title: ERK is an anti-inflammatory signal that suppresses expression of NF-kappaB-dependent inflammatory genes by inhibiting IKK activity in endothelial cells.
abstract: Unveiling of endothelial nuclear factor-kappaB (NF-kappaB) activation is pivotal for understanding the inflammatory reaction and the pathogenesis of inflammatory vascular diseases. We here report the novel function of extracellular signal-related kinase (ERK) in controlling endothelial NF-kappaB activation and inflammatory responses. In human endothelial cells, vascular endothelial growth factor (VEGF) induced NF-kappaB-dependent transcription of cell adhesion molecules (CAMs) and monocyte adhesion. These effects were prominently enhanced by either pretreatment with the MEK inhibitors, PD98059 and U0126 or overexpression of a dominant negative form of MEK, but blocked by a wild type ERK. Consistently, inhibition of ERK significantly increased IkappaB kinase (IKK) activity, IkappaBalpha phosphorylation, and nuclear translocation of NF-kappaB induced by VEGF, whereas overexpression of ERK resulted in the loss of these responses to VEGF. Using two PKC inhibitors has demonstrated that VEGF concomitantly stimulates IKK and its negative regulatory signal ERK through PKC that lies downstream of KDR/Flk-1. Strikingly, elevation of ERK in endothelial cells markedly inhibited CAM expression and NF-kappaB activation as well as monocyte adhesion induced by IL-1beta and TNF-alpha. The data collectively suggest that ERK serves as an anti-inflammatory signal that suppresses expression of NF-kappaB-dependent inflammatory genes by inhibiting IKK activity in endothelial cells. Measuring the existence of ERK activity in vascular endothelial cells may be useful for predicting the feasibility and potency of inflammatory reactions in the vasculature.
authors.affiliation: Department of Biochemistry College of Sciences, Yonsei University, Seoul 120-749, Korea.
authors.forename: Yong-Sun
authors.initials: YS
authors.lastname: Maeng
authors.forename: Jeong-Ki
authors.initials: JK
authors.lastname: Min
authors.forename: Jeong Hun
authors.initials: JH
authors.lastname: Kim
authors.forename: Akiko
authors.initials: A
authors.lastname: Yamagishi
authors.forename: Naoki
authors.initials: N
authors.lastname: Mochizuki
authors.forename: Ja-Young
authors.initials: JY
authors.lastname: Kwon
authors.forename: Yong-Won
authors.initials: YW
authors.lastname: Park
authors.forename: Young-Myeong
authors.initials: YM
authors.lastname: Kim
authors.forename: Young-Guen
authors.initials: YG
authors.lastname: Kwon
mesh_terms: D021581:Active Transport, Cell Nucleus; D002448:Cell Adhesion; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation; D042783:Endothelial Cells / Q000378:metabolism / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D007375:Interleukin-1 / Q000502:physiology; D009000:Monocytes / Q000502:physiology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000502:physiology; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
chemical_list: D005419:Flavonoids; D007375:Interleukin-1; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; D018799:Intercellular Adhesion Molecule-1; D051550:I-kappa B Kinase; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one