Ifosfamide impairs the allostimulatory capacity of human dendritic cells by intracellular glutathione depletion.
Ifosfamide, a clinically potent chemotherapeutic agent, causes the depletion of intracellular glutathione (GSH) levels in various cell types. GSH is the major intracellular reductant against oxidative stress. 4-Hydroxyifosfamide (4-OH-IF), the activated form of ifosfamide, depletes GSH levels in T cells and natural killer (NK) cells; this is accompanied by a decrease in T-cell and NK-cell function. Here we demonstrate for the first time that human monocyte-derived dendritic cells (DCs) express higher constitutive levels of GSH and are less sensitive to 4-OH-IF-induced GSH depletion than T cells and NK cells. Treatment of DCs with 4-OH-IF significantly reduced their ability to stimulate allogeneic T-cell proliferation and interferon-gamma (IFN-gamma) production. Ifosfamide also decreased DC interleukin-12p70 (IL-12p70) production after stimulation with lipopolysaccharide (LPS) and IFN-gamma. The decrease in allostimulatory capacity and in IFN-gamma and IL-12 production correlated with a decrease in intracellular GSH in the DCs. The responses could be restored by reconstituting DC GSH levels with glutathione monoethyl ester (GSH-OEt). 4-OH-IF had no inhibitory effect on the ability of DCs to present exogenously added tyrosinase peptide to tyrosinase-specific cytotoxic T lymphocytes (CTLs). These studies suggest that in cancer patients treated with ifosfamide, protection strategies based on glutathione reconstitution may enhance DC function.
Kuppner
Maria C
MC
Klinikum Grosshadern Medical Clinic II, Ludwig-Maximillians-University, Munich, Germany. kuppner@gsf.de
Scharner
Anabel
A
Milani
Valeria
V
Von Hesler
Christoph
C
Tschop
Katharina E
KE
Heinz
Oksana
O
Issels
Rolf D
RD
D017951:Antigen Presentation / Q000187:drug effects; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D005978:Glutathione / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007069:Ifosfamide / Q000009:adverse effects*; D007111:Immunity, Cellular / Q000187:drug effects; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000187:drug effects; D008213:Lymphocyte Activation / Q000187:drug effects; D009000:Monocytes / Q000166:cytology; D013601:T-Lymphocytes / Q000187:drug effects
D018906:Antineoplastic Agents, Alkylating; D018664:Interleukin-12; D007371:Interferon-gamma; D005978:Glutathione; D007069:Ifosfamide