IL-8 and MCP-1 Regulate the Transmigration of Acute Promyelocytic Leukemia toward Alveolar Type II Cells.

All-trans retinoic acid (ATRA) can induces complete remission in patients with acute promyelocytic leukemia (APL), and can also induce retinoic acid (RA) syndrome in upto 30 % of patients. Massive infiltration of APL cells can be found in the alveolar spaces in the patients with RA syndrome, indicating that ATRA-treated APL cells can migrate from blood vessels into the alveolar space and cause a cascade of reactions which results a clinical picture similar to adult respiratory distress syndrome. In this study, we determine the role of IL-8 and monocytes chemotactic protein-1 (MCP-1) in the cross-talk between APL cells and alveolar cells, and their role in the pathophysiology of RA syndrome. In the transmigration assay, ATRA-treated APL cells (NB4 cells) can transmigrate toward alveolar type II cells (A549 cells) in a dose dependent manner (ATRA: 0.01 to 1 mM), which is also in parallel with increased granulocytic differentiation. Chemoattractant activity can be found in the conditioning medium (CM) of A549 cells in the time dependent manner (1-3 days). When exposed to either IL-8 or MCP-1, chemotactic effect can also be found in the ATRA -treated NB4 cells, but not in untreated NB4 cells. We further determined the concentration of IL-8 or MCP-1 in the CM by ELISA. Our data show that the levels of both cytokines were progressively increased in the CM of A549 cells. Synergistic effect was found when A549 cells were co-cultured with NB4 cells. In the presence of ATRA, the levels of IL-8 and MCP-1 were further increased in the CM of co-culture of NB4 cells and A549 cells (p<0.05 & p<0.05; respectively). The chemotactic activity in CM of A549 cells was partially inhibited when the CM was neutralized with anti-IL-8 or anti-MCP-1 antibodies, respectively. In binding assay by flowcytometry, we further demonstrated that both IL-8 and MCP-1 were bound by the ATRA-treated NB4 cells, but not in un-treated NB4 cells. We conclude that both IL-8 and MCP can induce ATRA-treated APL transmigrating toward alveolar space and causing cascade of reactions leading to RA syndrome.