PPARγ Agonists Inhibit Adhesion Signal to Endothelial Cells in the Differentiation Induction of HL-60 Acute Promyelocytic Leukemia Cells

Abstract

All-trans retinoic acid (ATRA) has successfully been used in the treatment of acute promyelocytic leukemia (APL) patients, with a remission rate of greater than 90% . Despite the high cure rates, induction mortality is a still a problem in APL. One of the most common causes of death was the differentiation syndrome (DS) . The early administration of high-dose dexamethasone at the onset of the first signs or symptoms of DS is crucial, however specific biological therapies to counteract the syndrome are still not available. Peroxisome proliferator activated receptor gamma (PPARγ) is a ligand-dependent transcription factor and a member of the nuclear receptor superfamily, which is expressed in normal monocytes, various leukemias, and epithelial malignancies. PPARγ is highly induced in differentiating myeloid cells and subsequently contributes to their differentiation. Differentiation induction of APL cells is associated with increased expression of specific adhesion molecules and inflammatory cytokines, which may promote activation, migration, and adhesion of these cells. Here, we studied the effect of PPARγ agonists on the adhesion of a human leukemia cell line (HL-60) to endothelial cells. HL-60 cells were differentiated into macrophage-like cells by a PKC activator, 12-O-Tetradecanoylphorbol-13-acetate (TPA). Differentiation was determined by an increase in reactivity with the CD11b antibody. For the adhesion assay, the Matrigel transwell system was used. During the differentiation of HL-60 cells, PPARγ agonists acitvate TPA-induced CD11b expression. However, PPARγ agonists completely blocked TPA-induced ICAM-1 expression of endothelial cells, which resulted in the inhibition of adhesion of HL-60 cells to endothelial cells. These responses also were reversed by PPARγ antagonist (GW9662), indicating that PPARγ agonists inhibits the adhesion of the HL-60 cells to endothelial cells through a PPARγ dependent mechanism. These results suggest that PPARγ agonists inhibit TPA-induced adhesion signal in the between HL-60 cells and endothelial cells, and may control differentiation syndrome in APL patients. DisclosuresNo relevant conflicts of interest to declare.