Unveiling of endothelial nuclear factor-κB (NF-κB) 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-κB activation and inflammatory responses. In human endothelial cells, vascular endothelial growth factor (VEGF) induced NF-κB-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 IκB kinase (IKK) activity, IκBα phosphorylation, and nuclear translocation of NF-κB 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-κB activation as well as monocyte adhesion induced by IL-1β and TNF-α. The data collectively suggest that ERK serves as an anti-inflammatory signal that suppresses expression of NF-κB-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.
Bibliographical noteFunding Information:
This work was supported by a Next Generation Growth Engine Program Grant and Vascular System Research Center Grant from the Korean Ministry of Science and Technology.
All Science Journal Classification (ASJC) codes
- Cell Biology