TY  - JOUR
A1  - Drube, Sebastian
A1  - Weber, Franziska
A1  - Loschinski, Romy
A1  - Beyer, Mandy
A1  - Rothe, Mandy
A1  - Rabenhorst, Anja
A1  - Göpfert, Christiane
A1  - Meininger, Isabel
A1  - Diamanti, Michaela A.
A1  - Stegner, David
A1  - Häfner, Norman
A1  - Böttcher, Martin
A1  - Reinecke, Kirstin
A1  - Herdegen, Thomas
A1  - Greten, Florian R.
A1  - Nieswandt, Bernhard
A1  - Hartmann, Karin
A1  - Krämer, Oliver H.
A1  - Kamradt, Thomas
T1  - Subthreshold IKK activation modulates the effector functions of primary mast cells and allows specific targeting of transformed mast cells
JF  - Oncotarget
N2  - 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.
KW  - mast cells
KW  - subthreshold IKK activation
KW  - mitogenic signaling
KW  - NFκB-activation
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-143681
VL  - 6
IS  - 7
ER  -