title: Hepatic apoptosis postburn is mediated by c-Jun N-terminal kinase 2.
abstract: The trauma of a severe burn injury induces a hypermetabolic response that increases morbidity and mortality. Previously, our group showed that insulin resistance after burn injury is associated with endoplasmic reticulum (ER) stress. Evidence suggests that c-Jun N-terminal kinase (JNK) 2 may be involved in ER stress-induced apoptosis. Here, we hypothesized that JNK2 contributes to the apoptotic response after burn injury downstream of ER stress. To test this, we compared JNK2 knockout mice (-/-) with wild-type mice after inducing a 30% total body surface area thermal injury. Animals were killed after 1, 3, and 5 days. Inflammatory cytokines in the blood were measured by multiplex analysis. Hepatic ER stress and insulin signaling were assessed by Western blotting, and insulin resistance was measured by a peritoneal glucose tolerance test. Apoptosis in the liver was quantified by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining. Liver function was quantified by aspartate aminotransferase and alanine aminotransferase activity assays. Endoplasmic reticulum stress increased after burn in both JNK2 and wild-type mice, indicating that JNK2 activation is downstream of ER stress. Knockout of JNK2 did not affect serum inflammatory cytokines; however, the increase in interleukin 6 mRNA expression was prevented in the knockouts. Serum insulin did not significantly increase in the JNK2 group. On the other hand, insulin signaling (PI3K/Akt pathway) and glucose tolerance tests did not improve in JNK2. As expected, apoptosis in the liver increased after burn injury in wild-type mice but not in JNK2. Aspartate aminotransferase/alanine aminotransferase activity revealed that liver function recovered more quickly in JNK2. This study indicates that JNK2 is a central mediator of hepatic apoptosis after a severe burn.
authors: Sunnybrook Research Institute-Biological Sciences, Division of Plastic Surgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
authors: Alexandra H
authors: AH
authors: Marshall
authors: Natasha C
authors: NC
authors: Brooks
authors: Yaeko
authors: Y
authors: Hiyama
authors: Nour
authors: N
authors: Qa'aty
authors: Ahmed
authors: A
authors: Al-Mousawi
authors: Celeste C
authors: CC
authors: Finnerty
authors: Marc G
authors: MG
authors: Jeschke
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001219:Aspartate Aminotransferases / Q000378:metabolism; D002056:Burns / Q000201:enzymology*; D016207:Cytokines / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D007328:Insulin / Q000502:physiology; D007333:Insulin Resistance / Q000502:physiology; D008107:Liver Diseases / Q000201:enzymology*; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048056:Mitogen-Activated Protein Kinase 9 / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology
chemical_list: D016207:Cytokines; D007328:Insulin; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D019869:Phosphatidylinositol 3-Kinases; D048056:Mitogen-Activated Protein Kinase 9