Drube, Sebastian, Weber, Franziska, Loschinski, Romy, Beyer, Mandy, Rothe, Mandy, Rabenhorst, Anja, Goepfert, Christiane, Meininger, Isabel, Diamanti, Michaela A., Stegner, David ORCID: 0000-0003-1059-9865, Haefner, Norman, Boettcher, Martin, Reinecke, Kirstin, Herdegen, Thomas, Greten, Florian R., Nieswandt, Bernhard, Hartmann, Karin ORCID: 0000-0002-4595-8226, Kraemer, Oliver H. and Kamradt, Thomas ORCID: 0000-0001-8443-5893 (2015). Subthreshold IKK activation modulates the effector functions of primary mast cells and allows specific targeting of transformed mast cells. Oncotarget, 6 (7). S. 5354 - 5369. ORCHARD PARK: IMPACT JOURNALS LLC. ISSN 1949-2553

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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 kappa B kinases 2 (IKK2) which results in mast cell proliferation and survival but does not induce I kappa Ba-degradation and NF kappa B 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Drube, SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weber, FranziskaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Loschinski, RomyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beyer, MandyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rothe, MandyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rabenhorst, AnjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goepfert, ChristianeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meininger, IsabelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Diamanti, Michaela A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stegner, DavidUNSPECIFIEDorcid.org/0000-0003-1059-9865UNSPECIFIED
Haefner, NormanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boettcher, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reinecke, KirstinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Herdegen, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Greten, Florian R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nieswandt, BernhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hartmann, KarinUNSPECIFIEDorcid.org/0000-0002-4595-8226UNSPECIFIED
Kraemer, Oliver H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kamradt, ThomasUNSPECIFIEDorcid.org/0000-0001-8443-5893UNSPECIFIED
URN: urn:nbn:de:hbz:38-409898
DOI: 10.18632/oncotarget.3022
Journal or Publication Title: Oncotarget
Volume: 6
Number: 7
Page Range: S. 5354 - 5369
Date: 2015
Publisher: IMPACT JOURNALS LLC
Place of Publication: ORCHARD PARK
ISSN: 1949-2553
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CALCIUM SENSOR STIM1; C-KIT; TNF-ALPHA; KAPPA-B; INFLAMMATORY ARTHRITIS; INNATE IMMUNITY; MICE LACKING; RECEPTOR; KINASE; CYTOKINEMultiple languages
Oncology; Cell BiologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/40989

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