Research Papers:
Subthreshold IKK activation modulates the effector functions of primary mast cells and allows specific targeting of transformed mast cells
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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: [email protected]
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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