regulating responses to proapoptotic Fas signaling in mouse liver. In addition, this is the first reported example demonstrating the ability of antisense inhibitors to reduce expression of multiple proteins in animals by simultaneous dosing. The American Society for Pharmacology and Experimental Therapeutics