Reperfusion after liver transplantation in rats differentially activates the mitogen-activated protein kinases.
The injury resulting from cold ischemia and warm reperfusion during liver transplantation is a major clinical problem that limits graft success. Kupffer cell activation plays a pivotal role in reperfusion injury, and Kupffer cell products, including free radicals and tumor necrosis factor alpha (TNF-alpha), are implicated as damaging agents. However, the second messengers and signaling pathways that are activated by the stress of hepatic ischemia/reperfusion remain unknown. The purpose of this study is to assess the activation of the three known vertebrate mitogen activated protein kinase (MAPKs) and the activating protein 1 (AP-1) transcription factor in response to ischemia and reperfusion in the transplanted rat liver. There was a potent, sustained induction of c-jun N-terminal kinase (JNK), but not of the related MAPKs extracellular signal-regulated kinases (ERK) or p38, upon reperfusion after transplantation. TNF-alpha messenger RNA (mRNA) levels and transcription factors AP-1 and nuclear factor-kappaB (NF-kappaB) were induced in the liver after 60 minutes of reperfusion. Finally, there was an elevation of ceramide, but not diacylglycerol or sphingosine, in the transplanted liver. Ceramide is a second messenger generated by TNF-alpha treatment and is an activator of JNK. Because JNK activation preceded the elevations in ceramide and TNF-alpha mRNA, these results suggest that increased hepatic TNF-alpha and ceramide may perpetuate JNK induction, but that they are not the initiating signals of JNK activation during reperfusion injury in the transplanted liver.
Bradham
C A
CA
Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, 27599, USA.
Stachlewitz
R F
RF
Gao
W
W
Qian
T
T
Jayadev
S
S
Jenkins
G
G
Hannun
Y
Y
Lemasters
J J
JJ
Thurman
R G
RG
Brenner
D A
DA
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D004789:Enzyme Activation; D005260:Female; D008099:Liver / Q000201:enzymology* / Q000473:pathology; D016031:Liver Transplantation; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000201:enzymology*; D015398:Signal Transduction; D014184:Transplantation, Homologous
D017871:Calcium-Calmodulin-Dependent Protein Kinases