title: Activation of the insulin-like growth factor-I receptor inhibits tumor necrosis factor-induced cell death.
abstract: The effect of insulin-like growth factor (IGF) on tumor necrosis factor (TNF)-induced cell killing was determined for mouse BALB/c3T3 fibroblasts in vitro. Cells maintained in 0.5% fetal bovine serum (FBS) were killed by TNF within 6 h in a concentration-dependent manner, an effect that was prevented by IGF-I. TNF-induced cytotoxicity of 3T3 cells that overexpress the human IGF-I receptor (p6 cells) was prevented by IGF-I alone in the absence of serum. TNF-induced cell death was associated with the morphologic features of apoptosis and the release of low-molecular-weight DNA, both of which were prevented by IGF-I. Neither epidermal growth factor (EGF) nor platelet-derived growth factor (PDGF) protected p6 cells from TNF-induced apoptosis. The specific protective action of the IGF-I receptor was demonstrated further by the marked sensitivity to TNF of embryo fibroblasts derived from mice with targeted disruption of the IGF-I receptor (R-cells) but not of fibroblasts derived from wild-type littermates or R-cells transfected with the cDNA for the human IGF-I receptor. Cycloheximide or actinomycin D markedly reduced the protection offered by IGF-I. IGF-I protection of BALB/c3T3 cells persisted for up to 5 days in the presence of PDGF and EGF, whereas IGF-I lost its effectiveness after 2 days in the absence of growth factors. IGF-I did not prevent TNF-induced release of arachidonic acid. The results demonstrate a specific role for the IGF-I receptor in the protection against TNF cytotoxicity. This action of the IGF-I receptor is mediated by protective cytosolic proteins that exhibit a high rate of turnover and whose levels are regulated principally by factors within serum other than IGF-I.
authors.affiliation: Department of Pathology, Anatomy, and Cell Biology, Jefferson Medical College, Philadelphia, Pennsylvania 19107, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Wu
authors.forename: M
authors.initials: M
authors.lastname: Tewari
authors.forename: S
authors.initials: S
authors.lastname: Cui
authors.forename: R
authors.initials: R
authors.lastname: Rubin
mesh_terms: D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis; D016718:Arachidonic Acid / Q000502:physiology; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology / Q000502:physiology*; D051379:Mice; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000502:physiology*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D010982:Platelet-Derived Growth Factor; D011500:Protein Synthesis Inhibitors; D014409:Tumor Necrosis Factor-alpha; D003609:Dactinomycin; D016718:Arachidonic Acid; D004815:Epidermal Growth Factor; D007334:Insulin-Like Growth Factor I; D003513:Cycloheximide; D017526:Receptor, IGF Type 1