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Interleukin-18 directly activates T-bet expression and function via p38 mitogen-activated protein kinase and nuclear factor-κB in acute myeloid leukemia–derived predendritic KG-1 cells
Ist Teil von
Molecular cancer therapeutics, 2007-02, Vol.6 (2), p.723-731
Ort / Verlag
American Association for Cancer Research
Erscheinungsjahr
2007
Link zum Volltext
Quelle
EZB Electronic Journals Library
Beschreibungen/Notizen
The leukemic cell line KG-1 was isolated from a patient with acute myeloid leukemia and is regarded a cellular model of human
dendritic cell progenitors. The T helper type 1 cytokine interleukin (IL)-18 has been shown to induce the maturation of these
cells towards a dendritic phenotype and, moreover, is able to mediate IFNγ production in this model. Because T-box expressed
in T cells (T-bet) is considered to be of paramount importance for dendritic cell function, the effects of IL-18 on this transcription
factor have been investigated in the current study. Here, we show that activation of KG-1 cells by IL-18 induces T-bet mRNA
and protein within 4 to 6 h of incubation. This hitherto unrecognized function of IL-18 was suppressed by the inhibition of
p38 mitogen-activated protein kinase activity and nuclear factor-κB function. Blockage of translation by cycloheximide, usage
of neutralizing antibodies, and the inability of IFNγ to mediate significant p38 mitogen-activated protein kinase activation
in KG-1 cells clearly revealed that activation of T-bet was not via autocrine IFNγ. T-bet function was evaluated by short
interfering RNA technology. Notably, specific suppression of T-bet induction impaired secretion of IFNγ by KG-1 cells under
the influence of IL-18. Therapeutic application of IL-18 has the potential to profoundly affect the biology of acute myeloid
leukemia predendritic cells such as KG-1 cells. Under these conditions, activation of T-bet may play a key role in processes
that have the potential to correct the T helper type 1 deficiency associated with leukemia-mediated immunosuppression. [Mol
Cancer Ther 2007;6(2):723–31]