Format

Send to

Choose Destination
Oncotarget. 2015 Mar 10;6(7):5354-68.

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

Author information

1
Institut für Immunologie, Universitätsklinikum Jena, 07743 Jena, Germany.
2
Klinik und Poliklinik für Dermatologie und Venerologie, Universität zu Köln, 50937 Köln, Germany.
3
Georg-Speyer-Haus, Institute for Tumorbiology and Experimental Therapy, 60596 Frankfurt, Germany.
4
Rudolf Virchow Centrum für experimentelle Biomedizin, Universität Würzburg, 97080 Würzburg, Germany.
5
Gynäkologische Molekularbiologie, Klinik für Frauenheilkunde und Geburtshilfe, 07743 Jena, Germany.
6
Institut für Experimentelle und Klinische Pharmakologie, Universität Schleswig-Holstein, 24105 Kiel, Germany.
7
Institut für Toxikologie, Universitätsmedizin Mainz, 55131 Mainz, Germany.

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.

KEYWORDS:

NFκB-activation; mast cells; mitogenic signaling; subthreshold IKK activation

PMID:
25749030
PMCID:
PMC4467154
DOI:
10.18632/oncotarget.3022
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Impact Journals, LLC Icon for PubMed Central
Loading ...
Support Center