5-hydroxy-7-methoxyflavone inhibits N-formyl-l-methionyl-l-leucyl-l-phenylalanine-induced superoxide anion production by specific modulate membrane localization of Tec with a PI3K independent mechanism in human neutrophils

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• 作者：Hsiang-Ruei Liao^a ; ^{liaoch@mail.cgu.edu.tw} ; Jih-Jung Chen^b ; Yin-Huan Chien^a ; Shinn-Zhi Lin^a ; Shunchih Lin^a ; Ching-Ping Tseng^c
• 关键词：MCL-1 ; Neutrophil ; fMLP ; Tec ; Protein kinase C
• 刊名：Biochemical Pharmacology
• 出版年：2012
• 期刊代码：2_00062952
• 类别：pha
• 出版时间：15 July, 2012
• 卷：84
• 期：2
• 页码：182-191
• 文件大小：1386 K

摘要

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-7-methoxyflavone (MCL-1), a lignan extracted from the leaves of Muntingia calabura L. (Tiliaceae), on N-formyl-l-methionyl-l-leucyl-l-phenylalanine (fMLP)-induced respiratory burst and cathepsin G release in human neutrophils. Signaling pathways regulated by MCL-1 to oppose fMLP-induced respiratory burst were evaluated by membrane localization of Tec induced by fMLP and by immunoblotting analysis of downstream phosphorylation targets of Tec. Briefly, MCL-1 specific inhibited fMLP-induced superoxide anion production in a concentration-dependent (IC₅₀ = 0.16 卤 0.01 渭M) and Tec kinase-dependent manner, however, MCL-1 did not affect fMLP-induced cathepsin G release. Further, MCL-1 suppressed fMLP-induced Tec translocation from the cytosol to the inner leaflet of the plasma membrane, and subsequently activation of phospholipase C纬2 (PLC纬2). Moreover, MCL-1 attenuated PLC纬2 activity and intracellular calcium concentration notably through extracellular calcium influx. Consequently, fMLP-induced phosphorylation of protein kinase C (PKC) and membrane localization of p47^phox were decreased by MCL-1 in a Tec-dependent manner, while the phosphorylation of extracellular signal-regulated kinase (ERK), p38, AKT and Src tyrosine kinase family remained unaffected. In addition, MCL-1 neither inhibited NADPH oxidase activity nor increased cyclicAMP levels. MCL-1 specific opposes fMLP-mediated respiratory burst by inhibition of membrane localization of Tec and subsequently interfered with the activation of PLC纬2, protein kinase C, and p47^phox.