The effect of carboxydextran-coated superparamagnetic iron oxide nanoparticles on c-Jun N-terminal kinase-mediated apoptosis in human macrophages.
Superparamagnetic iron oxide nanoparticles are frequently used for cell labeling or as diagnostic contrast media, yet studies analyzing their effects on immune cells remain scarce. Here we investigated how nanosized carboxydextran-coated superparamagnetic iron oxide (SPIO) and ultrasmall superparamagnetic iron oxide (USPIO) might affect human macrophages. Within 1 h, both SPIO and USPIO were rapidly taken up by macrophages. Confocal microscopy revealed that after 24 h the particles were almost exclusively localized within the lysosomal compartment. Continued cultivation of the macrophages for several days was associated with apoptosis induction caused by a long-lasting activation of the c-Jun N-terminal kinase (JNK) pathway. JNK activation was due to significantly elevated levels of reactive oxygen species, whereas no TNF-alpha was produced by the macrophages treated with nanoparticles. Compared to SPIO, USPIO induced more pronounced biochemical alterations and cytotoxicity, which could be antagonized by the JNK inhibitor V. Alternatively, treatment of macrophages with Trolox or N-acetyl-L-cysteine, two functionally different scavengers of reactive oxygen species, abolished both the JNK activation and the subsequent cytotoxic effects. These data indicate that nanosized superparamagnetic iron oxide-based contrast media exert cytotoxicity in human macrophages that can be functionally antagonized with radical scavengers.
Lunov
Oleg
O
Institute of Pharmacology of Natural Products & Clinical Pharmacology, Helmholtzstr. 20, Ulm University, D-89081 Ulm, Germany.
Syrovets
Tatiana
T
Büchele
Berthold
B
Jiang
Xiue
X
Röcker
Carlheinz
C
Tron
Kyrylo
K
Nienhaus
G Ulrich
GU
Walther
Paul
P
Mailänder
Volker
V
Landfester
Katharina
K
Simmet
Thomas
T
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D020099:Coated Materials, Biocompatible / Q000008:administration & dosage*; D003911:Dextrans / Q000008:administration & dosage*; D052203:Ferrosoferric Oxide / Q000008:administration & dosage*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D058185:Magnetite Nanoparticles; D053758:Nanoparticles / Q000008:administration & dosage*
D020099:Coated Materials, Biocompatible; D003911:Dextrans; D058185:Magnetite Nanoparticles; C097921:ferumoxtran-10; D048031:JNK Mitogen-Activated Protein Kinases; D052203:Ferrosoferric Oxide