In the liver, the JNK cascade is induced downstream of TNF receptors (TNFRs) in 
response to inflammatory, microbial, and toxic challenges. Sustained activation 
of JNK triggers programmed cell death (PCD), and hepatocyte survival during 
these challenges requires induction of the NF-kappaB pathway, which antagonizes 
this activation by upregulating target genes. Thus, modulation of JNK activity 
is crucial to the liver response to TNFR-mediated challenge. The basis for this 
modulation, however, is unknown. Here, we investigated the role of the NF-kappaB 
target Gadd45b in the regulation of hepatocyte fate during liver regeneration 
after partial hepatectomy. We generated Gadd45b(-/-) mice and found that they 
exhibited decreased hepatocyte proliferation and increased PCD during liver 
regeneration. Notably, JNK activity was markedly increased and sustained in 
livers of Gadd45b(-/-) mice compared with control animals after partial 
hepatectomy. Furthermore, imposition of a Jnk2-null mutation, attenuating JNK 
activity, completely rescued the regenerative response in Gadd45b(-/-) mice. 
Interestingly, Gadd45beta ablation did not affect hepatotoxic JNK signaling 
after a TNFR-mediated immune challenge, suggesting specificity in the inducible 
hepatic program for JNK restraint activated during distinct TNFR-mediated 
challenges. These data provide a basis for JNK suppression during liver 
regeneration and identify Gadd45beta as a potential therapeutic target in liver 
diseases.