Dual role of tumor necrosis factor-? in hepatic ischemia-reperfusion injury: Studies in tumor necrosis factor-? gene knockout mice

Abstract

Although hepatic ischemia-reperfusion (IR) injury is partially mediated by tumor necrosis factor-␣ (TNF), we recently found that low-dose TNF before IR is hepatoprotective. We examined the seemingly conflicting roles of TNF in mediating liver injury in a partial hepatic IR model using TNF gene knockout (TNF ko) mice to allow TNF replacement at specified times. Compared with wild-type mice, TNF ko mice exhibit minimal alanine aminotransferase release and few hepatonecrotic lesions during the early (time, 2 hours) and late (time, 24 hours) phases of IR. TNF ko mice differed from wild-type mice in that TNF ko mice exhibited no activation or induction of nuclear factor-B, p38, cyclin D1, or proliferating cell nuclear antigen after IR. A single low-dose TNF injection 1 minute before the onset of hepatic ischemia restored hepatic IR injury in TNF ko mice. To clarify the importance of TNF for hepatoprotection, preconditioning (10 minutes of ischemia and 10 minutes of reperfusion) was performed before the onset of IR for TNF ko mice whose capacity to undergo IR injury had been restored by TNF replacement. Ischemic preconditioning failed to protect these mice from TNF-augmented IR injury; however, following the administration of intravenous TNF (1 g per kg body weight, which mimics the early increase in hepatic and plasma TNF levels that is mobilized by ischemic preconditioning), significant hepatoprotection against both the early and late phases of TNF-augmented IR injury was observed. In conclusion, TNF appears to mediate both the early and late phases of liver injury in hepatic IR, but it also is an essential mediator of hepatoprotective effects brought about by ischemic preconditioning. ( H epatic ischemia-reperfusion (IR) is a significant complication of hepatic resection, liver transplantation, and circulatory shock, and it contributes to the mechanisms of certain types of toxic liver injury. IR-related liver injury results from an intense inflammatory response initiated by oxidative stress in the liver parenchyma during reperfusion. This response involves Kupffer cells, which release cytokines such as tumor necrosis factor-␣ (TNF); these cytokines amplify inflammation by inducing the expression of neutrophilattracting chemokines and by up-regulating vascular adhesion molecules. 1,2 TNF levels have been found to increase during hepatic ischemia and remain detectable in plasma and liver tissue until the late reperfusion phase. Nonetheless, to date, all evidence implicating TNF as a mediator of hepatic IR injury is indirect. Colletti et al. 3 found that pretreatment with anti-TNF antibody before the onset of hepatic IR significantly reduced pulmonary and hepatic injury in a rodent model. Rudiger et al. 4 subsequently demonstrated that pentoxifylline, a methylxanthine inhibitor of TNF production in vivo, dramatically reduced hepatic IR injury as assessed by serum aminotransferase release and animal survival.TNF exerts protean and often conflicting biologic effects, depending on cell type and context. In the liver, t...

Critical role of acidic sphingomyelinase in murine hepatic ischemia-reperfusion injury

“…TNF Release During I/R Activates ASMase. TNF upregulation by activated Kupffer cells plays a key role in hepatic I/R injury, 5,6,23 and TNF-induced hepatocellular death is mediated in part through ASMase activation. 11,16 During I/R we detected an early release of TNF and postulated that this cytokine may contribute to I/R-induced ASMase activation.…”

“…17,18,22 Previous studies using mice deficient in TNF gene or TNF receptor 1 (TNFR1) have identified TNF as a critical mediator in warm hepatic I/R injury. 5,6,23 Moreover, increased hepatic ceramide levels have been observed in cold ischemia and warm reperfusion, 24 although its consequences and regulation were not further examined. Furthermore, the regulation of SMases has been reported in a rat model of I/R, with NSMase being stimulated during the reperfusion of the ischemic liver, as opposed to ASMase, whose activity decreased.…”

A complement-dependent balance between hepatic ischemia/reperfusion injury and liver regeneration in mice

“…It was not clear why low-versus high-dose ASP had opposing effects in liver regeneration and injury in C3 -/-mice following PHx. However, while the complement activation products C3a and C5a have been shown to play a key role in the priming stages of liver regeneration via their effect on TNF-α and IL-6 expression, these cytokines can play dual roles in hepatocyte regeneration and injury, and increased and prolonged expression of these inflammatory cytokines is associated with hepatic injury (27)(28)(29). We therefore investigated the effect of high-versus low-dose ASP on TNF-α and IL-6 expression levels and on hepatic neutrophil infiltration (MPO activity) following PHx.…”

SP600125, a selective JNK inhibitor, aggravates hepatic ischemia-reperfusion injury

“…JNK is activated by environmental stresses such as oxidative stress (Mendelson et al, 1996), and also by cytokines, including TNF- (Liedtke et al, 2002) and IL-1 (Finch et al, 2001). These cytokines are considered to be major mediators in hepatic I/R injury (Kato et al, 2002;Teoh et al, 2004). JNK activation during reperfusion is believed to play a role in hepatocyte apoptosis (Marderstein et al, 2003;Uehara et al, 2004;Uehara et al, 2005).…”