Subthreshold IKK activation modulates the effector functions of primary mast cells and allows specific targeting of transformed mast cells.
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.
Institut für Immunologie, Universitätsklinikum Jena, 07743 Jena, Germany.
Sebastian
S
Drube
Institut für Immunologie, Universitätsklinikum Jena, 07743 Jena, Germany.
Franziska
F
Weber
Institut für Immunologie, Universitätsklinikum Jena, 07743 Jena, Germany.
Romy
R
Loschinski
Institut für Immunologie, Universitätsklinikum Jena, 07743 Jena, Germany.
Mandy
M
Beyer
Institut für Immunologie, Universitätsklinikum Jena, 07743 Jena, Germany.
Mandy
M
Rothe
Klinik und Poliklinik für Dermatologie und Venerologie, Universität zu Köln, 50937 Köln, Germany.
Anja
A
Rabenhorst
Institut für Immunologie, Universitätsklinikum Jena, 07743 Jena, Germany.
Christiane
C
Göpfert
Institut für Immunologie, Universitätsklinikum Jena, 07743 Jena, Germany.
Isabel
I
Meininger
Georg-Speyer-Haus, Institute for Tumorbiology and Experimental Therapy, 60596 Frankfurt, Germany.
Michaela A
MA
Diamanti
Rudolf Virchow Centrum für experimentelle Biomedizin, Universität Würzburg, 97080 Würzburg, Germany.
David
D
Stegner
Gynäkologische Molekularbiologie, Klinik für Frauenheilkunde und Geburtshilfe, 07743 Jena, Germany.
Norman
N
Häfner
Institut für Immunologie, Universitätsklinikum Jena, 07743 Jena, Germany.
Martin
M
Böttcher
Institut für Experimentelle und Klinische Pharmakologie, Universität Schleswig-Holstein, 24105 Kiel, Germany.
Kirstin
K
Reinecke
Institut für Experimentelle und Klinische Pharmakologie, Universität Schleswig-Holstein, 24105 Kiel, Germany.
Thomas
T
Herdegen
Georg-Speyer-Haus, Institute for Tumorbiology and Experimental Therapy, 60596 Frankfurt, Germany.
Florian R
FR
Greten
Rudolf Virchow Centrum für experimentelle Biomedizin, Universität Würzburg, 97080 Würzburg, Germany.
Bernhard
B
Nieswandt
Klinik und Poliklinik für Dermatologie und Venerologie, Universität zu Köln, 50937 Köln, Germany.
Karin
K
Hartmann
Institut für Toxikologie, Universitätsmedizin Mainz, 55131 Mainz, Germany.
Oliver H
OH
Krämer
Institut für Immunologie, Universitätsklinikum Jena, 07743 Jena, Germany.
Thomas
T
Kamradt
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000473:pathology*; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D018398:Homeodomain Proteins / Q000502:physiology; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D007377:Interleukin-3 / Q000494:pharmacology*; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D018398:Homeodomain Proteins; D007377:Interleukin-3; D016328:NF-kappa B; D012333:RNA, Messenger; C064658:RAG-1 protein; D051550:I-kappa B Kinase; D048055:Mitogen-Activated Protein Kinase 8
NFκB-activation; mast cells; mitogenic signaling; subthreshold IKK activation