Zinc L-Carnosine Inhibits The Secretion of Pro-Inflammatory HMGB1 Protein From Lipopolysaccharide-Induced RAW 264.7 Murine Macrophage

Abstract Dysregulation in the secretion of high mobility group box 1(HMGB1) protein has been shown to modulate the progression of sepsis. Hence, the primary objective of this study is to explore the potential of zinc L-carnosine (ZnC) in inhibiting the secretion of HMGB1 from RAW 264.7 murine macrophages after induced with lipopolysaccharide (LPS). Generally, RAW 264.7 cells were pretreated with ZnC (0–100 µM) for 2 hours before challenged with LPS (1 µg/mL). After 22 hours of LPS induction, RAW 264.7 cells pretreated with ZnC showed significantly higher intracellular HMGB1 protein levels in a dose-dependent manner, indicating that ZnC was capable to suppress the secretion of HMGB1 protein into the extracellular compartments. Besides, significant increment in intracellular free thiol level was also detected in ZnC pretreated cells. In addition, ZnC was demonstrated to inhibit the late phase NF-κB activation, but not the early phase NF-κB activation. Moreover, after induced with LPS for 30 minutes, pretreatment with ZnC was also demonstrated to increase the phosphorylated-Akt/Akt ratio in RAW 264.7 cells, indicating that the immunomodulatory effects of ZnC may associated with the Akt signaling pathway. In summary, ZnC can prevent the secretion of HMGB1 from RAW 264.7 cells and suppress the NF-κB activation after induction with LPS. Results from this present study propose that ZnC possesses good potential to be used in the management and treatment of sepsis by inhibiting the secretion of HMGB1 from immune cells.