5‐hydroxy‐2‐(4‐hydroxy‐3‐methoxyphenyl)‐3,7‐dimethoxy‐4H‐chromen‐4‐one (MSF‐2) suppresses fMLP‐mediated respiratory burst in human neutrophils by inhib‐iting phosphatidylinositol 3‐kinase activity

Abstract

This study investigates the effect and the underlying mechanism of MSF‐2, a lignan extracted from the fruit of Melicope Semecarprifolia, on fMLP‐induced respiratory burst in human neutrophils and suggests a possible thera‐peutic approach to ameliorate disease associated with neutrophil hyperactivation. MSF‐2 inhibited fMLP‐induced neutrophil superoxide anion production, cathepsin G release and migration in human neutrophils isolated from healthy volunteers, reflect‐ing inhibition of phosphatidylinositol 3‐kinase (PI3K) activation. Specifically, PI3K/AKT activation results in migration, degranulation and superoxide anion pro‐duction in neutrophils. MSF‐2 suppresses PI3K activation and PIP3 pro‐duction, and consequently inhibits downstream activa‐tion of PDK1 and AKT. Further, PI3K also stimulates respiratory burst via PLC‐dependent elevation of intracellular calcium. MSF‐2 reduces fMLP‐mediated PLCγ2 activation and intracellular calcium accumulation notably through extracellular calcium influx in a PI3K and PLC‐dependent manner. However, MSF‐2 is not a com‐petitive or allosteric antagonist of fMLP. Additionally, in an in vivo study, MSF‐2 prevents fMLP‐induced neutrophil infiltration and inflammation in mice. In conclu‐sion, MSF‐2 opposes fMLP‐mediated neutrophil activation and inflammation by inhibiting PI3K activation and subsequent activation of AKT and PLCγ2.