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Toxic proteins from European mistletoe (Viscum album L.): increase of intracellular IL-4 but decrease of IFN-gamma in
G M Stein1, U Pfüller, M Schietzel
1Krebsforschung Herdecke, Department of Applied Immunology, University Witten/Herdecke, Communal Hospital, Germany. stein.g@debitel.net
Background:
Mistletoe lectins (ML), the major biologically active components of mistletoe extracts, which are used for adjuvant cancer therapy, induce apoptosis in lymphocytes and tumor cells. In addition, ML at toxic concentrations induce the release of cytokines, but it remains unclear as to whether dying or activated cells are responsible.
Materials And Methods:
By flow cytometry, expression of IFN-gamma, IL-4, apoptosis marker Apo2.7 and anti-apoptotic Bcl-2 proteins were analyzed in response to ML or viscotoxins (VT) in PBMC from controls and plasmocytoma cells (U-266).
Results:
While ML inhibited 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, indicating that IL-4 expression is related to apoptosis but not to necrosis.
Conclusion:
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.
Insights
Mistletoe lectins (ML) induce apoptosis and increase Interleukin-4 (IL-4) in T-cells, primarily in dying cells. This suggests IL-4 plays a role in apoptosis beyond T-helper cell activation.
Area of Science:
- Immunology
- Cancer Therapy
Background:
- Mistletoe lectins (ML) are key components of mistletoe extracts used in cancer therapy.
- ML induce apoptosis in lymphocytes and tumor cells.
- The role of dying versus activated cells in cytokine release upon ML exposure is unclear.
Purpose of the Study:
- To investigate the role of ML and viscotoxins (VT) in cytokine production and apoptosis.
- To determine if IL-4 expression is linked to apoptosis or necrosis induced by ML.
Main Methods:
- Flow cytometry was used to analyze IFN-gamma, IL-4, Apo2.7 (apoptosis marker), and Bcl-2 protein expression.
- Peripheral blood mononuclear cells (PBMC) from controls and plasmocytoma cells (U-266) were treated with ML or VT.
Main Results:
- ML inhibited IFN-gamma production but increased IL-4 expression in CD8+ and CD4+ T-cells.
- IL-4 was predominantly found in apoptotic cells with low Bcl-2 levels.
- VT induced cell membrane permeabilization and Bcl-2 loss but not IL-4 production, indicating IL-4 is linked to apoptosis, not necrosis.
Conclusions:
- IL-4 expression is associated with apoptosis induced by mistletoe lectins.
- IL-4 may have an important, yet undefined, role in the apoptosis of normal and tumor cells.
- These findings contribute to understanding the mechanisms of mistletoe extract in cancer therapy.