Genetic delineation of the pathways mediated by bid and JNK in tumor necrosis factor-alpha-induced liver injury in adult and embryonic mice.
Tumor necrosis factor-alpha (TNFalpha)-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-kappaB activation, but not in embryonic mice in which NF-kappaB activation is suppressed by genetic deletion of p65RelA. JNK has also been found important in TNFalpha-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-kappaB activation was not suppressed. To determine the mechanistic relationship of pathways mediated by Bid and JNK, we investigated these two molecules in TNFalpha 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 TNFalpha-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 TNFalpha-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 TNFalpha injury. This work defined both linear and parallel relationships of Bid and JNK in TNFalpha-induced hepatocyte apoptosis and liver injury.
Ni
Hong-Min
HM
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
Chen
Xiaoyun
X
Shi
Ying-Hong
YH
Liao
Yong
Y
Beg
Amer A
AA
Fan
Jia
J
Yin
Xiao-Ming
XM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics / Q000378:metabolism*; D056486:Chemical and Drug Induced Liver Injury; D003208:Concanavalin A / Q000009:adverse effects / Q000494:pharmacology; D004195:Disease Models, Animal; D004622:Embryo, Mammalian / Q000378:metabolism* / Q000473:pathology; D005688:Galactosamine / Q000633:toxicity; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000293:injuries* / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008934:Mitogens / Q000009:adverse effects / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
D051023:BH3 Interacting Domain Death Agonist Protein; C494815:Bid protein, mouse; D008070:Lipopolysaccharides; D008934:Mitogens; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A; D005688:Galactosamine; D048670:MAP Kinase Kinase 4