Gadd45beta promotes hepatocyte survival during liver regeneration in mice by modulating JNK signaling.
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.
Papa
Salvatore
S
Ben May Department for Cancer Research and Department of Pathology, University of Chicago, Chicago, Illinois 60637, USA.
Zazzeroni
Francesca
F
Fu
Yang-Xin
YX
Bubici
Concetta
C
Alvarez
Kellean
K
Dean
Kathryn
K
Christiansen
Peter A
PA
Anders
Robert A
RA
Franzoso
Guido
G
D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology; D002470:Cell Survival; D004789:Enzyme Activation; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology*; D020287:In Situ Nick-End Labeling; D015850:Interleukin-6 / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000033:anatomy & histology / Q000378:metabolism / Q000473:pathology; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000097642:GADD45 Proteins
D000943:Antigens, Differentiation; D015850:Interleukin-6; D048031:JNK Mitogen-Activated Protein Kinases; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; C490125:Gadd45b protein, mouse; D000097642:GADD45 Proteins