High mobility group box 1 (HMGB1) is now recognized as a late mediator of sepsis. Although glycyrrhizin was known as inhibitor of HMGB1, it is not yet clear underlying mechanism(s). We found that glycyrrhizin activates translocation of Nrf2 from cytosol to nucleus and induces heme oxygenase (HO)-1 expression in RAW 264.7 cells. In addition, deletion of Nrf2 by siRNA significantly reduced mRNA expression of NQO1 and HO-1 suggesting that glycyrrhizin targets Nrf2 gene. The expression of iNOS protein and release of HMGB1 in LPS activated cells were significantly reduced by glycyrrhizin and cells transfected with mouse HO-1 expression vector. The p38MAPK inhibitor (SB203580) but not JNK inhibitor (SP600125) or ERK inhibitor (PD98059) significantly inhibited HO-1 induction by glycyrrhizin, which was confirmed by showing that siP38 transfected cells significantly reduced HO-1 induction. Pretreatment with SB203580 significantly reversed the expression of iNOS and release of NO and HMGB1 in LPS-activated cells. Most importantly, administration of glycyrrhizin (200mg/kg, i.p) significantly reduced hepatic injury and serum HMGB1 in a ZnPPIX-sensitive manner. Thus, it is concluded that glycyrrhizin reduces HMGB1 secretion in lipopolysaccharide-activated RAW 264.7 cells and endotoxemic mice by p38/Nrf2-dependent induction of HO-1.
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