Fludarabine induces growth arrest and apoptosis of cytokine- or alloantigen-stimulated peripheral blood mononuclear cells, and decreases production of Th1 cytokines via inhibition of nuclear factor kappaB.
Fludarabine is a purine analog that has demonstrated significant activity in B-cell malignancies, including CLL. Fludarabine also possesses an immunosuppressive effect and is being used to prevent GVHD in hematopoietic stem cell transplantation. However, the molecular mechanism by which fludarabine inhibits immunoreaction remains to be fully elucidated. This study found that fludarabine inhibited tumor necrosis factor alpha (TNF-alpha)-stimulated degradation of IkappaBalpha, resulting in blockade of nuclear translocation of nuclear factor kappaB (NF-kappaB) in Jurkat T cells, as measured by western blot analysis and immunocytochemistry. The ability of fludarabine to inhibit NF-kappaB was further confirmed by electrophoretic mobility shift assay. We also found that fludarabine induced growth arrest and apoptosis of alloreactive and TNF-alpha-stimulated PBMCs. In addition, fludarabine inhibited TNF-alpha-stimulated production of IL-2 and IFN-gamma, which play important roles in the onset of GVHD, in Jurkat cells. Taken together, fludarabine is useful for management of immune diseases, including GVHD, through inactivation of NF-kappaB.
Nishioka
C
C
Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan.
Ikezoe
T
T
Togitani
K
K
Yokoyama
A
A
D017209:Apoptosis / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D019169:Jurkat Cells / Q000187:drug effects; D007963:Leukocytes, Mononuclear / Q000187:drug effects*; D016328:NF-kappa B / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects*; D018417:Th1 Cells / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000494:pharmacology
D007166:Immunosuppressive Agents; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D014740:Vidarabine; C024352:fludarabine