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 inhibiting phosphatidylinositol 3-kinase activity
✍ Scribed by Chang-Hui Liao; Jih-Jung Chen; Jieru Egeria Lin; Chia-Hsin Liu; Ching-Ping Tseng; Yuan-Ji Day
- Publisher
- John Wiley and Sons
- Year
- 2011
- Tongue
- English
- Weight
- 939 KB
- Volume
- 226
- Category
- Article
- ISSN
- 0021-9541
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✦ Synopsis
Abstract
Respiratory burst mediates crucial bactericidal mechanism in neutrophils. However, undesirable respiratory burst leads to pathological inflammation and tissue damage. This study investigates the effect and the underlying mechanism of 5‐hydroxy‐2‐(4‐hydroxy‐3‐methoxyphenyl)‐3,7‐dimethoxy‐4H‐chromen‐4‐one (MSF‐2), a lignan extracted from the fruit of Melicope Semecarprifolia, on fMLP‐induced respiratory burst in human neutrophils and suggests a possible therapeutic 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, reflecting inhibition of phosphatidylinositol 3‐kinase (PI3K) activation. Specifically, PI3K/AKT activation results in migration, degranulation and superoxide anion production in neutrophils. MSF‐2 suppresses PI3K activation and phosphatidylinositol (3,4,5)‐trisphosphate (PIP3) production, and consequently inhibits downstream activation 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 competitive or allosteric antagonist of fMLP. Additionally, in an in vivo study, MSF‐2 prevents fMLP‐induced neutrophil infiltration and inflammation in mice. In conclusion, MSF‐2 opposes fMLP‐mediated neutrophil activation and inflammation by inhibiting PI3K activation and subsequent activation of AKT and PLCγ2. J. Cell. Physiol. 226: 1519–1530, 2011. © 2010 Wiley‐Liss, Inc.