Induction of CXC and CC chemokines by all-trans retinoic acid in acute promyelocytic leukemia cells

We previously reported the induction of interleukin-8 (IL-8), one of the CXC chemokines, by all-trans retinoic acid (ATRA) in PL-21 and NB4 human myeloid leukemia cells, which may be implicated in APL differentiation syndrome that is a relatively frequent complication in patients with acute promyelocytic leukemia (APL) during treatment with ATRA. We, therefore, further investigated the effects of ATRA on the expression of chemokine family in NB4 cells and APL cells prepared from two APL patients. The RNase protection assay using a multi-probe template set for human chemokines revealed that ATRA induced gene expressions of a number of CC chemokines, such as monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein (MIP)-1α and MIP-1β in NB4 cells. Their antigen levels were also increased in the cultured media. APL cells prepared from two APL patients showed gene expression of chemokines, such as IL-8, MCP-1, MIP-1α, and MIP-1β when stimulated with ATRA in vitro. Furthermore, serum levels of IL-8, MIP-1β and RANTES were increased during the course of ATRA treatment in both APL patients who developed APL differentiation syndrome. These chemokines are all chemoattractants of particular inflammatory cell types, including neutrophils, monocytes and lymphocytes; therefore, the simultaneous induction of these chemokines after stimulation with ATRA may exacerbate the hyper-inflammation observed in ATRA-induced APL differentiation syndrome.