Lovastatin stimulates p75 TNF receptor (TNFR2) expression in primary human endothelial cells.
HMG-CoA reductase inhibitors (statins) exert pleiotropic physiological effects. Among others they attenuate cellular responses to genotoxic and inflammatory stress. We investigated the effect of lovastatin on the expression level of TNF receptors (TNFR) in primary human endothelial cells (HUVEC). ELISA, FACS and immunocytochemical analyses show that lovastatin selectively increases the cell surface expression of TNFR2 without affecting the expression level of TNFR1. This effect of lovastatin is independent from inhibition of cell-cycle progression since cells both in G1- and G2-phase showed elevated levels of TNFR2 after lovastatin treatment. To analyze the physiological relevance of lovastatin-mediated upregulation of TNFR2, we investigated the expression of the cell adhesion molecule E-selectin, which is inducible by TNFalpha. While lovastatin on its own did not change the number of HUVEC expressing E-selectin protein, it promoted the TNFalpha-stimulated increase in the percentage of E-selectin expressing endothelial cells in a dose-dependent manner. This indicates that lovastatin sensitizes HUVEC towards TNFalpha-induced signaling by upregulation of TNFR2 expression. Based on the data, we suggest that statins have impact on endothelial responses to inflammatory stress by modulation of the expression of cytokine receptors.
Nübel
Tobias
T
Department of Toxicology, University of Mainz, Mainz, Germany.
Schmitt
Steffen
S
Kaina
Bernd
B
Fritz
Gerhard
G
D002453:Cell Cycle / Q000187:drug effects; D002478:Cells, Cultured; D019040:E-Selectin / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D008148:Lovastatin / Q000494:pharmacology*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects*
D019040:E-Selectin; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D008148:Lovastatin