Toxic proteins from European mistletoe (Viscum album L.: Increase of intracellular IL-4 but decrease of IFN-gamma in apoptotic cells

Background: Mistletoe lectins;(ML), the major biologically active component s of mistletoe extracts, which are used for adjuvant cancer therapy, induce apoptosis in lymphocytes and tumor cells. In addition, ML at toxic concent rations induce the release of cytokines, but it remains unclear, as to whet her dying or activated cells are responsible. Materials and Methods: By flo w cytometry, expression of IFN-gamma, IL-4, apoptosis marker Apo2.7 and ant i-apoptotic Bcl-2 proteins were analyzed in response to ML or viscotoxins ( VT) in PBMC om controls and plasmocytoma cells (U-266). Results: While ML i nhibited PMA/Ca-ionophore/monensin co-stimulated IFN-gamma production, they increased IL-4 expression in CD8(+) and CD4(+) T-cells. Thereby, IL-4 was mainly expressed in apoptotic cells with a low level of Bcl-2 proteins. In contrast, the cell membrane permeabilising VT induced complete loss of Bcl- 2 proteins but did not stimulate IL-4 production within 24 hours, indicatin g that IL-4 expression is related to apoptosis but not to necrosis. Conclus ion: Despite the role of IL-4 during activation of type2 T-helper cells, IL -4 expression may play an important yet undefined role during apoptosis of normal and tumor cells.