title: Interleukin-18 directly activates T-bet expression and function via p38 mitogen-activated protein kinase and nuclear factor-kappaB in acute myeloid leukemia-derived predendritic KG-1 cells.
abstract: 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 IFNgamma 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-kappaB function. Blockage of translation by cycloheximide, usage of neutralizing antibodies, and the inability of IFNgamma to mediate significant p38 mitogen-activated protein kinase activation in KG-1 cells clearly revealed that activation of T-bet was not via autocrine IFNgamma. T-bet function was evaluated by short interfering RNA technology. Notably, specific suppression of T-bet induction impaired secretion of IFNgamma 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.
authors.affiliation: Pharmazentrum Frankfurt, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: Malte
authors.initials: M
authors.lastname: Bachmann
authors.forename: Cristina
authors.initials: C
authors.lastname: Dragoi
authors.forename: Marco A
authors.initials: MA
authors.lastname: Poleganov
authors.forename: Josef
authors.initials: J
authors.lastname: Pfeilschifter
authors.forename: Heiko
authors.initials: H
authors.lastname: Mühl
mesh_terms: D019898:Autocrine Communication; D015153:Blotting, Western; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D018922:HL-60 Cells; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D020382:Interleukin-18 / Q000494:pharmacology*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D053707:Receptors, Interleukin-12 / Q000378:metabolism; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018417:Th1 Cells; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000098815:T-bet Transcription Factor
chemical_list: D020382:Interleukin-18; D016328:NF-kappa B; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D053707:Receptors, Interleukin-12; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D007371:Interferon-gamma; D048051:p38 Mitogen-Activated Protein Kinases