LXR activation inhibits chemokine-induced CD4-positive lymphocyte migration.
Migration of CD4-positive lymphocytes into the vessel wall is a critical step in atherogenesis. Recent data suggest that CD4-positive lymphocytes express the nuclear transcription factors Liver-X-Receptor (LXR) alpha and beta with an effect of LXR activators on TH1-cytokine release from these cells. However, the role of LXR in lymphocyte migration remains currently unexplored. Therefore, the present study investigated whether LXR activation might modulate chemokine-induced migration of these cells. Stimulation of CD4-positive lymphocytes with SDF-1 leads to a 2.5 +/- 0.8-fold increase in cell migration (P < 0.05; n = 12). Pretreatment of cells with the LXR activator T0901317 reduces this effect in a concentration-dependent manner to a maximal 0.9 +/- 0.4-fold induction at 1 micromol/L T0901317 (P < 0.05 compared to SDF-1-treated cells; n = 12). Similar results were obtained with the LXR activator GW3965. The effect of LXR activators on CD4-positive lymphocyte migration was mediated through an early inhibition of chemokine-induced PI-3 kinase activity as determined by PI-3 kinase activity assays. Downstream, T0901317 inhibited activation of the small GTPase Rac and phosphorylation of the myosin light chain (MLC). Moreover, LXR activator treatment reduced f-actin formation as well as ICAM3 translocation to the uropod of the cell, thus interfering with two important steps in T cell migration. Transfection of CD4-positive lymphocytes with LXRalpha/beta siRNA abolished T0901317 inhibitory effect on MLC phosphorylation and ICAM3 translocation. LXR activation by T0901317 or GW3965 inhibits chemokine-induced migration of CD4-positive lymphocytes. Given the crucial importance of chemokine-induced T cell migration in early atherogenesis, LXR activators may be promising tools to modulate this effect.
Walcher
Daniel
D
Department of Internal Medicine II-Cardiology, University Ulm, Robert-Koch-Strasse 8, Ulm, Germany. daniel.walcher@uniklinik-ulm.de
Vasic
Dusica
D
Heinz
Philipp
P
Bach
Helga
H
Durst
Renate
R
Hausauer
Angelina
A
Hombach
Vinzenz
V
Marx
Nikolaus
N
D000199:Actins / Q000378:metabolism; D015703:Antigens, CD / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D054441:Cell Migration Assays, Leukocyte; D002465:Cell Movement; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000378:metabolism; D006801:Humans; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D018994:Myosin Light Chains / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction; D013449:Sulfonamides; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D000199:Actins; D015703:Antigens, CD; D015815:Cell Adhesion Molecules; D018946:Chemokine CCL5; D054377:Chemokine CXCL12; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D018994:Myosin Light Chains; D057093:Orphan Nuclear Receptors; D019869:Phosphatidylinositol 3-Kinases; D013449:Sulfonamides; D020830:rac1 GTP-Binding Protein; C483616:ICAM3 protein, human; C000605213:NR1H3 protein, human; C107953:RAC1 protein, human; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides