This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Bachmann, M. Articles by Mühl, H. Search for Related Content PubMed PubMed Citation Articles by Bachmann, M. Articles by Mühl, H.

Research Articles: Therapeutics, Targets, and Development

Interleukin-18 directly activates T-bet expression and function via p38 mitogen-activated protein kinase and nuclear factor-B in acute myeloid leukemia–derived predendritic KG-1 cells

Pharmazentrum Frankfurt/ZAFES, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany

Requests for reprints: Heiko Mühl, Pharmazentrum Frankfurt, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. Phone: 49-69-6301-6955; Fax: 49-69-6301-7942. E-mail: H.Muehl{at}em.uni-frankfurt.de

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 IFN 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-B function. Blockage of translation by cycloheximide, usage of neutralizing antibodies, and the inability of IFN to mediate significant p38 mitogen-activated protein kinase activation in KG-1 cells clearly revealed that activation of T-bet was not via autocrine IFN. T-bet function was evaluated by short interfering RNA technology. Notably, specific suppression of T-bet induction impaired secretion of IFN 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]

Grant support: Deutsche Forschungsgemeinschaft DFG MU 1284 (H. Mühl).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: M. Bachmann and C. Dragoi contributed equally to this work.

Received 8/17/06; revised 12/ 1/06; accepted 12/28/06.