Protein kinase C beta mediates CD40 ligand-induced adhesion of monocytes to endothelial cells

• Published in: PloS one 2013-09, Vol.8 (9), p.e72593-e72593
• Main Authors: Wu, Zeyu, Zhao, Gang, Peng, Lin, Du, Jialin, Wang, Sanming, Huang, Yijie, Ou, Jinrui, Jian, Zhixiang
• Format: Article
• Language: English
• Subjects: Adhesion; Adhesion tests; Animals; Aorta; Apolipoproteins; Atherogenesis; Atherosclerosis; CD40 antigen; CD40 Antigens - genetics; CD40 Antigens - metabolism; CD40 Ligand - physiology; CD40L protein; Cell activation; Cell Adhesion; Cell adhesion & migration; Cell adhesion molecules; Cell Line; Coculture Techniques; Coupling (molecular); Endothelial cells; Endothelial Cells - physiology; Endothelium; Endothelium, Vascular - cytology; Exposure; Gene expression; Humans; I-kappa B Proteins - metabolism; Inflammation; Inhibition; Inhibitors; Kinases; Leukocytes; Ligands; Macrophages; Male; Mice; Mice, Inbred C57BL; Molecular modelling; Monocytes; Monocytes - physiology; mRNA; NF-KappaB Inhibitor alpha; NF-κB protein; Phosphorylation; Protein kinase C; Protein Kinase C beta - metabolism; Protein kinases; Protein Processing, Post-Translational; Proteins; Recruitment; RNA; Signal transduction; Signaling; Surgery; Transcription Factor RelA - metabolism; Tumor necrosis factor-TNF; Vascular cell adhesion molecule 1; Vascular Cell Adhesion Molecule-1 - metabolism; White blood cells
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0072593

Accumulating evidence supports the early involvement of monocyte/macrophage recruitment to activated endothelial cells by leukocyte adhesion molecules during atherogenesis. CD40 and its ligand CD40L are highly expressed in vascular endothelial cells, but its impact on monocyte adhesion and the related molecular mechanisms are not fully understood. The present study was designed to evaluate the direct effect of CD40L on monocytic cell adhesion and gain mechanistic insight into the signaling coupling CD40L function to the proinflammatory response. Exposure of cultured human aortic endothelial cells (HAECs) to clinically relevant concentrations of CD40L (20 to 80 ng/mL) dose-dependently increased human monocytic THP-1 cells to adhere to them under static condition. CD40L treatment induced the expression of vascular cell adhesion molecule-1 (VCAM-1) mRNA and protein expression in HAECs. Furthermore, exposure of HAECs to CD40L robustly increased the activation of protein kinase C beta (PKCβ) in ECs. A selective inhibitor of PKCβ prevented the rise in VCAM-1 and THP-1 cell adhesion to ECs. Moreover, stimulation of ECs to CD40L induced nuclear factor-κB (NF-κB) activation. PKCβ inhibition abolished CD40L-induced NF-κB activation, and NF-κB inhibition reduced expression of VCAM-1, each resulting in reduced THP-1 cell adhesion. Our findings provide the evidence that CD40L increases VCAM-1 expression in ECs by activating PKCβ and NF-κB, suggesting a novel mechanism for EC activation. Finally, administration of CD40L resulted in PKCβ activation, increased VCAM-1 expression and activated monocytes adhesiveness to HAECs, processes attenuated by PKCβ inhibitor. Therefore, CD40L may contribute directly to atherogenesis by activating ECs and recruiting monocytes to them.