Involvement of tumor necrosis factor (TNF-α) in arsenic trioxide induced apoptotic cell death of murine myeloid leukemia cells

Arsenic trioxide (As 2O 3) has recently been shown to be effective to inhibit the growth and to induce apoptosis in acute promyelocytic leukemia (APL) but not in acute myeloid leukemia (AML) cells. Recently, we have isolated an As 2O 3 sensitive subclone JCS-16 from the murine myeloid leukemia WEHI 3B (JCS). At the concentrations of 0.3–3 μM, As 2O 3 induces a dose-dependent cytotoxicity and growth inhibition on the JCS-16 cells. As 2O 3 also induces apoptotic cell death, as judged by the presence of apoptotic nuclei, at 6 h after treatment. Morphological differentiation was not observed in As 2O 3 treated JCS cells. Neutralizing anti-TNF-α antibody was found to reduce the As 2O 3-mediated apoptotic cell death of JCS-16 cells. Growth inhibitory effect of As 2O 3 was also reduced after the addition of anti-TNF-α. In addition, reverse transcription polymerase chain reaction (RT-PCR) and reverse northern blot analysis demonstrated that the expression of TNF receptor (TNF-R2), IL-4, and IL-4R was down-regulate at 1 h after As 2O 3 treatment. The expression of TNF-α and TNF-R1 was not affected. Our results suggest that the autocrine action of TNF-α might play a role in As 2O 3-induced apoptotic cell death of JCS-16 leukemia cells.