Ac-SDKP suppresses TNF-α-induced ICAM-1 expression in endothelial cells via inhibition of IκB kinase and NF-κB activation
Zhu L, Yang XP, Janic B, Rhaleb NE, Harding P, Nakagawa P, Peterson EL, Carretero OA. Ac-SDKP suppresses TNFalpha-induced ICAM-1 expression in endothelial cells via inhibition of IkappaB kinase and NF-kappaB activation. Am J Physiol Heart Circ Physiol. 2016;310(9):H1176-83.
American journal of physiology. Heart and circulatory physiology
N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a naturally occurring tetrapeptide that prevents inflammation and fibrosis in hypertension and other cardiovascular diseases. We previously showed that, in angiotensin II-induced hypertension, Ac-SDKP decreased the activation of nuclear transcription factor NF-κB, whereas, in experimental autoimmune myocarditis and hypertension animal models, it also reduced the expression of endothelial leukocyte adhesion molecule ICAM-1. However, the mechanisms by which Ac-SDKP downregulated ICAM-1 expression are still unclear. TNF-α is a proinflammatory cytokine that induces ICAM-1 expression in various cell types via TNF receptor 1 and activation of the classical NF-κB pathway. We hypothesized that in endothelial cells Ac-SDKP suppresses TNF-α-induced ICAM-1 expression by decreasing IKK phosphorylation that as a consequence leads to a decrease of IκB phosphorylation and NF-κB activation. To test this hypothesis, human coronary artery endothelial cells were treated with Ac-SDKP and then stimulated with TNF-α. We found that TNF-α-induced ICAM-1 expression was significantly decreased by Ac-SDKP in a dose-dependent manner. Ac-SDKP also decreased TNF-α-induced NF-κB translocation from cytosol to nucleus, as assessed by electrophoretic mobility shift assay, which correlated with a decrease in IκB phosphorylation. In addition, we found that Ac-SDKP decreased TNF-α-induced IKK phosphorylation and IKK-β expression. However, Ac-SDKP had no effect on TNF-α-induced phosphorylation of p38 MAP kinase or ERK. Thus we conclude that Ac-SDKP inhibition of TNF-α activation of canonical, i.e., IKK-β-dependent, NF-κB pathway and subsequent decrease in ICAM-1 expression is achieved via inhibition of IKK-β.
Medical Subject Headings
Active Transport, Cell Nucleus; Anti-Inflammatory Agents; Cells, Cultured; Dose-Response Relationship, Drug; Endothelial Cells; Humans; I-kappa B Kinase; Intercellular Adhesion Molecule-1; NF-kappa B; Oligopeptides; Phosphorylation; Signal Transduction; Tumor Necrosis Factor-alpha; Up-Regulation