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

Oncotarget. 2015 Mar 10;6(7):5354-68. doi: 10.18632/oncotarget.3022.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Blotting, Western
  • Bone Marrow / drug effects
  • Bone Marrow / metabolism
  • Bone Marrow / pathology
  • Cell Proliferation / drug effects
  • Cell Transformation, Neoplastic / drug effects
  • Cell Transformation, Neoplastic / pathology*
  • Cells, Cultured
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Flow Cytometry
  • Homeodomain Proteins / physiology
  • Humans
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / metabolism*
  • Interleukin-3 / pharmacology*
  • Male
  • Mast Cells / drug effects
  • Mast Cells / metabolism
  • Mast Cells / pathology*
  • Mice
  • Mice, Inbred DBA
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 8 / genetics
  • Mitogen-Activated Protein Kinase 8 / metabolism
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Homeodomain Proteins
  • Interleukin-3
  • NF-kappa B
  • RNA, Messenger
  • RAG-1 protein
  • I-kappa B Kinase
  • Mitogen-Activated Protein Kinase 8