Massive hepatic apoptosis associated with TGF-beta1 activation after Fas ligand treatment of IGF binding protein-1-deficient mice.
Acute liver failure caused by viral hepatitis or toxic damage involves both apoptotic and necrotic pathways. IGF binding protein-1 (IGFBP-1), a hepatocyte-derived secreted protein, is required for normal liver regeneration. To determine whether IGFBP-1 could prevent liver injury that entails direct stimulation of hepatocyte apoptosis, IGFBP-1(-/-) mice, IGFBP-1(+/+) mice, and mice pretreated with Ab's against IGFBP-1 were treated with a normally sublethal dose of Fas agonist. IGFBP-1 deficiency was associated with massive hepatocyte apoptosis and caspase activation within 3 hours of Fas agonist treatment, which could be corrected by pretreatment with IGFBP-1. IGFBP-1-deficient livers had enhanced signaling via the integrin receptor at early times (0.5 to 1 hour) after Fas agonist treatment accompanied by elevated activated matrix metalloproteinase-9 (MMP-9), a known target of fibronectin signaling and activator of TGF-beta. Within 3 hours of Fas agonist treatment, elevated expression of active TGF-beta1, a hepatocyte apoptogen, was observed in IGFBP-1-deficient livers that correlated with the appearance of the apoptotic process. Both MMP-9 and TGF-beta1 expression were suppressed by IGFBP-1 treatment, supporting their role in the apoptotic process. IGFBP-1(-/-) mice also displayed increased injury in a toxic hepatic injury model caused by CCl(4). These findings indicate that IGFBP-1 functions as a critical hepatic survival factor in the liver by reducing the level of proapoptotic signals.
Leu
Julia I
JI
Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Crissey
Mary Ann S
MA
Taub
Rebecca
R
D000818:Animals; D017209:Apoptosis; D002251:Carbon Tetrachloride / Q000494:pharmacology; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation; D004789:Enzyme Activation; D053222:Fas Ligand Protein; D005353:Fibronectins / Q000378:metabolism; D022781:Hepatocytes / Q000473:pathology*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000235:genetics* / Q000502:physiology*; D016023:Integrins / Q000378:metabolism; D008099:Liver / Q000473:pathology*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D008957:Models, Genetic; D015398:Signal Transduction; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D015854:Up-Regulation; D019014:fas Receptor / Q000378:metabolism*
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D005353:Fibronectins; D018970:Insulin-Like Growth Factor Binding Protein 1; D016023:Integrins; D008562:Membrane Glycoproteins; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D019014:fas Receptor; D002251:Carbon Tetrachloride; C505409:Casp3 protein, mouse; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D020780:Matrix Metalloproteinase 9