Curcuminoids Modulate the PKC delta/NADPH Oxidase/Reactive Oxygen Species Signaling Pathway and Suppress Matrix Invasion during Monocyte-Macrophage Differentiation

摘要

Monocyte recruitment and invasion play critical roles in the initiation and progression of atherosclerosis. The reduction in monocyte adhesion and infiltration is thought to exert antiatherosderotic effects. Curcumin, demethoxycurcurnin (DMC), and bisdemethoxycurcumin (BDMC) are the major active components of curcuminoids and exhibit several biological activities, including anti-inflammatory, anticarcinogenic, and hypocholesterolemic activities. The aim of this study was to investigate the antiatherogenic effects and mechanisms of curcuminoids during monocyte to macrophage differentiation. The results showed that curcumin, DMC, and BDMC (20 mu M) suppressed matrix invasion from 100.0 +/- 5.0% to 24.8 +/- 1.4%, 26.6 +/- 2.9%, and 33.7 +/- 1.7%, respectively, during PMA-induced THP-1 differentiation. We found that curcuminoids significantly reduced PMA-induced CD11b and MMP-9 expression by THP-1 cells. Production of reactive oxygen species (ROS) induced by PMA (126.7 +/- 2.1%) was markedly attenuated by curcumin, DMC, and BDMC to 99.5 +/- 7.8%, 87.8 +/- 8.2%, and 89.8 +/- 7.6%, respectively, resulting in the down-regulation of CD11b and MMP-9 expression. We demonstrated that curcuminoids inhibited NADPH oxidase through the down-regulation of NOX2 expression and the reduction of p47phox membrane translocation. Moreover, we found involvement of PKC delta in the PMA-induced NOX2, CD11b, and MMP-9 mRNA expression. Curcumin, DMC, and BDMC decreased the active form of PKC delta protein stimulated by PMA in THP-1 cells. Overall, our results reveal that curcuminoids suppress matrix invasion through the inhibition of the PKC delta/NADPH oxidase/ROS signaling pathway during monocyte-macrophage differentiation.