Involvement of TWEAK in interferon gamma-stimulated monocyte cytotoxicity

TWEAK, a new member of the tumor necrosis factor (TNF) family, induces cell death in some tumor cell Lines, but its physiological functions are largel y unknown. In this study, we investigated the expression and function of TW EAK in human peripheral blood mononuclear cells (PBMCs) by using newly gene rated anti-human TWEAK mAbs. Although freshly isolated PBMCs expressed no d etectable level of TWEAK on their surfaces, a remarkable TWEAK expression w as rapidly observed on monocytes upon stimulation with interferon (IFN)-gam ma but not with IFN-alpha or lipopolysaccharide. Cytotoxic activity of IFN- gamma -stimulated monocytes against human squamous carcinoma cell line HSC3 was inhibited partially by anti-TWEAK mAb alone and almost completely by c ombination with anti-TRAIL (TNF-related apoptosis-inducing ligand) mAb. The se results revealed a novel pathway of monocyte cytotoxicity against tumor cells that is mediated by TWEAK and potentiated by IFN-gamma.