Genetic Delineation of the Pathways Mediated by Bid and JNK in Tumor Necrosis Factor-α-induced Liver Injury in Adult and Embryonic Mice

Abstract

Tumor necrosis factor-␣ (TNF␣)-induced hepatocyte death and liver injury can be mediated by multiple mechanisms, which could be evaluated by different animal models. Previous studies have defined the importance of Bid in mitochondrial apoptosis activation in adult mice treated with lipopolysaccharides in the presence of galactosamine (GalN), which suppresses NF-B activation, but not in embryonic mice in which NF-B activation is suppressed by genetic deletion of p65RelA. JNK has also been found important in TNF␣-induced mitochondria activation and liver injury in the lipopolysaccharide/GalN and concanavalin A (ConA)/GalN models, but not in a ConA-only model in which NF-B activation was not suppressed. To determine the mechanistic relationship of pathways mediated by Bid and JNK, we investigated these two molecules in TNF␣ injury models that had not been previously examined. Most importantly, we created and studied mice deficient in both Bid and JNK. We found that, like JNK, Bid was also required for TNF␣-induced injury induced by concanavalin A/GalN but not by ConA alone. Furthermore, our results indicate that these two molecules function in a largely overlapped manner, with Bid being downstream of JNK in the adult livers. However, JNK, but not Bid, was able to contribute to the TNF␣-induced liver apoptosis in RelA-deficient embryos. The Bid-independent role of JNK was also observed in the adult mice, mainly in the promotion of the lethal progression of the TNF␣ injury. This work defined both linear and parallel relationships of Bid and JNK in TNF␣-induced hepatocyte apoptosis and liver injury.

Immune cell-mediated liver injury

“…Similarly, pretreatment of mice with JNK inhibitors rescued the animals from the development of severe liver injury. Moreover, TNFα-induced activation of JNK correlated with liver damage after injection of ConA, and JNK inhibitors could block hepatocyte cell death induced by ConA [57,58]. In contrast to these observations, it was recently demonstrated that JNK is critically required for TNFα expression in hematopoietic cells and it is not mandatory for TNFα-triggered hepatocyte cell death during the development of liver damage [59].…”

A Liver Full of JNK: Signaling in Regulation of Cell Function and Disease Pathogenesis, and Clinical Approaches

“…They also indicate that a mitochondrial activation loop that produces ROS, rather than only continuous TNFR signaling, sustains JNK activation. Upon TNF stimulation, Bid, a BH3-only protein, is cleaved by caspase-8 in a JNK2-dependent manner 27,30 . The cleaved Bid translocates to the mitochondrial outer membrane to induce cytochrome-c release and caspase-9/caspase-3 activation, resulting in TNF-mediated hepatocyte death 27,31 .…”

“…The cleaved Bid translocates to the mitochondrial outer membrane to induce cytochrome-c release and caspase-9/caspase-3 activation, resulting in TNF-mediated hepatocyte death 27,31 . The requirement for Bid in hepatocyte death has been demonstrated by the resistance of Bid −/− mice to TNF-induced liver injury 30 .…”

Mechanisms of liver disease: cross-talk between the NF-κB and JNK pathways

“…These analyses, however, await confirmation in animal models, including models of liver injury. Analyses of Jnk1 −/− and Jnk2 −/− mice challenged with either LPS/GalN or ConA/GalN, however, have recently suggested that activation of Bid is independent of JNK activity, suggesting a parallel role for Bid and JNK signalling in mediating TNFα-induced liver injury (Ni et al, 2009). …”