Oncotarget

Research Papers:

Subthreshold IKK activation modulates the effector functions of primary mast cells and allows specific targeting of transformed mast cells

Sebastian Drube _, Franziska Weber, Romy Loschinski, Mandy Beyer, Mandy Rothe, Anja Rabenhorst, Christiane Göpfert, Isabel Meininger, Michaela A. Diamanti, David Stegner, Norman Häfner, Martin Böttcher, Kirstin Reinecke, Thomas Herdegen, Florian R. Greten, Bernhard Nieswandt, Karin Hartmann, Oliver H. Krämer and Thomas Kamradt

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Oncotarget. 2015; 6:5354-5368. https://doi.org/10.18632/oncotarget.3022

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Abstract

Sebastian Drube1, Franziska Weber1,*, Romy Loschinski1,*, Mandy Beyer1, Mandy Rothe1, Anja Rabenhorst2, Christiane Göpfert1, Isabel Meininger1, Michaela A. Diamanti3, David Stegner4, Norman Häfner5, Martin Böttcher1, Kirstin Reinecke6, Thomas Herdegen6, Florian R. Greten3, Bernhard Nieswandt4, Karin Hartmann2, Oliver H. Krämer7, Thomas Kamradt1

1Institut für Immunologie, Universitätsklinikum Jena, 07743 Jena, Germany

2Klinik und Poliklinik für Dermatologie und Venerologie, Universität zu Köln, 50937 Köln, Germany

3Georg-Speyer-Haus, Institute for Tumorbiology and Experimental Therapy, 60596 Frankfurt, Germany

4Rudolf Virchow Centrum für experimentelle Biomedizin, Universität Würzburg, 97080 Würzburg, Germany

5Gynäkologische Molekularbiologie, Klinik für Frauenheilkunde und Geburtshilfe, 07743 Jena, Germany

6Institut für Experimentelle und Klinische Pharmakologie, Universität Schleswig-Holstein, 24105 Kiel, Germany

7Institut für Toxikologie, Universitätsmedizin Mainz, 55131 Mainz, Germany

*These authors have contributed equally to this work

Correspondence to:

Sebastian Drube, e-mail: Sebastian.Drube@med.uni-jena.de

Keywords: Mast cells, subthreshold IKK activation, mitogenic signaling, NFκB-activation

Received: December 19, 2014     Accepted: December 31, 2014     Published: January 22, 2015

ABSTRACT

Mast cell differentiation and proliferation depends on IL-3. IL-3 induces the activation of MAP-kinases and STATs and consequently induces proliferation and survival. Dysregulation of IL-3 signaling pathways also contribute to inflammation and tumorigenesis. We show here that IL-3 induces a SFK- and Ca2+-dependent activation of the inhibitor of κB kinases 2 (IKK2) which results in mast cell proliferation and survival but does not induce IκBα-degradation and NFκB activation. Therefore we propose the term “subthreshold IKK activation”.

This subthreshold IKK activation also primes mast cells for enhanced responsiveness to IL-33R signaling. Consequently, co-stimulation with IL-3 and IL-33 increases IKK activation and massively enhances cytokine production induced by IL-33.

We further reveal that in neoplastic mast cells expressing constitutively active Ras, subthreshold IKK activation is associated with uncontrolled proliferation. Consequently, pharmacological IKK inhibition reduces tumor growth selectively by inducing apoptosis in vivo.

Together, subthreshold IKK activation is crucial to mediate the full IL-33-induced effector functions in primary mast cells and to mediate uncontrolled proliferation of neoplastic mast cells. Thus, IKK2 is a new molecularly defined target structure.


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