Mycophenolate mofetil preconditioning protects mouse liver against ischemia/reperfusion injury in wild type and toll-like receptor 4 knockout mice

Abstract

Background: Mycophenolate mofetil (MMF), an immunosuppressive drug, exerts anti-inflammatory effects on organs during ischemia/reperfusion (I/R) injury. However, the exact function of MMF in hepatic I/R injury remains largely unknown. The purpose of this study was to explore the role and potential mechanism of MMF protection in hepatic I/R injury.

Methods: Male wild type (WT) and TLR4 knockout (KO) mice were injected intraperitoneally with MMF or normal saline. Animals underwent 90 min of partial hepatic ischemia, followed by 1, 6, or 24 h of reperfusion. Hepatic histology, serum amiotransferase, inflammatory cytokines, hepatocyte apoptosis, and hepatocyte autophagy were examined to assess liver injury.

Results: Treatment with MMF significantly decreased hepatic I/R injury as indicated by a reduction in serum aminotransferase levels, Suzuki scores, and the overall degree of necrosis. MMF treatment inhibited TLR4 activation dramatically. MMF administration also significantly inhibited the activation of the NF-κB pathway and the expression of pro-inflammatory cytokines. In TLR4 KO mice, MMF still exerted protection from hepatic I/R injury. MMF treatment inhibited hepatocyte apoptosis, as indicated by reduced TUNEL staining, and reduced the accumulation of cleaved caspase-3. In addition, MMF may induce autophagy and increase autophagic flux before and after hepatic reperfusion by augmenting the expression of LC3-II, P62, and Beclin-1. The induction of autophagy by MMF treatment may be related to TLR4 activation.

Conclusions: Our results indicate that MMF treatment ameliorates hepatic I/R injury. The mechanism of action likely involves the ability of MMF to decrease apoptosis and the inflammatory response while inducing autophagy.

Keywords: Ischemia/reperfusion; Liver; Mycophenolate mofetil; Toll-like receptor 4.