17Beta-estradiol inhibits monocyte adhesion via down-regulation of Rac1 GTPase.
Estrogens confer atheroprotective effects that remain poorly understood. We hypothesised that estrogens directly target monocytes, and investigated the pathways via which estrogens might impact on monocyte adhesion. In an in vitro model of the vasculature (parallel plate laminar flow chamber, 2 dynes/cm2), 17beta-estradiol (24 h, 0.1-1 microM) potently inhibits monocyte adhesion. In parallel, 17beta-estradiol down-regulates Rac1 GTPase activity in monocytes. Transfection of monocytic cells with dominant-negative Rac1N17 significantly decreases adhesion to human endothelial cells, while constitutively-active Rac1L61 augments adhesion. As determined by pull-down assays, Rac1 is rapidly activated by the chemokine stromal-derived factor-1 (SDF-1) in human monocytes (100 nM, 30 s). Within the same time period, SDF-1 mediates both ICAM-1/beta2- and VCAM-1/beta1-integrin-dependent monocyte adhesion, which is significantly decreased in cells overexpressing dominant-negative Rac1N17. Inhibitor studies revealed that Rac1-triggered monocyte adhesion is dependent upon actin rearrangement, while production of reactive oxygen species via Rac1 is not involved. Estrogen directly inhibits monocyte adhesion via down-regulation of Rac1, which is both necessary and sufficient to enhance monocyte adhesion under physiological flow conditions. These studies extend current knowledge about the mechanisms responsible for the vascular recruitment of pro-inflammatory cells, and potentially open up new avenues for the therapy of atherosclerosis.
Friedrich
Erik B
EB
Department for Internal Medicine III, University Hospital of the Saarland, 66421 Homburg/Saar, Germany.
Clever
Yvonne P
YP
Wassmann
Sven
S
Hess
Christoph
C
Nickenig
Georg
G
D000199:Actins / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects*; D018929:Cell Culture Techniques / Q000379:methods; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism / Q000494:pharmacology; D015536:Down-Regulation; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
D000199:Actins; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C107953:RAC1 protein, human; D017382:Reactive Oxygen Species; D019718:Receptors, CXCR4; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D004958:Estradiol; D020830:rac1 GTP-Binding Protein