TY - JOUR
T1 - A novel immunomodulatory effect of ugonin U in human neutrophils via stimulation of phospholipase C
AU - Chen, Chun Yu
AU - Liaw, Chih Chuang
AU - Chen, Yi Hsuan
AU - Chang, Wen Yi
AU - Chung, Pei Jen
AU - Hwang, Tsong Long
PY - 2014/7
Y1 - 2014/7
N2 - Neutrophils have a crucial role in the immune system and are the first line of defense against pathogenic invaders. Neutrophil activation is required for their defensive function and can be induced by diverse stimuli, through either binding to cell surface receptors or direct intracellular target molecule stimulation. In this study, we found that 4″a,5″,6″,7″, 8″,8″a-hexahydro-5,3′,4′-trihydroxy-5″,5″, 8″a-trimethyl-4H-chromeno [2″,3″:7,6]flavone (ugonin U), a flavonoid isolated from Helminthostachys zeylanica (L) Hook, significantly induced superoxide production and release in a time- and concentration-dependent manner. A series of experiments was performed to dissect the mechanism of ugonin U-induced respiratory burst in human neutrophils. Our results demonstrated that ugonin U induced a slow increase in intracellular Ca 2+, which was necessary for ugonin U-stimulated superoxide release. Use of a formyl peptide receptor (FPR) blocker, G protein inhibitor, and protein tyrosine kinase (PTK) inhibitor proved that FPR, G proteins, and PTKs were not associated with ugonin U-induced respiratory burst. Additionally, immunoblotting results revealed that ugonin U did not affect the phosphorylation of mitogen-activated protein kinases and protein tyrosine. Nevertheless, a phospholipase C (PLC) inhibitor and an inositol triphosphate (IP3) receptor antagonist considerably suppressed ugonin U-stimulated Ca2+ mobilization and subsequent superoxide release. Ugonin U also induced an increase in intracellular IP3 formation, which could be blocked using a PLC inhibitor. In conclusion, our study reveals that ugonin U represents the first identified natural flavonoid compound to directly stimulate PLC. Moreover, ugonin U induces respiratory burst via the PLC/IP3/Ca2+ pathway in human neutrophils.
AB - Neutrophils have a crucial role in the immune system and are the first line of defense against pathogenic invaders. Neutrophil activation is required for their defensive function and can be induced by diverse stimuli, through either binding to cell surface receptors or direct intracellular target molecule stimulation. In this study, we found that 4″a,5″,6″,7″, 8″,8″a-hexahydro-5,3′,4′-trihydroxy-5″,5″, 8″a-trimethyl-4H-chromeno [2″,3″:7,6]flavone (ugonin U), a flavonoid isolated from Helminthostachys zeylanica (L) Hook, significantly induced superoxide production and release in a time- and concentration-dependent manner. A series of experiments was performed to dissect the mechanism of ugonin U-induced respiratory burst in human neutrophils. Our results demonstrated that ugonin U induced a slow increase in intracellular Ca 2+, which was necessary for ugonin U-stimulated superoxide release. Use of a formyl peptide receptor (FPR) blocker, G protein inhibitor, and protein tyrosine kinase (PTK) inhibitor proved that FPR, G proteins, and PTKs were not associated with ugonin U-induced respiratory burst. Additionally, immunoblotting results revealed that ugonin U did not affect the phosphorylation of mitogen-activated protein kinases and protein tyrosine. Nevertheless, a phospholipase C (PLC) inhibitor and an inositol triphosphate (IP3) receptor antagonist considerably suppressed ugonin U-stimulated Ca2+ mobilization and subsequent superoxide release. Ugonin U also induced an increase in intracellular IP3 formation, which could be blocked using a PLC inhibitor. In conclusion, our study reveals that ugonin U represents the first identified natural flavonoid compound to directly stimulate PLC. Moreover, ugonin U induces respiratory burst via the PLC/IP3/Ca2+ pathway in human neutrophils.
KW - Flavonoid
KW - Free radicals
KW - Helminthostachys zeylanica
KW - Neutrophils
KW - Phospholipase C
KW - Superoxide
KW - Ugonin U
UR - http://www.scopus.com/inward/record.url?scp=84900848929&partnerID=8YFLogxK
U2 - 10.1016/j.freeradbiomed.2014.04.018
DO - 10.1016/j.freeradbiomed.2014.04.018
M3 - 文章
C2 - 24747490
AN - SCOPUS:84900848929
SN - 0891-5849
VL - 72
SP - 222
EP - 231
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
ER -