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

Sebastian Drube,Kirstin Reinecke,Romy Loschinski,Franziska Weber,Isabel Meininger,Florian R Greten,Christiane Göpfert,Norman Häfner,Mandy Rothe,Michaela A Diamanti,Bernhard Nieswandt,Oliver H Krämer,Thomas Herdegen,Thomas Kamradt,David Stegner,Anja Rabenhorst,Karin Hartmann,Mandy Beyer,Martin Böttcher

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.

Highlights

Mast cells are located in peripheral tissues and regulate innate and adaptive immune responses [1] by producing mediators that recruit and activate, granulocytes, dendritic cells, T-lymphocytes and other cells [1,2,3,4,5]
We found an crosstalk between activated c-Kit and the IL-1R or the IL-33R [27, 28] resulting in potentiated cytokine production in response to IL-1 or IL-33
We found that IL-3 induces IKK activation, IκBα phosphorylation but not degradation in bone marrow-derived mast cells (BMMCs) (Figure 1A)

Summary

Introduction

Mast cells are located in peripheral tissues and regulate innate and adaptive immune responses [1] by producing mediators (e.g., histamine, proteases, leukotrienes or cytokines) that recruit and activate, granulocytes, dendritic cells, T-lymphocytes and other cells [1,2,3,4,5]. They are critical in type I hypersensitivity and central to the pathogenesis of allergic diseases [6]. It has been demonstrated that mast cells are critical regulators of the tumor www.impactjournals.com/oncotarget microenvironment [10] and that expression of constitutively active Ras- or c-Kit-mutants leads to development of mast cell tumors [11, 12].

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Results

Conclusion