Treatment with IFNαin vivo up‐regulates serum‐soluble TNF‐related apoptosis inducing ligand (sTRAIL) levels and TRAIL mRNA expressions in neutrophils in chronic myelogenous leukemia patients

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an interferon alpha (IFNalpha)-induced, apoptosis-inducing molecule. TRAIL could be one of the reagents for therapeutic use in combination with imatinib in chronic myeloid leukemia (CML). Here we examined serum-soluble TRAIL (sTRAIL) levels in CML patients either before or during therapies with IFNalpha or imatinib. In untreated CML patients, serum sTRAIL was detectable and the levels were substantially comparable with those in healthy donors. sTRAIL levels significantly increased in patients during IFNalpha therapy, but not at all in patients during imatinib therapy. TRAIL mRNA expressions in neutrophils in CML patients undergoing IFNalpha therapy was significantly elevated when compared with those in patients prior to therapy. TRAIL mRNA expressions were also detectable in CD34-positive cells in bone marrow, and the levels increased in patients during IFNalpha therapy. In vitro IFNalpha stimulation of CML neutrophils increased intracellular TRAIL rather than cell-surface TRAIL, and the secretion of sTRAIL in the culture supernatant was observed. This sTRAIL secretion was augmented with lipopolysaccharide (LPS) stimulation only in IFNalpha-primed neutrophils, whereas LPS alone had no effect. Taken together, in vivo IFNalpha treatment provokes the release of sTRAIL when administered systematically in CML patients. The main source of the IFNalpha-induced serum sTRAIL may be neutrophils in CML, and sTRAIL may be one of the mechanisms of the anti-proliferative action of IFNalpha on CML. These findings give another rationale for the use of IFNalpha or recombinant sTRAIL in CML, and also implicate the potential importance of neutrophils in tumor immunosurveillance.