title: Protein kinase C beta mediates CD40 ligand-induced adhesion of monocytes to endothelial cells.
abstract: 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.
authors.affiliation: Department of General Surgery, Guangdong General Hospital, Guangzhou, Guangdong Province, China ; Guangdong Academy of Medical Sciences, Guangzhou, Guangdong Province, China.
authors.forename: Zeyu
authors.initials: Z
authors.lastname: Wu
authors.forename: Gang
authors.initials: G
authors.lastname: Zhao
authors.forename: Lin
authors.initials: L
authors.lastname: Peng
authors.forename: Jialin
authors.initials: J
authors.lastname: Du
authors.forename: Sanming
authors.initials: S
authors.lastname: Wang
authors.forename: Yijie
authors.initials: Y
authors.lastname: Huang
authors.forename: Jinrui
authors.initials: J
authors.lastname: Ou
authors.forename: Zhixiang
authors.initials: Z
authors.lastname: Jian
mesh_terms: D000818:Animals; D019013:CD40 Antigens / Q000235:genetics / Q000378:metabolism; D023201:CD40 Ligand / Q000502:physiology*; D002448:Cell Adhesion; D002460:Cell Line; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000502:physiology*; D000072000:NF-KappaB Inhibitor alpha; D010766:Phosphorylation; D064546:Protein Kinase C beta / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D051996:Transcription Factor RelA / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D019013:CD40 Antigens; D020672:I-kappa B Proteins; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; C498143:RELA protein, human; D051996:Transcription Factor RelA; D019010:Vascular Cell Adhesion Molecule-1; D000072000:NF-KappaB Inhibitor alpha; D023201:CD40 Ligand; D064546:Protein Kinase C beta
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