Low-dose TNF-alpha protects against hepatic ischemia-reperfusion injury in mice: implications for preconditioning.
Tumor necrosis factor alpha (TNF-alpha) is implicated in the pathogenesis of hepatic ischemia reperfusion injury but can also prime hepatocytes to enter the cell cycle. Ischemic preconditioning protects against ischemia-reperfusion (IR) liver injury and is associated with activation of nuclear factor kappaB (NF-kappaB) and cell cycle entry. We examined the pattern of TNF-alpha release during hepatic IR in the presence or absence of ischemic preconditioning, and we tested whether a single low-dose injection of TNF could mimic the biologic effects of ischemic preconditioning. In naïve mice, hepatic and plasma levels of TNF-alpha rose during hepatic ischemia, reaching high levels after 90 minutes; values remained elevated during reperfusion until 44 hours. Following the ischemic preconditioning stimulus, there was an early rise in hepatic and serum TNF-alpha levels, but, during a second prolonged ischemic interval peak, TNF-alpha values were lower than in naïve mice and declined to negligible levels by 2 hours reperfusion. An injection with 1 microg or 5 microg/kg body weight TNF-alpha 30 minutes prior to hepatic IR substantially reduced liver injury determined by liver histology and serum alanine aminotransferase (ALT) levels. As in ischemic preconditioning, TNF-alpha pretreatment activated NF-kappaB DNA binding, STAT3, cyclin D1, cyclin-dependent kinase 4 (cdk4) expression, and cell cycle entry, determined by proliferating cell nuclear antigen (PCNA) staining of hepatocyte nuclei. In conclusion, the hepatoprotective effects of "preconditioning" can be simulated by TNF-alpha injection, which has identical downstream effects on cell cycle entry. We propose that transient increases in TNF-alpha levels may substitute for, as well as, mediate the hepatoprotective effects of ischemic preconditioning against hepatic IR injury.
Teoh
Narci
N
Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital, NSW, Australia.
Leclercq
Isabelle
I
Pena
Aileen Dela
AD
Farrell
Geoffrey
G
D000818:Animals; D000970:Antineoplastic Agents / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D020672:I-kappa B Proteins / Q000378:metabolism; D019194:Ischemic Preconditioning / Q000379:methods*; D048031:JNK Mitogen-Activated Protein Kinases; D008099:Liver / Q000737:chemistry / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D019938:Cyclin D1; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases