IFNalpha-stimulated neutrophils and monocytes release a soluble form of TNF-related apoptosis-inducing ligand (TRAIL/Apo-2 ligand) displaying apoptotic activity on leukemic cells.

Tumor necrosis factor (TNF)–related apoptosis-inducing ligand (TRAIL) is a memberof the TNF superfamily exerting cytotoxicactivities toward tumor cells. Herein,we demonstrate that therapeutic concentrationsof interferon (IFN) stimulatethe expression of high levels of TRAILmRNA and the release of elevatedamounts of a soluble bioactive form ofTRAIL (sTRAIL) in both human neutrophilsand monocytes. Supernatants harvestedfrom IFN-treated neutrophils/monocytes elicited, on TRAIL-sensitiveleukemic cell lines, proapoptotic activitiesthat were significantly reduced byeither a combination of TRAIL-R1/Fc andTRAIL-R2/Fc chimeras or neutralizing anti-TRAIL, anti–TRAIL-R1, and anti–TRAIL-R2antibodies, suggesting that they were mediatedby released sTRAIL acting on bothTRAIL receptors. Since diseases such aschronic myeloid leukemia (CML) and melanomaare effectively treated with IFN, wealso demonstrate that CML neutrophilsand peripheral blood mononuclear cells(PBMCs) cultured with IFN at therapeuticconcentrations retain the capacity ofreleasing sTRAIL, suggesting that CMLleukocytes, in vivo, might represent animportant source of sTRAIL. In this regard,we show that sTRAIL serum levelsas well as leukocyte-associated TRAILsignificantly increase in melanoma patientsfollowing IFN administration. Collectively,these findings indicate thatsTRAIL released by IFN-activated neutrophilsand monocytes contributes not onlyto the immunoregulatory actions but alsoto the therapeutic activities of IFN.