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Effects of Antisense Oligonucleotide-Mediated Depletion of Tumor Necrosis Factor (TNF) Receptor 1-Associated Death Domain Protein on TNF-Induced Gene Expression

Isis Pharmaceuticals, Carlsbad, California (A.M.S., S.K., E.L.M., B.P.M., B.F.B.); and Interdepartmental Program in Vascular Biology and Transplantation, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, Connecticut (L.A.M., J.S.P.)

Tumor necrosis factor (TNF) receptor 1-associated death domain protein (TRADD) is an adaptor protein known to be involved in the TNF signaling pathway as well as signaling of other members of the TNF receptor superfamily, including DR3, DR6, p75^NTR, and the Epstein-Barr virus latent membrane protein 1. Current knowledge of the function of the adaptor protein has been derived from studies examining its over-expression in either wild-type or mutated forms. In this study, we analyzed the consequences of antisense oligonucleotide (ASO)-mediated depletion of endogenous TRADD on TNF induction of inflammation-related gene products, such as intercellular adhesion molecule-1, and associated kinase signaling pathways in human umbilical vein endothelial cells. A broader perspective of TRADD's role in TNF signaling was indicated by microarray gene expression analysis, where 20 of 24 genes that showed a 5-fold or greater increase in TNF-induced mRNA expression levels displayed a reduction in TNF-induced expression as a consequence of ASO-mediated knockdown of TRADD. Reduced activation of the nuclear factor-B and c-Jun NH₂-terminal kinase pathways, as measured by IB- protein levels and the extent of c-Jun phosphorylation, was also observed. These results indicate usage of antisense inhibitors of TRADD expression for modulating diseases associated with TRADD-dependent signal transduction pathways.

Address correspondence to: Brenda F. Baker, Isis Pharmaceuticals, Inc., 2292 Faraday Avenue, Carlsbad, CA 92008. E-mail: bbaker{at}isisph.com

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