Differential Roles of JNK in ConA/GalN and ConA-Induced Liver Injury in Mice

Ni, Hong; Chen, Xiaoyun; Ding, Wen; Schuchmann, Marcus; Yin, Xiao Ming

doi:10.2353/ajpath.2008.080358

Cited by 48 publications

(41 citation statements)

References 43 publications

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“…Previous work had indicated that liver injury induced by ConA alone was not primarily caused by a caspase-mediated apoptotic process (23,28). Consistently, caspase activation was not detected in either wild type or Bid-deficient livers 8 h after treatment when cellular injury was already apparent (Fig.…”

Section: And B)supporting

confidence: 57%

“…S1) or ConA/GalN-induced (23) hepatocyte apoptosis and liver injury. We also found that JNK1-deficient mice had similar phenotypes, although less significant than JNK2-deficient mice (23) (Fig. S1).…”

Section: And B)supporting

confidence: 48%

“…These studies indicated that ConA alone initiated a noncaspase-dependent liver injury, as shown before (23,28), which was not affected by the deletion of Bid. However, in the ConA/ GalN scenario, deletion of Bid provided a significant protection against caspase activation and attenuated the injury and mortality.…”

Section: And B)mentioning

confidence: 87%

“…3 and Fig. S1) and by ConA/GalN (23) but not by ConA alone (23), although others found that JNK participated in ConA alone-induced liver injury (18). The present study evaluated the contribution of Bid to TNF␣-induced liver injury in the ConA and ConA/GalN models and the contribution of JNK1 and JNK2 to TNF␣-induced liver injury in the RelA deletion model.…”

Section: Discussionmentioning

confidence: 99%

“…Sustained JNK phosphorylation is correlated with TNF␣ toxicity and is observed when NF-B activation is suppressed. Although there is a redundancy of JNK1 and JNK2, deletion of either could significantly block TNF␣-induced death in hepatocytes in vitro (19,20) and in vivo (18,(21)(22)(23).…”

Section: Tnf␣mentioning

confidence: 99%

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

Chen

Shi

et al. 2009

Journal of Biological Chemistry

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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.

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Section: And B)supporting

confidence: 57%

Section: And B)supporting

confidence: 48%

Section: And B)mentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%