Abstract
We investigated whether phosphatidic acid (PA) can differentiate the promyelocytic leukemia (PML)‐retinoic acid receptor α (RARα)‐expressing acute promyelocytic leukemic cell line, NB4, to dendritic cell (DC)‐like cells. Dioctanoyl‐PA alone upregulated the expression of DC markers. The expression of DC markers on NB4 cells was potentiated by the overexpression of phospholipase D and upregulation was blocked by the addition of n‐butanol, an inhibitor of PA production. The expression of CD11c, CD83, and CCR7 in PA‐treated NB4 cells was further increased by tumor necrosis factor (TNF)‐α treatment. Increased functional capacities were also found in PA‐differentiated and TNF‐α‐activated NB4 cells with respect to changes in T‐cell proliferation, cytokine production, endocytic activity, and cytolytic capacity against undifferentiated NB4 cells. PA alone increased the phosphorylation of extracellular signal‐regulated kinase (ERK)‐1/2. The expression of DC markers was downregulated by PD98059, a specific inhibitor of ERK kinase or transient transfection of mutant‐ERK. The level of PML‐RARα fusion protein was decreased by PA treatment and PD98059 blocked the decrease of PML‐RARα. These results suggest that PA induces differentiation of NB4 cells into DC‐like cells and that the upregulation of antigen presenting cell markers is mediated by the activation of ERK and the downregulation of PML‐RARα levels. J. Cell. Biochem. 100: 191–203, 2007. © 2006 Wiley‐Liss, Inc.