Massive hepatic apoptosis associated with TGF-β1 activation after Fas ligand treatment of IGF binding protein-1–deficient mice

Abstract

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-β. Within 3 hours of Fas agonist treatment, elevated expression of active TGF-β1, a hepatocyte apoptogen, was observed in IGFBP-1-deficient livers that correlated with the appearance of the apoptotic process. Both MMP-9 and TGF-β1 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. transcription factors (20, 21) that is also required for liver regeneration. C/EBPβ deficiency in the liver confers resistance to Fas-mediated apoptosis in the hepatocytes, as shown by reduced activation of caspase-3 and increased expression of antiapoptotic protein Bcl-x L in Fas-treated C/EBPβ -/-livers (22).We wondered if IGFBP-1 deficiency would result in an apoptotic defect that was similar to that observed with C/EBPβ deficiency. On the contrary, we found that abnormalities in C/EBPβ expression did not play a prominent role in Fas-mediated hepatic injury sustained in IGFBP-1 -/-livers. Instead, after Fas stimulation, IGFBP-1 deficiency was associated with rapid onset of massive hepatocyte apoptosis that could be corrected by pretreatment with IGFBP-1. Fibronectin signaling was elevated early in IGFBP-1-deficient livers and was associated with proteolytic activation of matrix metalloproteinase-9 (MMP-9), enhanced activation of the proapoptotic TGF-β1, caspase-3 and caspase-8 activation, and ultimately breakdown of fibronectin. Treatment of IGFBP-1 -/-livers with IGFBP-1 corrected these abnormalities and the associated morbidity and hepatic defects, establishing IGFBP-1 as a critical hepatic survival factor. MethodsAnimal studies and generation of mutant mice. Generation of IGFBP-1 -/-animals was described previously (2). Studies were performed on IGFBP-1 -/-and IGFBP-1 +/+ mice 12-16 weeks of age in a B6.129 hybrid background. Littermates and backcrossing were used to provide a uniform background. IGFBP-1 -/-phenotype was confirmed by ...

Insulin-like growth factor binding protein (IGFBP) signalling

“…1). In contrast, IGFBP-1 has very recently been shown to function as a critical hepatic survival factor by reducing the levels of pro-apoptotic signals like proteolytic activation of matrix metalloproteinase-9 (MMP-9), activation of pro-apoptotic TGF-b1, and caspase activation [38]. Again, the discrepancies between results emphasizes the complexity of the systems under study, suggesting signalling pathways peculiar to each cell type that sometimes lead to diametrically opposite physiological effects.…”

IGFBP-1 protease activity and IGFBP-1 fragments in a patient with multiple myeloma

“…IGFBP-1 is secreted by liver in a highly phosphorylated form that has high IGF-I affinity and is likely to have an important endocrine function in nutrition by inhibiting the insulin-like activity of IGFs [3,4]. It also plays paracrine/autocrine roles in liver and reproductive tissues, and in tumours [5][6][7].…”

Temporal and spatial expression of IGF-I and IGFBP-1 during acute-phase response induced by localized inflammation in rats

“…In addition, IGFBP-1 is one of the liver-specific immediate-early genes rapidly induced by a liver injury [50,51]. This protein functions as a critical hepatic survival factor that has a strong antiapoptotic activity [52]. Expression of IGFBP-1 is negatively regulated by insulin [28].…”