title: Mycophenolic acid regulates spleen tyrosine kinase to repress tumour necrosis factor-alpha-induced monocyte chemotatic protein-1 production in cultured human aortic endothelial cells.
abstract: Atherosclerosis develops from cascades of inflammatory processes. Spleen tyrosine kinase (Syk) and monocyte chemotatic protein-1 (MCP-1) play important roles in the pathogenesis of atherosclerosis. Mycophenolic acid (MPA) has an anti-inflammatory effect. We have investigated whether MPA regulates Syk to repress tumour necrosis factor-α (TNF-α)-induced MCP-1 production in cultured human aortic endothelial cells. Expression of MCP-1 mRNA and its protein were measured by real time RT-PCR and ELISA, respectively. Reactive oxygen species (ROS) production were measured using 2'7'-dichlorofluorescein diacetate. Activation of AP-1 and NF-κB were assessed by electrophoretic mobility shift assay. Tyrosine phosphorylation of Syk was examined by Western blot analysis. TNF-α increased MCP-1 at both mRNA and protein levels. TNF-α-induced MCP-1 mRNA expression was inhibited by N-acetylcysteine (NAC), Syk inhibitor, Syk-siRNA and MPA. TNF-α-induced MCP-1 protein production was also inhibited by Syk inhibitor and MPA. TNF-α increased DNA binding activity of AP-1 and NF-κB, whereas both AP-1 and NF-κB decoy oligodeoxynucleotides downregulated TNF-α-induced MCP-1 mRNA expression. TNF-α increased ROS generation, which was inhibited by NAC and MPA, but not by Syk inhibitor. TNF-α increased tyrosine phosphorylation of Syk, which was attenuated by NAC and MPA. MPA and Syk inhibitor attenuated TNF-α-induced DNA binding activity of NF-κB and AP-1. TNF-α induced MCP-1 expression via activation of AP-1 and NF-κB. AP-1 and NF-κB were mediated through ROS, followed by Syk. MPA exerts anti-inflammatory effect by inhibiting MCP-1 expression via suppression of ROS and Syk.
authors: Division of Nephrology, Department of Internal Medicine, Asan Medical Center, University of Ulsan, Seoul, Republic of Korea.
authors: Tai Yeon
authors: TY
authors: Koo
authors: Yoon Ji
authors: YJ
authors: Kim
authors: Won Seok
authors: WS
authors: Yang
authors: Jung Sik
authors: JS
authors: Park
authors: Nam Jeong
authors: NJ
authors: Han
authors: Joo Mi
authors: JM
authors: Lee
authors: Su Kil
authors: SK
authors: Park
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001011:Aorta / Q000166:cytology / Q000378:metabolism; D018932:Chemokine CCL2 / Q000096:biosynthesis*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D009173:Mycophenolic Acid / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D000072377:Syk Kinase; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D018932:Chemokine CCL2; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D009173:Mycophenolic Acid