Abstract 5165: Liver-x-receptor 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 activation of the nuclear transcription factor Liver-X-Receptor (LXR) limits plaque formation in animal models by modulating macrophage function. Previous data demonstrated LXR alpha and beta mRNA and protein expression in human CD4-positive lymphocytes. In addition, activation of LXR limits TH1-cytokine release from CD4-positive cells, but 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 μmol/L T0901317 (p<0.05 compared to SDF-1-treated cells, n=12). Similar results were received with the LXR activator GW3965. In addition, T0901317 also reduced RANTES-induced cell migration, suggesting an effect independent of the chemotactic stimulus employed. The effect of T0901317 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 the activation of the small GTPase Rac and the phosphorylation of the Myosin Light Chain (MLC). Pretreatment with the LXR activator also reduces f-actin formation as well as ICAM3 translocation to the uropod, both important steps in T cell migration. Transfection of CD4-positive lymphocytes with LXRα/β siRNA abolished T0901317 inhibitory effect on MLC-phosphorylation. 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.