Hepatic preconditioning using lipopolysaccharide: association with specific negative regulators of the Toll-like receptor 4 signaling pathway.

BACKGROUND: Preconditioning using lipopolysaccharide (LPS), a Toll-like receptor (TLR)-4 ligand, has been demonstrated to attenuate ischemia-reperfusion injury (IRI) in several organs but has not been sufficiently elucidated in the liver. We investigated the molecular mechanism of protection induced by LPS preconditioning against hepatic IRI.

METHODS: BALB/c mice underwent 70% hepatic ischemia for 90 min. LPS was injected intraperitoneally 20 hr before ischemia at a range of 1 to 1000 μg/kg. Hepatic injury was evaluated based on serum alanine aminotransferase levels and histopathology. Inflammatory cytokine expression, nuclear factor-κB activation, and c-Jun N-terminal kinase phosphorylation were investigated after reperfusion. Additionally, preischemic expression of negative feedback inhibitors of the TLR4 cascade was examined.

RESULTS: Only the 100 μg/kg LPS pretreatment significantly reduced serum alanine aminotransferase levels and histopathologic damage 6 hr after reperfusion; there was no difference among other LPS concentrations. In mice pretreated with LPS, intrahepatic expression of tumor necrosis factor-α and interleukin (IL)-6 as well as activation of nuclear factor-κB and c-Jun N-terminal kinase were inhibited 1 hr after reperfusion, whereas expression of IL-10, an anti-inflammatory cytokine, was induced. Suppressor of cytokine signaling (SOCS)-1, SOCS-3 and IL-1 receptor-associated kinase-M were upregulated by LPS exposure in the preischemic period.

CONCLUSIONS: Hepatic LPS preconditioning elicited the upregulation of specific negative regulators in the TLR4 signaling pathway. Preischemic induction of these regulators plays an important role as immunologic preparation for the subsequent ischemia-reperfusion and produces resistance to liver injury. Preoperative modulation of the TLR4 pathway might become an alternative therapeutic strategy against hepatic IRI.