Glutathione S-transferase P1 Regulates LPS-induced Inflammatory Responses By Inhibiting The Release Of High Mobility Group Box Protein B1 (HMGB1)

Glutathione S-transferase P1 is a ubiquitous expressed protein which plays an important role in the detoxification and xenobiotics metabolism.Previous studies show that GSTP1 is a cancer marker and associates with anticancer drug resistance.In addition,GSTP1 as an anti-inflammatory factor in cellular response to LPS induced inflammatory response and show a function of GSTP1 to regulate MAPKs.As a late proinflammatory factor,HMGB1 is involved in many inflammatory disease.HMGB1 could produced by LPS stimulated monocyte/macrophages,which is an extremely important endogenous proinflammatory factor.Firstly,we show that GSTP1 is involved in LPS-induced HMGB1 release in RAW264.7.The translation level of HMGBlwere upregulation by the LPS stimulation in RAW264.7 macrophage-like cells.Overexpression of GSTP1 inhibited LPS-induced HMGB1 release.According to nucleocytoplasmic separation,we found that GSTP1 shuttle into the nuclear and then form the complex with HMGB1,thereby inhibition the nucleoplasm shuttle of HMGB1.These data suggest that GSTP1 prevents LPS-induced inflammatory response by bind to the HMGB1 protein.Subsequently,we found that the phosphorylation of GSTP1 play an important role in the transportation of GSTP1 into the nucleus.The present experiments showed that endogenous GSTP1 shuttle into the nuclear by the LPS stimulated.The level of phosphorylated GSTP1 reached peak in 30 min and reveal an time-independent manner.Then,the data suggest that ATM kinase were involved in the transportation of GSTP1 into the nuclear.In conclusion,our study reveals a novel role of GSTP1 as an anti-inflammatory factor in cellular response to LPS induced HMGB1 release.Meanwhile,we discovered the phosphorylation effect in the transportation of GSTP1 into the nuclear.Our data provides a new insight for analyzing the protective effects of GSTP1 in inflammatory response.